The Importance of Teaching Human Evolution
Theodosius Dobzhansky’s “Nothing in biology makes sense except in the light of evolution” is my favorite science quote, as it sums up perfectly how important evolution is to our understanding of biology. Unfortunately, in far too many schools evolution is not taught all, or not taught to its full extent . When it comes to human evolution in particular, the statistics are even more depressing. According to a 2008 survey by Berkman and Plutzer , 17% of high school biology teachers omit human evolution entirely, while the majority (60%) spend just one to five hours of class time on it. In the United States, there are very few states ( seven plus the District of Columbia in 2007 ) with science standards that specifically include human evolution; and human evolution is missing from the NGSS standards that were finalized in 2013. There are many reasons why human evolution may not be part of the formal curriculum, but “controversy” surrounding our origins and fear of push back from parents due to religious concerns are certainly among them.
To skip or minimize discussion of human evolution, however, is to miss an opportunity to engage students. From an early age we wonder where we come from; evolution explains that for us. From the amazing array of fossils that have been found in Africa, Asia, and Europe we can piece together our evolutionary lineage from Australopithecus to early Homo sapiens and explore the different species that branched off in between. By studying the fossil record we can understand when we began walking upright, by noting all the huge morphological changes that distinguish us from other great apes, such as our wide bowl-shaped pelvis, big toes in line with the rest of our feet and shorter arms. We can see when our brain size increased (when Homo erectus came about) and the subsequent huge change in our technology. As they say, the rest is history.
Tapping into our inherent curiosity about our history and origins is a great way to get students excited about science. Who does not want to know why we do the things we do and look the way we do? Learning about our own evolution helps students feel connected to science. It can be cool to watch chemistry experiments but they may not relate directly to our own lives. Many students would never picture themselves as a “typical” scientist who wears a white lab coat and works in a lab all day. But human evolution is instantly relatable, and shows students who are interested in science but don’t realize that spending your days out in the field digging up fossils or observing our primate relatives in the wild are examples of “doing science.” I was one of those students who never thought I could go into science. I was focused on becoming an actress. I struggled with math but always did well in biology. After not getting into drama school but instead into Bucknell University, my love of animals led me to study animal behavior. It was the best decision I ever made and while in Tanzania for my semester abroad, surrounded by vervet monkeys during my research project, I knew I wanted to be a primatologist. It was my love of primates that led me to the field of evolutionary anthropology and made me so interested and passionate about it.
Learning about human evolution is a lens through which students, and people in general, can see how we are connected to the world. We are primates, just like the living animals we call apes and monkeys, though our own evolutionary path rewarded walking on two legs and having a really big brain. Evolution is not directional; it is not striving for better. Animals who are the best adapted to their environment survive long enough to reproduce and pass those genes onto their offspring. Our unique human-defining traits do not make us better than our other primate relatives—just different. Chimpanzees are well adapted to their environments where they live and thrive; they are in no way “less evolved” than we are. True, we humans have dominated and altered the world around us, but if we understand our evolutionary place in the world, it becomes harder to justify the idea that we are better than the organisms we share the planet with. In this way, studying human evolution is humbling, and in this day and age, we all need a little humility.
We are dealing with climate change on an unprecedented scale because of our actions, putting Earth at risk for us and all the other plants and animals that live here. We need to start using these big brains for good to stop the changes that could spell the end of our run on this planet. There were early hominid species, like Australopithecus afarensis, that lived for about 900,000 years, almost four times as long as we have been around, but they eventually went extinct. Such examples show students that our species is not the be-all and end-all of human evolution. We are not immune to the forces that can cause extinction. We can see now how vulnerable we are to disease epidemics like Ebola, HIV, and even the common flu. Natural disasters—on the rise due to climate change—can render us defenseless and vulnerable. Technology can help us, but we can’t assume it will save us.
Lauren Saville is the owner and creator of Primate Tales , Toronto’s only educational outreach company that brings the world of primates and evolution into K–12 classrooms. Saville has her MA in Evolutionary Anthropology and her BSc in Animal Behavior. She has studied baboon maternal behavior in Kenya, vervet monkey grooming and aggressive behavior in Tanzania, and squirrel monkey cognition at Bucknell University. You can check out her blog where she writes about evolution, education, and primates on her web page .
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Foundations of evolutionary biology, adaptation, chance, and history, applications that affect our lives, meeting society's needs, contributions in biology and beyond, advancing human understanding.
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Evolution and Today's Society
Professor of Plant Biology in the Institute of Environmental and Evolutionary Biology, University of St. Andrews, St. Andrews, Fife KY16 9TH, Scotland. E-mail: [email protected]
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Thomas R. Meagher, Evolution and Today's Society, BioScience , Volume 49, Issue 11, November 1999, Pages 923–925, https://doi.org/10.2307/1313651
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There is a dynamic tension in the perception of evolution in the United States. On the one hand, the scientific community holds evolution to be a central unifying principle of biology, with sufficient supporting evidence that evolution is regarded as scientific fact. On the other hand, there is a lingering public view that the process of evolution, both in contemporary and historical biological populations, is controversial. This dichotomy has been brought into stark focus in recent months, as an issue of Science (25 June 1999) featured major scientific advances in evolution and the Kansas Board of Education decided (in August 1999) to no longer require evolution as part of their school curriculum. Such contrasts underscore a significant challenge in terms of communicating science to the public. The importance of this challenge is emphasized in the recent NAS report, Teaching about Evolution and the Nature of Science (1998, National Academy Press, Washington, DC), a key recommendation of which is that evolution is essential to school curricula if students—the public of the future—are to understand biology.
In fact, a clear understanding of evolutionary biology is essential for professionals in all biological fields if they are to push ahead the frontiers of their disciplines. Current research initiatives to deepen knowledge of the genetic basis of complex characters, recent advances in developmental morphology, and attempts to generate a comprehensive phylogenetic tree of life all draw heavily on evolutionary insights. Evolutionary biology is also contributing to ongoing advances in the study of human origins and behavior. Finally, there has been a long-term interplay between evolutionary theory and nonbiological fields such as statistics, economics, and computation.
In addition to its centrality in biology and its contributions to basic science, evolutionary biology addresses a wide array of current and emerging societal needs, ranging from biomedical applications to conservation efforts. For example, it provides a solid scientific framework for understanding the emergence of antibiotic resistance in pathogenic bacteria and for analyzing the emergence and epidemiology of novel diseases, such as HIV. Evolutionary biology also provides a scientific basis for policy decisions concerning the conservation of rare and endangered species, the adaptive implications of invasive species or new genetic varieties (including genetically engineered organisms), and the genetic responses to human perturbation of the environment.
So that an informed public can recognize connections between scientific advances and pressing societal needs, it is critical that evolutionary biologists communicate important scientific advances, ongoing research, and the nature of the scientific enterprise to the public as well as to scientists outside of their immediate discipline. In so doing, the foundations are laid for better public understanding of science as well as a stronger policy base for support of science itself.
To promote awareness of the contributions of evolutionary biology, representatives from eight scientific societies (the American Society of Naturalists, the Society for the Study of Evolution, the Society for Molecular Biology and Evolution, the Ecological Society of America, the Society of Systematic Biologists, the Genetics Society of America, the Animal Behavior Society, and the Paleonto-logical Society) met in April 1995 to discuss the need for a white paper on behalf of the scientific field of evolutionary biology. Co-chairs Douglas J. Futuyma and Thomas R. Meagher were elected to seek funding for the project and to coordinate and oversee writing and publication of the white paper. With support from the Alfred P. Sloan Foundation and the National Science Foundation, a working group of 17 scientists drawn from a broad geographic and institutional base and representing major disciplines in evolutionary biology was convened to draft the document. The existence of this working group and its charge were announced in The American Naturalist, Ecology, Evolution, Genetics, Molecular Biology and Evolution , and Science , and a Web site was established to enable the input of the broader scientific community.
The resulting documents—a report entitled Evolution, Science, and Society: Evolutionary Biology and the National Research Agenda and an executive summary of that report—are addressed to government agencies, private foundations, college and university administrations, corporations, scientific and educational societies, science educators on all levels, and the scientific community itself. They are also addressed to anyone interested in understanding the current and potential accomplishments of evolutionary biology.
The documents were written with the following major goals:
to describe our present understanding of evolution and the major intellectual accomplishments of evolutionary biology;
to identify major questions and challenges in which progress in evolutionary science can be expected in the near future;
to describe past and expected contributions of evolutionary biology, both to other sciences and to societal needs in areas such as health, agriculture, and the environment; and
to suggest ways in which progress can be facilitated in basic research, in applications of evolutionary biology to social needs, and in biological science education.
Both versions of Evolution, Science, and Society —the executive summary and the more detailed executive document—are currently available in either a printed form (from the author) or on the Web ( www.amnat.org ).
The executive summary is reproduced on the following pages. Our goal in publishing the executive summary in BioScience is to ensure that Evolution, Science, and Society is widely accessible, as well as available in a form that can be readily cited in the scientific literature and elsewhere. In addition, it is replicated here to assist those who are interested in promoting broader public understanding of science. In a similar vein, the more detailed version will be published as a supplement to The American Naturalist in 2000. It is the intention of the Evolution, Science, and Society working group that this report be reproduced and used in a variety of contexts supporting research and education in evolution.
Futuyma DJ. 1995. The uses of evolutionary biology. Science 267: 41-42.
Meagher LR, Meagher TR, eds. 1994. Leaping into the Future with Evolutionary Biology: The Emerging Relevance of Evolutionary Biology Applied to Problems and Opportunities . New Brunswick (NJ): Rutgers University Press.
National Academy of Sciences, Working Group on Teaching Evolution. 1998. Teaching about Evolution and the Nature of Science . Washington (DC): National Academy Press.
President's Committee of Advisors on Science and Technology. 1998. Teaming with Life: Investing in Science to Understand and Use Americas Living Capital . Washington (DC): PCAST.
Systematics Agenda 2000. 1994. Systematics Agenda 2000: Charting the Biosphere . New York:, Department of Ornithology, American Museum of Natural History.
Evolutionary biology is the study of the history of life and the processes that lead to its diversity. Based on principles of adaptation, chance, and history, evolutionary biology seeks to explain all the characteristics of organisms, and, therefore, occupies a central position in the biological sciences.
R elevance of E volutionary B iology to the N ational R esearch A genda
The twenty-first century will be the “Century of Biology.” Driven by a convergence of accelerating public concerns, the biological sciences will be increasingly called on to address issues vital to our future well-being: threats to environmental quality, food production needs due to population pressures, new dangers to human health prompted by the emergence of antibiotic resistance and novel diseases, and the explosion of new technologies in biotechnology and computation. Evolutionary biology in particular is poised to make very significant contributions. It will contribute direcly to pressing societal challenges as well as inform and accelerate other biological disciplines.
Evolutionary biology has unequivocally established that all organisms evolved from a common ancestor over the last 3.5 billion years; it has documented many specific events in evolutionary history; and it has developed a well-validated theory of the genetic, developmental, and ecological mechanisms of evolutionary change. The methods, concepts, and perspectives of evolutionary biology have made and will continue to make important contributions to other biological disciplines, such as molecular and developmental biology, physiology, and ecology, as well as to other basic sciences, such as psychology, anthropology, and computer science.
In order for evolutionary biology to realize its full potential, biologists must integrate the methods and results of evolutionary research with those of other disciplines both within and outside of biology. We must apply evolutionary research to societal problems, and we must include the implications of that research in the education of a scientifically informed citizenry.
To further such goals, delegates from eight major professional scientific societies in the United States, whose subject matter includes evolution, have prepared this document. It includes contributions by other specialists in various areas. Feedback on earlier drafts was elicited from the community of evolutionary biologists in the United States, and the draft was made public on the World Wide Web. The delegates arrived at a series of recommendations that address the areas that follow.
A dvancing U nderstanding through R esearch
To capitalize on evolutionary biology as an organizing and integrating principle, we urge that:
▪ evolutionary perspectives be incorporated as a foundation for interdisciplinary research to address complex scientific problems
▪ evolutionary biologists work toward building meaningful links between basic research and practical application
▪ evolutionary biology play a more explicit role in the overall mission of federal agencies that could benefit from contributions made by this field
A dvancing U nderstanding through E ducation
We encourage major efforts to strengthen curricula in primary and secondary schools, as well as in colleges and universities, including:
▪ support of supplemental training for primary school teachers and/or midcareer training for secondary school science teachers in evolutionary biology
▪ greater emphasis on evolution in undergraduate college curricula for biology majors and premedical students, with accessible alternative courses for nonmajors
▪ integration of relevant evolutionary concepts into the postbaccalaureate training of all biologists and of professionals in areas such as medicine, law, agriculture, and environmental sciences
A dvancing U nderstanding through C ommunication
We urge the following roles for evolutionary biologists:
▪ communicating to federal agencies, and to other institutions that support basic or applied research, the relevance of evolutionary biology to the missions of these organizations
▪ training the next generation of evolutionary biologists to be aware of the relevance of their field to societal needs
▪ informing the public about the nature, progress, and implications of evolutionary biology
W hat D oes the F uture H old for E volutionary B iology ?
Researchers in molecular and developmental biology, physiology, ecology, animal behavior, psychology, anthropology, and other disciplines continue to adopt the methods, principles, and concepts of evolutionary biology as a framework. Likewise, applied research in forestry, agriculture, fisheries, human genetics, medicine, and other areas has increasingly attracted scientists trained in evolutionary biology. Evolutionary biologists have expanded their vision, addressing both basic questions throughout the biological disciplines and problems posed by society's needs. As a result of both the rapid growth of this “evolutionary work force” and technological advances in areas such as molecular methodology, computing, and information processing, progress in evolutionary biology and related areas is more rapid now than ever before. With appropriate and necessary support in education and research, the evolutionary disciplines will make ever greater contributions to applied and basic knowledge.
In the applied realm, evolutionary biologists are embracing their social responsibilities. There are many ways in which their scientific efforts can help humanity:
▪ to understand and combat genetic, systemic, and infectious diseases
▪ to understand human physiological adaptations to stresses, pathogens, and other causes of ill health
▪ to improve crops and mitigate damage by pathogens, insects, and weeds
▪ to develop tools for analyzing human genetic diversity as it applies to health, law, and the understanding of human behavior
▪ to use and develop biological resources in a responsible manner
▪ to remedy damage to the environment
▪ to predict the consequences of global and regional environmental change
▪ to conserve biodiversity and discover its uses
In basic science, we stand at the threshold of:
▪ fully documenting biodiversity and describing the phylogenetic relationships among ail organisms
▪ more completely understanding the causes of major changes in the history of life
▪ discovering and explaining processes of evolution at the molecular level
▪ understanding how developmental mechanisms evolve and give rise to new anatomical structures
▪ elucidating the processes that both cause and constrain adaptations in physiology, endocrinology, and anatomy
▪ deriving a deeper understanding of the adaptive meaning and mechanisms of behavior
▪ developing a predictive theory of coevolution among species, such as pathogens, parasites, and their hosts, and of the effects of coevolution on populations and ecological communities
Evolutionary biology plays a central role in the complexity of biological systems. Evolution is the source of biocomplexity. The continued and enhanced support of this field is critical to maximizing the nation's research progress in both basic and applied arenas. In terms of societal needs for the twenty-first century, the time to make the investment in evolutionary biology is now, while there is still time either to change current trends or to better prepare us to deal with their consequences. Current and projected population levels will result in increasing environmental impacts, increasing pressure on food production, ever greater challenges to biological diversity, and enhanced opportunities for the emergence of new diseases. A healthy scientific base in evolutionary biology is an essential element in preparing us to address these issues. Evolutionary biology must be at the heart of the nation's research agenda in biology, just as it is at the heart of the field of biology.
Universal phylogenetic tree showing the relationships among Bacteria (e.g. most bacteria and blue-green algae), Archaea (e.g. methanogens and halophiles) and Eucarya (e.g. protists, plants, animals, and fungi).
Deane Bowers, University of Colorado-Boulder. Baltimore Checkerspot butterfly (Euphydryas phaeton) , Eastern United States
Julie Margaret Cameron, c/o Clements Museum, University of Michigan. Carte de visite photograph of Charles Darwin (1874)
Bruce Baldwin, University of California–Berkeley. Mauna Kea silversword (Argyroxiphium sandwicense subsp. sandwicense ), Wailuku drainage, Hawaii
R. Kellogg, c/o Annalisa Berta, San Diego State University. Line drawing of archaeocete (fossil whale) skeleton. Abstracted with permission from A. Berta, 1994. What Is a Whale? Science 263:180. © 1994, American Association for the Advancement of Science
H. Douglas Pratt, c/o Lenny Freed, University of Hawaii. Hawaiian honeycreeper bill variation
Aravinda Chakravarti, Case Western Reserve University. Gradient of distribution in Europe of the major mutation causing cystic fibrosis relative to overall cf genes
Karl Ammann, c/o NOAHS Center, National Zoological Park. Cheetah
Charles W. Myers, American Museum of Natural History. Poison-dart frog (Phyllobates terribilis) , Colombia, South America
Charles Rick, University of California-Davis. Cultivated tomato and its wild relatives
Sean B. Carroll, University of Wisconsin. Hox gene organization and expression in Drosophila and mouse embryos. Reproduced with permission from S.B. Carroll et al., 1995. Homeotic genes and the evolution of arthropods and chordates. Nature 376: 479–485. © 1995, Macmillan Magazines Ltd.
David Maddison, University of Arizona. Tree of Life logo
National Museum of Kenya, c/o Craig S. Feibel, Rutgers University. 1.9-million-year-old hominid skull (Homo habilis) , Koobi Fora, Rift Valley, Africa
African mask, Rutgers University photo archives
Norman R. Pace, University of California–Berkeley. Universal phylogenetic tree based on ribosomal RNA sequence differences. Abstracted with permission from N.R. Pace, 1997. A Molecular View of Microbial Diversity and the Biosphere. Science 276: 734–740. © 1997, American Association for the Advancement of Science
John Weinstein, Field Museum of Natural History, and David Jablonski, University of Chicago. Fossil crinoids, Cretaceous Period (85 million years old), Kansas. Negative GE085594c
EVOLUTION BY NATURAL SELECTION . Nineteenth-century biologists Charles Darwin and Alfred Russell Wallace established the foundations for evolutionary theory.
PHYLOGENETIC ANALYSIS . Recent advances in DNA sequencing and computation permit precise reconstruction of evolutionary relationships among species. For example, molecular data have enabled deeper understanding of the evolutionary origins of the local species of the silverswords, a group of plants endemic to Hawaii.
MORPHOLOGICAL AND MOLECULAR VARIATION . Variation is a key feature of evolution. Differentiation in bill form among related species of honeycreepers provides insight into evolutionary adaptation for feeding. Molecular variation provides insight into genetic processes underlying evolutionary change.
THE FOSSIL RECORD . Fossils provide dues about the evolutionary origins of adaptations. Intermediate, or transitional, forms in the fossil record have shown that whales and other cetaceans evolved from land-dwelling ancestors.
W hat I s E volution ?
Biological evolution consists of change in the hereditary characteristics of groups of organisms over the course of generations. From a long-term perspective, evolution is the descent with modification of different lineages from common ancestors. From a short-term perspective, evolution is the ongoing adaptation of organisms to environmental challenges and changes. Thus evolution has two major components: the branching of lineages and changes within lineages.
W hat A re the G oals of E volutionary B iology ?
Evolutionary biology seeks to explain the diversity of life: the variety of organisms and their characteristics, and their changes over time. Evolutionary biology also seeks to interpret and understand organismal adaptation to environmental conditions. The two encompassing goals of evolutionary biology are to discover the history of life on earth and to understand the causal processes of evolution. Insights achieved through efforts to meet these goals greatly enhance our understanding of biological systems.
Evolutionary biologists often work at the interface of many subdisciplines of biology, leading to the development of subject areas such as behavioral evolution, evolutionary developmental biology, evolutionary ecology, evolutionary genetics, evolutionary morphology, evolutionary systematics, and molecular evolution. The subdisciplines of evolutionary biology also have formed direct links with fields such as statistics, economics, geology, anthropology, and psychology.
H ow I s E volution S tudied ?
Evolutionary biology draws on a wide range of methodologies and conceptual approaches.
Methods for understanding the history of evolution include observations of the fossil record and categorization and classification of variations among living organisms. Differences and similarities among species in anatomy, genes, and other features can be analyzed by molecular and statistical methods that enable us to estimate historical relationships among species and the sequence in which their characteristics evolved.
Studies of ongoing evolutionary change employ observation and experimentation. Analysis of genetic variation enables us to characterize mutation, genetic drift, natural selection, and other processes of evolution. The “comparative method” contrasts features of species that have adapted to different environments. Sophisticated mathematical models and analyses are frequently employed for both description and predication.
W hy I s E volutionary B iology I mportant ?
Evolutionary biology provides the key to understanding the principles governing the origin and extinction of species. It provides causal explanations, based on history and on processes of genetic change and adaptation, for the full sweep of biological phenomena, ranging from the molecular to the ecological. Thus, evolutionary biology allows us to determine not only how and why organisms have become the way they are, but also what processes are currently acting to modify or change them.
Response to change is a feature of evolution that is becoming increasingly important in terms of scientific input into societal issues. We live in a world that is undergoing constant change on many levels, and much of that change is a direct consequence of human activity. Evolutionary biology can contribute explicitly to enhanced awareness and prediction of mid- and long-term consequences of environmental disturbances, whether they be deforestation, application of pesticides, or global warming.
Distinctive perspectives on biology offered by evolutionary biology include emphasis on the interplay between chance and adaptation as conflicting agents of biological change, on variation as an inherent feature of biological systems, and on the importance of biological diversity. Variation is a key concept, since evolutionary change ultimately depends on the differential success of competing genetic lineages. The ultimate consequence of variation and evolutionary divergence is biological diversity.
Biological species are not fixed entities, but rather are subject to ongoing modification through chance or adaptation. Understanding why and how some species are able to change apace with new environmental challenges is critical to the sustainability of human endeavor.
EVOLUTION OF HUMAN GENETIC DISORDERS . Some genetic diseases, such as cystic fibrosis, are caused by mutations that occur at high frequencies in certain human populations in Europe. Evolutionary geneticists are working to understand how natural selection keeps deleterious genes at such high frequencies. Their findings may lend insight to the broader physiological impacts of the cystic fibrosis gene.
CONSERVATION GENETICS . Evolutionary analysis reveals extremely low levels of genetic diversity among living cheetah, likely due to a dramatic population decline—and associated inbreeding—thousands of years ago. This hinders the cheetah's ability to reproduce successfully, which threatens the species' survival. Such information is being used to develop management recommendations for this endangered species.
NATURAL PRODUCTS FROM POISON FROGS . Knowledge of evolutionary relationships has helped to guide research scientists to the discovery of new natural compounds from Central and South American poison frogs. Potential biomedical applications include heart-stimulating activity and use in painkillers.
GENETIC RESOURCES FOR CROP IMPROVEMENT . Evolutionary relationships between crops and wild relatives provide insight into potentially useful genes for crop improvement.
H ow D oes E volutionary B iology C ontribute to S ociety ?
In addition to the historical dimension, evolution is an important feature in our everyday lives. Evolution is happening all around us: in our digestive tracts, in our lawns, in woodland lots, in ponds and streams, in agricultural fields, and in hospitals. For shortlived organisms such as bacteria and insects, evolution can happen on a very short time scale. This immediacy brings evolutionary biology directly into the applied realm. Indeed, evolutionary biology has a long history and a bright future in terms of its ability to address pressing societal needs. Evolutionary biology has already made particularly strong contributions in the following areas:
Environment and conservation . Evolutionary insights are important in both conservation and management of renewable resources. Population genetic methods are frequently used to assess the genetic structure of rare or endangered species as a means of determining appropriate conservation measures. Studies of the genetic composition of wild relatives of crop species can be used to discover potentially useful new genes that might be transferred into cultivated species. Studies of wild plants' adaptations to polluted or degraded soils contribute to the reclamation of damaged land.
Agriculture and natural resources . The principles of plant and animal breeding strongly parallel natural evolutionary mechanisms, and there is a rich history of interplay between evolutionary biology and agricultural science. Evolutionary insights play a clear role in understanding the ongoing evolution of various crop pathogens and insect pests, including the evolution of resistance to pest-control measures. The methods of evolutionary genetics can be used to identify different gene pools of commercially important fish and other organisms, their migration routes, and differences in their physiology, growth, and reproduction.
Finding useful natural products . Many thousands of natural products are used in medicine, food production and processing, cosmetics, biotechnology, pest control, and industry, but millions of other potentially useful natural products have yet to be screened or even discovered. Evolutionary principles allow a targeted search by predicting adaptations to environmental selection pressures and by identifying organisms related to those that have already yielded useful natural products. Exploration of related species also has made it possible to develop natural products from more accessible relatives of rare species in which natural products have been found, as occurred when the rare and endangered Pacific yew was found to contain a substance that led to development of a drug (tamoxifen) useful in treating breast cancer.
Human health and medicine . Methods and principles from evolutionary biology have contributed to understanding the links between genes and human genetic diseases, such as cystic fibrosis. Evolutionary methods help to trace the origins and epidemiology of infectious diseases, and to analyze the evolution of antibiotic resistance in pathogenic microorganisms. Evolutionary principles are used to interpret human physiological functions and dietary needs. Methods developed by evolutionary geneticists are playing an important role in mapping defective human genes, in genetic counseling, and in identifying genetic variants that alter risks for common systemic diseases and responses to medical treatments.
Biotechnology . The interplay between biotechnology and evolutionary biology holds great promise for application to important societal needs. As genetic engineering has reached the field implementation stage, evolutionary biologists have been prominently involved in risk assessment as well as interpretation of phenotypic consequences of trans-gene insertion. Finally, the automation of DNA sequencing has made it possible to reconstruct the precise genealogical relationship among specific genes, such as those of the human immunodeficiency virus (HIV).
Understanding humanity . Evolutionary biology has contributed greatly to human understanding of ourselves by describing our origins, our relationships to other living things, and the history and significance of variation within and among different groups of people. Evolutionary anthropologists, psychologists, and biologists have advanced hypotheses on the biological bases of human culture and behavior. In addition, the evolutionary framework for understanding humanity has had a profound impact on literature, the arts, philosophy, and other areas of the humanities.
DEVELOPMENTAL BIOLOGY . Recent studies of many different types of animals suggest that much of animal diversity has evolved by changes in a common set of regulatory genes. The organization of such regulatory genes has been studied in detail in model organisms, such as fruit flies, and parallel genetic effects have been identified in a wide range of organisms.
THE TREE OF LIFE . Advances in molecular, morphological, and computational approaches have enabled the emergence of a comprehensive framework for the evolutionary history of all life on earth. The Tree of Life project provides a unified network for systematic investigation on all levels.
HUMAN ORIGINS . Studies of variation in modern populations, recent analysis of DNA extracted from fossil remnants, and an ever more complete fossil record have provided deeper insight into the evolutionary emergence of modern humans and their culture.
H ow D oes E volutionary B iology C ontribute to B asic S cience ?
Evolutionary biology has far-reaching scientific impact. Among their accomplishments in studying the history and processes of evolution, evolutionary biologists have:
▪ established that all organisms have evolved from a common ancestor over more than 3.5 billion years of earth's history
▪ developed methods of inferring phylogenetic, or genealogical, relationships among organisms
▪ described patterns of diversification and extinction in both the fossil record and contemporary ecosystems
▪ developed and tested general theories that account for the evolution of phenotypic traits, including complex characters such as cooperative behavior and senescence
▪ made substantial progress in understanding evolution at the molecular level
▪ elucidated many aspects of human evolution
Contributions to Other Biological Disciplines
Evolution is central to biological understanding. Biologists in diverse fields regard at least a portion of what they do as evolutionary. Recent accomplishments to which evolutionary biology has contributed include the following:
Molecular biology . Evolutionary approaches have contributed insight into the function and structure of molecular processes within cells. Examples include reconstruction and functional analysis of ancestral protein sequences, and elucidation of the significance of different types of DNA. Evolutionary research thus points the way to research on fundamental molecular mechanisms.
Developmental biology . A resurgence in interaction between developmental biology and evolutionary biology is now under way, in part through comparisons among families of genes that play critical roles in development. For example, the same genes in organisms as different as insects and mammals play surprisingly similar developmental roles in some instances, and different roles in other cases. Such studies help to identify the developmental functions of genes and lead to a deeper understanding of the processes that transform a fertilized egg into a complex adult.
Physiology and anatomy . Evolutionary biology has long influenced the study of physiology and anatomy in animals and plants, and has the potential to make many other contributions that only now are being developed. Some of these contributions will affect the study of human physiology, including related areas such as clinical psychology. The logical perspectives, methods, and comparative data of evolutionary biology can advance our understanding of functional anatomy and physiological mechanisms, and can be applied to areas such as medicine, agriculture, and veterinary science.
Neurobiology and behavior . From its inception, the field of animal behavior has had a strong evolutionary base, for its goals have included understanding the evolutionary origin of behavioral traits and their adaptiveness. The evolutionary study of animal behavior has joined with comparative psychology in several areas of research, such as the study of learning and the search for adaptive mechanisms in human cognitive processes.
Applications beyond biology . There have long been rewarding interactions between evolutionary biology and other analytical fields, notably statistics and economics. Some of the basic tools in statistics, including analysis of variance and path analysis, were originally developed by evolutionary biologists. Along the same lines, evolutionary algorithms that mimic natural selection in biological systems are currently being used in computer and systems applications.
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Six million years of human evolution.
Human evolution is the lengthy process of change by which people originated from apelike ancestors. Scientific evidence shows that the physical and behavioral traits shared by all people originated from apelike ancestors and evolved over a period of approximately six million years.
Paleoanthropology is the scientific study of human evolution which investigates the origin of the universal and defining traits of our species. The field involves an understanding of the similarities and differences between humans and other species in their genes, body form, physiology, and behavior. Paleoanthropologists search for the roots of human physical traits and behavior. They seek to discover how evolution has shaped the potentials, tendencies, and limitations of all people.
What Can Human Fossils Tell Us?
Early human fossils and archeological remains offer the most important clues about this ancient past. These remains include bones, tools and any other evidence (such as footprints, evidence of hearths , or butchery marks on animal bones) left by earlier people. Usually, the remains were buried and preserved naturally. They are then found either on the surface (exposed by rain, rivers, and wind erosion) or by digging in the ground. By studying fossilized bones, scientists learn about the physical appearance of earlier humans and how it changed. Bone size, shape, and markings left by muscles tell us how those predecessors moved around, held tools, and how the size of their brains changed over a long time.
Archeological evidence refers to the things earlier people made and the places where scientists find them. By studying this type of evidence, archeologists can understand how early humans made and used tools and lived in their environments.
Humans and Our Evolutionary Relatives
Humans are primates . Physical and genetic similarities show that the modern human species, Homo sapiens, has a very close relationship to another group of primate species, the apes. Modern humans and the great apes (large apes) of Africa – chimpanzees (including bonobos, or so-called “pygmy chimpanzees”) and gorillas – share a common ancestor that lived between 8 and 6 million years ago.
Humans first evolved in Africa, and much of human evolution occurred on that continent. The fossils of early humans who lived between 6 and 2 million years ago come entirely from Africa. Early humans first migrated out of Africa into Asia probably between 2 million and 1.8 million years ago. They entered Europe somewhat later, between 1.5 million and 1 million years. Species of modern humans populated many parts of the world much later. For instance, people first came to Australia probably within the past 60,000 years and to the Americas within the past 15,000 years or so.
Most scientists currently recognize some 15 to 20 different species of early humans. Scientists do not all agree, however, about how these species are related or which ones simply died out. Many early human species – certainly the majority of them – left no living descendants. Scientists also debate over how to identify and classify particular species of early humans, and about what factors influenced the evolution and extinction of each species.
One of the earliest defining human traits, bipedalism – the ability to walk on two legs – evolved over 4 million years ago. Other important human characteristics – such as a large and complex brain, the ability to make and use tools, and the capacity for language – developed more recently. Many advanced traits -- including complex symbolic expression, art , and elaborate cultural diversity – emerged mainly during the past 100,000 years. The beginnings of agriculture and the rise of the first civilizations occurred within the past 12,000 years.
Smithsonian Research Into Human Evolution
The Smithsonian’s Human Origins Program explores the universal human story at its broadest time scale. Smithsonian anthropologists research many aspects of human evolution around the globe, investigating fundamental questions about our evolutionary past, including the roots of human adaptability.
For example, Paleoanthropologist Dr. Rick Potts – who directs the Human Origins Program – co-directs ongoing research projects in southern and western Kenya and southern and northern China that compare evidence of early human behavior and environments from eastern Africa to eastern Asia. Rick’s work helps us understand the environmental changes that occurred during the times that many of the fundamental characteristics that make us human - such as making tools and large brains – evolved, and that our ancestors were often able to persist through dramatic climate changes. Rick describes his work in the video Survivors of a Changing Environment .
Dr. Briana Pobiner is a Prehistoric Archaeologist whose research centers on the evolution of human diet (with a focus on meat-eating), but has included topics as diverse as cannibalism in the Cook Islands and chimpanzee carnivory. Her research has helped us understand that at the onset of human carnivory over 2.5 million years ago some of the meat our ancestors ate was scavenged from large carnivores, but by 1.5 million years ago they were getting access to some of the prime, juicy parts of large animal carcasses. She uses techniques similar to modern day forensics for her detective work on early human diets.
Paleoanthropologist Dr. Matt Tocheri conducts research into the evolutionary history and functional morphology of the human and great ape family, the Hominidae. His work on the wrist of Homo floresiensis , the so-called “hobbits” of human evolution discovered in Indonesia, received considerable attention worldwide after it was published in 2007 in the journal Science. He now co-directs research at Liang Bua on the island of Flores in Indonesia, the site where Homo floresiensis was first discovered.
Geologist Dr. Kay Behrensmeyer has been a long-time collaborator with Rick Potts’ human evolution research at the site of Olorgesailie in southern Kenya. Kay’s role with the research there is to help understand the environments of the sites at which evidence for early humans – in the form of stone tools as well as fossils of the early humans themselves – have been found, by looking at the sediments of the geological layers in which the artifacts and fossils have been excavated.
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Human evolution evidence.
Evidence of Evolution
Scientists have discovered a wealth of evidence concerning human evolution, and this evidence comes in many forms. Thousands of human fossils enable researchers and students to study the changes that occurred in brain and body size, locomotion, diet, and other aspects regarding the way of life of early human species over the past 6 million years. Millions of stone tools, figurines and paintings, footprints, and other traces of human behavior in the prehistoric record tell about where and how early humans lived and when certain technological innovations were invented. Study of human genetics show how closely related we are to other primates – in fact, how connected we are with all other organisms – and can indicate the prehistoric migrations of our species, Homo sapiens , all over the world. Advances in the dating of fossils and artifacts help determine the age of those remains, which contributes to the big picture of when different milestones in becoming human evolved.
Exciting scientific discoveries continually add to the broader and deeper public knowledge of human evolution. Find out about the latest evidence in our What’s Hot in Human Origins section.
Explore the evidence of early human behavior—from ancient footprints to stone tools and the earliest symbols and art – along with similarities and differences in the behavior of other primate species.
From skeletons to teeth, early human fossils have been found of more than 6,000 individuals. Look into our digital 3-D collection and learn about fossil human species.
Explore our 3D collection of fossils, artifacts, primates, and other animals.
Our genes offer evidence of how closely we are related to one another – and of our species’ connection with all other organisms.
As plants and animals die, their remains are sometimes preserved in Earth’s rock record as fossils.
Human Evolution Interactive Timeline
Explore the evidence for human evolution in this interactive timeline - climate change, species, and milestones in becoming human.
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- Human Family Tree
The human family tree shows the various species that constitute the human evolutionary family.
Snapshots in Time
In these video interactives, put together clues and explore discoveries the prehistoric sites of Swartkrans, South Africa, Olorgesailie, Kenya, and Shanidar Cave, Iraq.
- Climate Effects on Human Evolution
- Survival of the Adaptable
- Human Evolution Timeline Interactive
- 2011 Olorgesailie Dispatches
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- Evolution of Human Innovation
- Adventures in the Rift Valley: Interactive
- 'Hobbits' on Flores, Indonesia
- Earliest Humans in China
- Bose, China
- Anthropocene: The Age of Humans
- Fossil Forensics: Interactive
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- Carnivore Dentition
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- Primate Behavior
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- Footprints from Engare Sero, Tanzania
- Hammerstone from Majuangou, China
- Handaxe and Tektites from Bose, China
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- Oldowan Tools from Lokalalei, Kenya
- Olduvai Chopper
- Stone Tools from Majuangou, China
- Middle Stone Age Tools
- Burin from Laugerie Haute & Basse, Dordogne, France
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- One Species, Living Worldwide
- Human Skin Color Variation
- Ancient DNA and Neanderthals
- Swartkrans, South Africa
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- Walking Upright
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- Introduction to Human Evolution
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- The early human tool kit
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A Brief Account of Human Evolution for Young Minds
Most of what we know about the origin of humans comes from the research of paleoanthropologists, scientists who study human fossils. Paleoanthropologists identify the sites where fossils can be found. They determine the age of fossils and describe the features of the bones and teeth discovered. Recently, paleoanthropologists have added genetic technology to test their hypotheses. In this article, we will tell you a little about prehistory, a period of time including pre-humans and humans and lasting about 10 million years. During the Prehistoric Period, events were not reported in writing. Most information on prehistory is obtained through studying fossils. Ten to twelve million years ago, primates divided into two branches, one included species leading to modern (current) humans and the other branch to the great apes that include gorillas, chimpanzees, bonobos, and orangutans. The branch leading to modern humans included several different species. When one of these species—known as the Neanderthals—inhabited Eurasia, they were not alone; Homo sapiens and other Homo species were also present in this region. All the other species of Homo have gone extinct, with the exception of Homo sapiens , our species, which gradually colonized the entire planet. About 12,000 years ago, during the Neolithic Period, some (but not all) populations of H. sapiens passed from a wandering lifestyle of hunting and gathering to one of sedentary farming, building villages and towns. They developed more complex social organizations and invented writing. This was the end of prehistory and the beginning of history.
What Is Evolution?
Evolution is the process by which living organisms evolve from earlier, more simple organisms. According to the scientist Charles Darwin (1809–1882), evolution depends on a process called natural selection. Natural selection results in the increased reproductive capacities of organisms that are best suited for the conditions in which they are living. Darwin’s theory was that organisms evolve as a result of many slight changes over the course of time. In this article, we will discuss evolution during pre-human times and human prehistory. During prehistory, writing was not yet developed. But much important information on prehistory is obtained through studies of the fossil record [ 1 ].
How Did Humans Evolve?
Primates, like humans, are mammals. Around ten to twelve million years ago, the ancestral primate lineage split through speciation from one common ancestor into two major groups. These two lineages evolved separately to become the variety of species we see today. Members of one group were the early version of what we know today as the great apes (gorillas, chimpanzees, and bonobos in Africa, orangutans in Asia) ( Figures 1 , 2 ); that is, the modern great apes evolved from this ancestral group. They mostly remained in forest with an arboreal lifestyle, meaning they live in trees. Great apes are also quadrupeds which means they move around with four legs on the ground (see Figure 2 ). The other group evolved in a different way. They became terrestrial, meaning they live on land and not in trees. From being quadrupeds they evolved to bipeds, meaning they move around on their two back legs. In addition the size of their brain increased. This is the group that, through evolution, gave rise to the modern current humans. Many fossils found in Africa are from the Australopithecus afarensis, Homo sapiens ."> genus named Australopithecus (which means southern ape). This genus is extinct, but fossil studies revealed interesting features about their adaptation toward a terrestrial lifestyle.
- Figure 1 - Evolutionary scheme, showing that great apes and humans all evolved from a common ancestor.
- The Neanderthal picture is a statue designed from a fossil skeleton.
- Figure 2 - Great Apes in nature.
- (above) Arboreal (in trees) locomotion of orangutans and (under) the quadrupedal (four-foot) locomotion of gorillas and chimpanzees.
Australopithecus afarensis and Lucy
In Ethiopia (East Africa) there is a site called Hadar, where several fossils of different animal species were found. Among those fossils was Australopithecus afarensis . In 1974, paleoanthropologists found an almost complete skeleton of one specimen of this species and named it Lucy, from The Beatles song “Lucy in the Sky with Diamonds.” The whole world found out about Lucy and she was in every newspaper: she became a global celebrity. This small female—only about 1.1 m tall—lived 3.2 million years ago. Analysis of her femurs (thigh bones) showed that she used terrestrial locomotion. Lucy could have used arboreal and bipedal locomotion as well, as foot bones of another A. afarensis individual had a curve similar to that found in the feet of modern humans [ 2 ]. Authors of this finding suggested accordingly that A. afarensis was exclusively bipedal and could have been a hunter-gatherer.
Homo habilis , Homo erectus , and Homo neanderthalensis
Homo is the genus (group of species) that includes modern humans, like us, and our most closely related extinct ancestors. Organisms that belong to the same species produce viable offspring. The famous paleoanthropologist named Louis Leakey, along with his team, discovered Homo habilis (meaning handy man) in 1964. Homo habilis was the most ancient species of Homo ever found [ 2 ]. Homo habilis appeared in Tanzania (East Africa) over 2.8 million years ago, and 1.5 million years ago became exinct. They were estimated to be about 1.40 meter tall and were terrestrial. They were different from Australopithecus because of the form of the skull. The shape was not piriform (pear-shaped), but spheroid (round), like the head of a modern human. Homo habilis made stone tools, a sign of creativity [ 3 ].
In Asia, in 1891, Eugene Dubois (also a paleoanthropologist) discovered the first fossil of Homo erectus (meaning upright man), which appeared 1.8 million years ago. This fossil received several names. The best known are Pithecanthropus (ape-man) and Sinanthropus (Chinese-man). Homo erectus appeared in East Africa and migrated to Asia, where they carved refined tools from stone [ 4 ]. Dubois also brought some shells of the time of H erectus from Java to Europe. Contemporary scientists studied these shells and found engravings that dated from 430,000 and 540,000 years ago. They concluded that H. erectus individuals were able to express themselves using symbols [ 5 ].
Several Homo species emerged following H. erectus and quite a few coexisted for some time. The best known one is Homo neanderthalensis ( Figure 3 ), usually called Neanderthals and they were known as the European branch originating from two lineages that diverged around 400,000 years ago, with the second branch (lineage) Homo sapiens known as the African branch. The first Neanderthal fossil, dated from around 430,000 years ago, was found in La Sima de los Huesos in Spain and is considered to originate from the common ancestor called Homo heidelbergensis [ 6 ]. Neanderthals used many of the natural resources in their environment: animals, plants, and minerals. Homo neanderthalensis hunted terrestrial and marine (ocean) animals, requiring a variety of weapons. Tens of thousands of stone tools from Neanderthal sites are exhibited in many museums. Neanderthals created paintings in the La Pasiega cave in the South of Spain and decorated their bodies with jewels and colored paint. Graves were found, which meant they held burial ceremonies.
- Figure 3 - A comparison of the skulls of Homo sapiens (Human) (left) vs. Homo neanderthalensis (Neanderthal) (right).
- You can see a shape difference. From Scientific American Vol. 25, No. 4, Autumn 2016 (modified).
Denisovans are a recent addition to the human tree. In 2010, the first specimen was discovered in the Denisova cave in south-western Siberia. Very little information is known on their behavior. They deserve further studies due to their interactions with Neandertals and other Homo species (see below) [ 7 ].
Fossils recently discovered in Morocco (North Africa) have added to the intense debate on the spread of H. sapiens after they originated 315,000 years ago [ 8 ]. The location of these fossils could mean that Homo sapiens had visited the whole of Africa. In the same way, the scattering of fossils out of Africa indicated their migrations to various continents [ 9 ]. While intensely debated, hypotheses focus on either a single dispersal or multiple dispersals out of the African continent [ 10 , 11 ]. Nevertheless, even if the origin of the migration to Europe is still a matter of debate [ 12 ], it appears that H. sapiens was present in Israel [ 13 ] 180,000 years ago. Therefore, it could be that migration to Europe was not directly from Africa but indirectly through a stay in Israel-Asia. They arrived about 45,000 years ago into Europe [ 14 ] where the Neanderthals were already present (see above). Studies of ancient DNA show that H. sapiens had babies with Neanderthals and Denisovans. Nowadays people living in Europe and Asia share between 1 and 4% of their DNA with either Neanderthals or Denisovans [ 15 ].
Several thousand years ago H. sapiens already made art, like for example the wall painting in the Chauvet cave (36,000 years ago) ( Figure 4 ) and the Lascaux cave (19,000 years ago), both in France. The quality of the paintings shows great artistic ability and intellectual development. Homo sapiens continued to prospect the Earth. They crossed the Bering Land Bridge, connecting Siberia and Alaska and moved south 12,500 years ago, to what is now called Chile. Homo sapiens gradually colonized our entire planet ( Figure 5 ).
- Figure 4 - The lions in the Chauvet cave (−36,000 years).
- In this period wild lions were present in Eurasia . Photo: Bradshaw foundation.com. Note the lively character of the picture.
- Figure 5 - Homo sapiens traveled in the world at various periods as shown on the map.
- They had only their legs to move!
The Neolithic Revolution
Neolithic Period means New Stone Age, due to the new stone technology that was developed during that time. The Neolithic Period started at the end of the glacial period 11,700 years ago. There was a change in the way humans lived during the Neolithic Period. Ruins found in Mesopotamia tell us early humans lived in populated villages. Due to the start of agriculture, most wandering hunter-gatherers became sedentary farmers. Instead of hunting dogs familiar with hunter-gatherers, farmers preferred sheepdogs [ 16 ]. In the Neolithic age, humans were farming and herding, keeping goats and sheep. Aurochs (extinct wild cattle), shown in the paintings from the Lascaux cave, are early ancestors of the domesticated cows we have today [ 17 ]. The first produce which early humans began to grow in Mesopotamia (a historical region in West Asia, situated between the Tigris and Euphrates rivers) was peas and wheat [ 18 ]. Animals and crops were traded and written records were kept of these trades. Clay tokens were the first money for these transactions. The Neolithic Period saw the creation of commerce, money, mathematics, and writing ( Figure 6 ) in Sumer, a region of Mesopotamia. The birth of writing started the period that we call “history,” in which events are written down and details of big events as well as daily life can easily be passed on. This tremendous change in human lifestyle can be called the Neolithic Revolution .
- Figure 6 - From the beginning to final evolution of cuneiform writing.
- Writing on argil support showed changes from pictograms to abstract design. Picture modified from British Museum. Dates in year BC.
From the time of Homo erectus , Homo species migrated out of Africa. Homo sapiens extended this migration over the whole planet. In the fifteenth and sixteenth centuries, Europeans explored the world. On the various continents, explorers met unknown populations. The Europeans were wondering if those beings were humans or not. But actually, those populations were also descendants of the men and women who colonized the earth at the dawn of mankind. In much earlier times, there was a theory that there were several races of humans, based mostly on skin color, but this theory was not supported by science. Current studies of DNA show that more than seven billion people who live on earth today are not of different races. There is only one human species on earth today, named Homo sapiens .
Species and Speciation. What defines a species? How new species can arise from existing species. https://www.khanacademy.org/science/biology/her/tree-of-life/a/species-speciation
Speciation : ↑ The formation of new and distinct species in the course of evolution.
Genus : ↑ In the classification of biology, a genus is a subdivision of a family. This subdivision is a grouping of living organisms having one or more related similarities. In the binomial nomenclature, the universally used scientific name of each organism is composed of its genus (capitalized) and a species identifier (lower case), for example Australopithecus afarensis, Homo sapiens.
Eurasia : ↑ A term used to describe the combined continental landmass of Europe and Asia.
Clay : ↑ Fine-grained earth that can be molded when wet and that is dried and baked to make pottery.
Revolution : ↑ Fundamental change occurring relatively quickly in human society.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors thank Emma Clayton (Frontiers) for her advice and careful reading. Photo of Neanderthal statue was from Stephane Louryan, one of the designers of Neanderthal’s statue project [Faculty of Medicine, Université libre de Bruxelles (ULB), Brussels, Belgium].
 ↑ Godfraind, T. 2016. Hominisation et Transhumanisme . Bruxelles: Académie Royale de Belgique.
 ↑ Ward, C. V., Kimbel, W. H., and Johanson, D. C. 2011. Complete fourth metatarsal and arches in the foot of Australopithecus afarensis. Science 331:750–3. doi: 10.1126/science.1201463
 ↑ Harmand, S., Lewis, J. E., Feibel, C. S., Lepre, C. J., Prat, S., Lenoble, A., et al. 2015. 3.3-million-year-old stone tools from Lomekwi 3, West Turkana, Kenya. Nature 521:310–5. doi: 10.1038/nature14464
 ↑ Carotenuto, F., Tsikaridze, N., Rook, L., Lordkipanidze, D., Longo, L., Condemi, S., et al. 2016. Venturing out safely: the biogeography of Homo erectus dispersal out of Africa. J. Hum. Evol. 95:1–12. doi: 10.1016/j.jhevol.2016.02.005
 ↑ Joordens, J. C., d’Errico, F., Wesselingh, F. P., Munro, S., de Vos, J., Wallinga, J., et al. 2015. Homo erectus at Trinil on Java used shells for tool production and engraving. Nature 518:228–31. doi: 10.1038/nature13962
 ↑ Arsuaga, J. L., Martinez, I., Arnold, L. J., Aranburu, A., Gracia-Tellez, A., Sharp, W. D., et al. 2014. Neandertal roots: cranial and chronological evidence from Sima de los Huesos. Science 344:1358–63. doi: 10.1126/science.1253958
 ↑ Vernot, B., Tucci, S., Kelso, J., Schraiber, J. G., Wolf, A. B., Gittelman, R. M., et al. 2016. Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. Science 352:235–9. doi: 10.1126/science.aad9416
 ↑ Richter, D., Grun, R., Joannes-Boyau, R., Steele, T. E., Amani, F., Rue, M., et al. 2017. The age of the hominin fossils from Jebel Irhoud, Morocco, and the origins of the Middle Stone Age. Nature 546:293–6. doi: 10.1038/nature22335
 ↑ Vyas, D. N., Al-Meeri, A., and Mulligan, C. J. 2017. Testing support for the northern and southern dispersal routes out of Africa: an analysis of Levantine and southern Arabian populations. Am. J. Phys. Anthropol . 164:736–49. doi: 10.1002/ajpa.23312
 ↑ Reyes-Centeno, H., Hubbe, M., Hanihara, T., Stringer, C., and Harvati, K. 2015. Testing modern human out-of-Africa dispersal models and implications for modern human origins. J. Hum. Evol . 87:95–106. doi: 10.1016/j.jhevol.2015.06.008
 ↑ Templeton, A. 2002. Out of Africa again and again. Nature 416:45–51. doi: 10.1038/416045a
 ↑ Arnason, U. 2017. A phylogenetic view of the Out of Asia/Eurasia and Out of Africa hypotheses in the light of recent molecular and palaeontological finds. Gene 627:473–6. doi: 10.1016/j.gene.2017.07.006
 ↑ Callaway, E. 2018. Israeli fossils are the oldest modern humans ever found outside of Africa. Nature 554:15–6. doi: 10.1038/d41586-018-01261-5
 ↑ Benazzi, S., Douka, K., Fornai, C., Bauer, C. C., Kullmer, O., Svoboda, J., et al. 2011. Early dispersal of modern humans in Europe and implications for Neanderthal behaviour. Nature 479:525–8. doi: 10.1038/nature10617
 ↑ Vernot, B., and Akey, J. M. 2014. Resurrecting surviving Neandertal lineages from modern human genomes. Science 343:1017–21. doi: 10.1126/science.1245938
 ↑ Ollivier, M., Tresset, A., Frantz, L. A. F., Brehard, S., Balasescu, A., Mashkour, M., et al. 2018. Dogs accompanied humans during the Neolithic expansion into Europe. Biol. Lett. 14:20180286. doi: 10.1098/rsbl.2018.0286
 ↑ Gerling, C., Doppler, T., Heyd, V., Knipper, C., Kuhn, T., Lehmann, M. F., et al. 2017. High-resolution isotopic evidence of specialised cattle herding in the European Neolithic. PLoS ONE 12:e0180164. doi: 10.1371/journal.pone.0180164
 ↑ Revedin, A., Aranguren, B., Becattini, R., Longo, L., Marconi, E., Lippi, M. M., et al. 2010. Thirty thousand-year-old evidence of plant food processing. Proc. Natl. Acad. Sci. U.S.A . 107:18815–9. doi: 10.1073/pnas.1006993107
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Big History Project
Course: big history project > unit 6.
- READ: Collective Learning (Part 1)
WATCH: Why Human Evolution Matters
- WATCH: The Common Man (H2)
- WATCH: Early Evidence of Collective Learning
- ACTIVITY: Claim Testing – Collective Learning
- READ: Gallery — What Makes Humans Different?
- Quiz: Collective Learning
Want to join the conversation?
- The Biology of Sex and Death
- 1.01 Scientific Methodology
- What is life?
- Life on earth
- Tree Thinking
- What is evolution and why do biologists think it’s important?
- Population & Community Ecology
- Life interacts
- Reproduction without sex (Asexual Reproduction)
- What is sex?
- Trait Inheritance & Genetic Variation
- Human Reproductive Cycle
- Plant Growth and Reproduction
- Sexual Dimorphism and Selection Selection
- Animal Mating Systems
- Chromosomes, genes, and DNA
- Gene expression and development
- In Vitro Fertilization and Gene Editing
- Genetically Modified (Transgenic) Organisms
- Senescence, Aging, and Death
- Heritable disease and Complex traits
- Infectious disease spread
- Innate and Adaptive Immune Responses
- Immunization and Allergies, or How the immune system can help or hurt us
- Cancer Biology
- Extinction & Conservation Biology
What is evolution and why do biologists think it’s important?
- List the conditions that cause populations of living organisms to evolve
- Distinguish biological evolution of populations from changes to individual organisms over a lifetime.
- Know that two mechanisms of evolution are mutation and natural selection, and recognize examples of each.
- Cite evidence that all life on earth has a common origin
- Identify common misconceptions about evolution
Evolution as an emergent property of life
A key part of any definition of life is that living organisms reproduce. Let’s now add a couple of observations:
- The process of reproduction, while mostly accurate, is imperfect. When cells divide, they have to replicate their DNA. Although DNA replication is highly accurate, it still makes about 1 mistake in 10 million nucleotides. Over generations, the population will contain lots of heritable variation.
- The population of a given type of organism will tend to grow exponentially, but will reach a limit, where the individuals have to compete with each other for the limiting resource (food, space, mates, sunlight, etc.)
Suppose some heritable variations (speed, strength, sharper claws, bigger teeth) make some individuals more competitive for the limiting resource – what will happen?
The individuals with superior variants will acquire more resources, and have more progeny. If the superior variants are heritable, then their progeny will have the same superior variants. Over generations, then, a larger and larger proportion of the population will consist of individuals with the superior heritable variants. This is biological evolution.
Definition: Biological evolution is change in the heritable characteristics of a population over succeeding generations. In more technical terms, evolution is defined as change in the gene pool of a population, measurable as changes in allele frequencies in a population.
Suppose there is heritable variation in a population, and the heritable variation makes a difference in the survival and reproduction of individual organisms. If these conditions exist, and they do for all natural populations of living organisms, evolution must occur. Life evolves!
Charles Darwin called this process evolution by natural selection. In On the Origin of Species by Natural Selection (1859), Charles Darwin described four requirements for evolution by natural selection:
- the trait under selection must be variable in the population, so that the encoding gene has more than one variant, or allele.
- the trait under selection must be heritable , encoded by a gene or genes
- the struggle of existence , that many more offspring are born than can survive in the environment.
- individuals with different alleles have differential survival and reproduction that is governed by the fit of the organism to its environment
Darwin and Alfred Wallace were the first to propose that evolution by natural selection could explain the origin of all the multitudes of species on Earth and how they appear so well-adapted in form and function to their particular environments. Moreover, Darwin proposed that all of life on Earth descended from a common ancestor, via slow, incremental accumulation of heritable (genetic) changes.
Because the definition of evolution is change in the heritable characteristics of a population over generations, evolution can occur by means other than natural selection. Evolution can also occur via random processes, especially in small populations, where the frequency of some heritable traits may rise or fall just by chance.
One of these other mechanisms of evolution is called mutation .
Mutation generates variation
Evolution by mutation occurs when the heritable cells of organisms make a mistake when they replicate their DNA. In single-celled asexual organisms, such as bacteria and archaea, the whole cell and its DNA is passed on to the next generation because these organisms reproduce via binary fission. For sexual organisms, mutations are passed to the next generation if they occur in the egg or sperm cells used to create offspring. Mutations occur at random in the genome, but mutations of large effect are often so bad for the organism that the organism dies as it develops, so mutations of smaller effect or even neutral mutations are theoretically more common in a population.
The random process of mutation generates standing genetic variation in a population, and this variation must be present for evolution to occur. Mutation is the raw stuff of evolution because it creates new heritable phenotypes without regard for how good those phenotypes are for the survival and reproduction of the organism. How frequent are mutations? Mutation rates are actually pretty low for most genes, ranging from 1 in a million for the average human gene to less than 1 in a billion for the average bacterial gene (from http://bionumbers.hms.harvard.edu/ ). Because mutation rates are low relative to population growth in most species, mutation alone doesn’t have much of an effect on evolution.
The video below defines and gives examples of biological evolution, and ends with a teaser about the role of natural selection in biological evolution.
Evolution is a theory, not just a hypothesis
Darwin published his theory of evolution in the Origin of Species (1859), with carefully reasoned evidence to support this theory that all life on earth evolved from a common ancestor. This theory has been tested in numerous ways by the work of many thousands of scientists. Every test has produced results that are consistent with the theory. Evolutionary biologists conduct research to elaborate or refine the theory and understand the mechanisms at work in specific populations. Evolutionary theory now forms a framework for biological thinking, so that one famous evolutionary biologist wrote that “ Nothing in Biology Makes Sense Except in the Light of Evolution ” (Dobzhansky, 1973).
The scientific use of the word theory is very different from the casual, every-day use. A scientific theory is an overarching, unifying explanation of phenomena that is well supported by multiple, independent lines of evidence – i.e., composed of hundreds or thousands of independent, well-supported hypotheses. For example, germ theory is the theory that explains how microorganisms cause disease, and cell theory explains how cells function as the basic unit of life.
Title page of Darwin’s The Origin of Species, 1859 from Wikipedia
A few key lines of supporting evidence:
- geological and fossil record, showing that the Earth is about 4.5 billion years old, and sequential changes in the kinds and forms of living organisms over geological time scales
- homologies in body plans, structures, and DNA sequences indicative of common ancestry
- a common biochemistry for all life on Earth – the same amino acids, the same biological building blocks, the same genetic code
- inference of evolutionary relationships from gene sequence comparisons largely agree with the fossil record, and are consistent with a common origin for all extant life on Earth.
The video below highlights some of this key supporting evidence in the context of the evolution of whales:
Common misconceptions about evolution
There are many common misconceptions about evolution in general, and evolution by natural selection:
Here are corrections to some common misconceptions about evolution by natural selection:
- The individual undergoing natural selection does not evolve–it just lives or dies! Instead, the population of organisms is evolving. Recall that evolution is the change in allele frequencies, and only populations have allele frequencies. Individuals just have alleles.
- Evolution is not a directed process with a fixed end point, or a best phenotype. Rather, the environment serves as a selective agent . No amount of planning on the part of the organism can predict whether an organism will be a good fit for the environment it finds itself in. An individual cannot “try” to evolve or “anticipate” the types of mutations it should have for future environmental change.
- Organisms, and the genes they contain, do not behave for the ‘good of the species.’ Rather, each individual lives and reproduces, which increases its representation in the gene pool, or it dies or fails to reproduce and is not represented in the gene pool. Those most represented after encountering a selective agent are considered the “most fit” for that environment, in that time and place.
- Selection doesn’t always result in the best possible fit of an organism to its environment because of constraints and trade-offs . Sometimes the same genes that code for a trait also cause a second, suboptimal trait to occur.
- Mutations are not caused or induced as a result of environmental change. Variation is already present in the population. When the environment changes, those individuals that already have some beneficial variation (mutations) that is well suited to the new environment are more likely to survive and reproduce; organisms do not develop new mutations in response to the environmental change. (And if there is no variation present in the population such that some individuals survive and reproduce, then the population is likely to go extinct).
At its simplest, evolution distills down to the idea that as long as there is variation in a population, as long as that variation is heritable, and as long as there is differential reproductive success (not everyone reproduces equally), then the next generation will be genetically different from the previous generation. We will explore the mechanisms that contribute to evolution over the next class sessions.
For thought and discussion
- Think of some ways that evolution can be or has been tested. What testable predictions arise from evolutionary theory?
- How does the work of many geologists or some physicists test evolutionary theory?
- What are some common misconceptions about evolution?
Evolution 101 University of California Berkeley evolution site, a complete resource for learning and teaching about evolution. Engaging, well-illustrated, accurate.
How did feathers evolve? Carl Zimmer’s TED-Ed video, 3 1/2 minutes.
Evolution animation by Tyler Rhodes, produced from drawings made by children copying a drawing of a salamander-like animal with successive generations of variation, mass extinction and selection. The process is described in this Scientific American blog post http://blogs.scientificamerican.com/psi-vid/2012/02/29/an-evolution-animation-unlike-any-youve-seen-before/ and Tyler Rhodes blog http://evolutionanimation.wordpress.com/ describes both the drawing “game” and his animation process. His “ wheel of life ” is an amazing phylogenetic tree of the drawings.
Newly found: the world’s oldest fossils A post in the Why Evolution Is True blog by Jerry Coyne, explaining the paper by Wacey, D.,M. R. Kilburn, M. Saudners, J. Cliff, and M. D. Brasier. 2011. Microfossils of sulphur-metabolizing cells in 3.4-billion-year-old rocks of Western Australia . Nature Geoscience online: doi:10.1038/ngeo1238
Darryl Cunningham Investigates: Evolution A lucid, inviting comic-strip presentation of basic evolutionary theory and evidence. Aimed at beginning learners.
Evolution Made Simple BBC Bang illustrates evolution beginning with a simple straight line, and replication with errors leads rapidly to diversification.
Nothing in Biology Makes Sense Except in the Light of Evolution Dobzhansky’s 1973 essay in The American Biology Teacher 35:125-129, just as relevant today as then, and I have yet to read a better explanation.
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- Review Article
- Published: 06 January 2021
The influence of evolutionary history on human health and disease
- Mary Lauren Benton ORCID: orcid.org/0000-0002-5485-1041 1 , 2 ,
- Abin Abraham 3 , 4 ,
- Abigail L. LaBella ORCID: orcid.org/0000-0003-0068-6703 5 ,
- Patrick Abbot 5 ,
- Antonis Rokas ORCID: orcid.org/0000-0002-7248-6551 1 , 3 , 5 &
- John A. Capra ORCID: orcid.org/0000-0001-9743-1795 1 , 5 , 6
Nature Reviews Genetics volume 22 , pages 269–283 ( 2021 ) Cite this article
- Evolutionary genetics
- Genetic variation
- Medical genetics
Nearly all genetic variants that influence disease risk have human-specific origins; however, the systems they influence have ancient roots that often trace back to evolutionary events long before the origin of humans. Here, we review how advances in our understanding of the genetic architectures of diseases, recent human evolution and deep evolutionary history can help explain how and why humans in modern environments become ill. Human populations exhibit differences in the prevalence of many common and rare genetic diseases. These differences are largely the result of the diverse environmental, cultural, demographic and genetic histories of modern human populations. Synthesizing our growing knowledge of evolutionary history with genetic medicine, while accounting for environmental and social factors, will help to achieve the promise of personalized genomics and realize the potential hidden in an individual’s DNA sequence to guide clinical decisions. In short, precision medicine is fundamentally evolutionary medicine, and integration of evolutionary perspectives into the clinic will support the realization of its full potential.
Genetic disease is a necessary product of evolution (Box 1 ). Fundamental biological systems, such as DNA replication, transcription and translation, evolved very early in the history of life. Although these ancient evolutionary innovations gave rise to cellular life, they also created the potential for disease. Subsequent innovations along life’s long evolutionary history have similarly enabled both adaptation and the potential for dysfunction. Against this ancient background, young genetic variants specific to the human lineage interact with modern environments to produce human disease phenotypes. Consequently, the substrates for genetic disease in modern humans are often far older than the human lineage itself, but the genetic variants that cause them are usually unique to humans.
The advent of high-throughput genomic technologies has enabled the sequencing of the genomes of diverse species from across the tree of life 1 . Analysis of these genomes has, in turn, revealed the striking conservation of many of the molecular pathways that underlie the function of biological systems that are essential for cellular life 2 . The same technologies have also spearheaded a revolution in human genomics 3 ; currently, more than 120,000 individual whole human genome sequences are publicly available, and genome-scale data from hundreds of thousands more have been generated by consumer genomics companies 4 . Huge nationwide biobanks are also characterizing the genotypes and phenotypes of millions of people from around the world 5 , 6 , 7 . These studies are radically changing our understanding of the genetic architecture of disease 8 . It is also now possible to extract and sequence ancient DNA from remains of organisms that are thousands of years old, enabling scientists to reconstruct the history of recent human adaptation with unprecedented resolution 9 , 10 . These breakthroughs have revealed the recent, often complicated, history of our species and how it influences the genetic architecture of disease 8 , 11 . With the expansion of clinical whole-genome sequencing and personalized medicine, the influence of our evolutionary past and its implications for understanding human disease can no longer remain overlooked by medical practice; evolutionary perspectives must inform medicine 12 , 13 .
Much like a family’s medical history over generations, the genome is fundamentally a historical record. Decoding the evolution of the human genome provides valuable context for interpreting and modelling disease. This context is not limited to recent human evolution but also includes more ancient events that span life’s history. In this Review, we trace the 4 billion-year interplay between evolution and disease by illustrating how innovations during the course of life’s history have established the potential for, and inevitability of, disease. Beginning with events in the very deep past, where most genes and pathways involved in human disease originate, we explain how ancient biological systems, recent genetic variants and dynamic environments interact to produce both adaptation and disease risk in human populations. Given this scope, we cannot provide a comprehensive account of all evolutionary events relevant to human disease. Instead, our goal is to illustrate through examples the relevance of both deep and recent evolution to the study and treatment of genetic disease. Many of these key insights stem from recent discoveries, which have yet to be integrated into the broader canvas of evolutionary biomedicine (Box 2 ).
Box 1 The evolutionary necessity of disease
The definition of disease varies across biological, medical and evolutionary perspectives. Viewing disease through the lens of evolution provides a flexible and powerful framework for defining and classifying disease 12 . As illustrated in the reaction norms plotted in the figure, disease risk ( y axis) is a function of both genotype (coloured lines) and environment ( x axis).
Some genotypes lead to disease in all environments (line A); high-penetrance Mendelian disorders fall into this group. At the other extreme, disease risk may only occur in the case of a very specific pairing of environment and genotype (line D). Phenylketonuria (PKU), which manifests only in the presence of mutations that render both copies of the phenylalanine hydroxylase enzyme non-functional and a diet that includes phenylalanine, illustrates this case. Most diseases fall between these extremes (lines B and C). Disease often arises from fundamental evolutionary ‘mismatches’ between genotype and environment. For example, the high risk for obesity, a chronic disease with substantial heritability (30–40%) 177 , in many modern populations is due (at least in part) to rapid and recent changes in human lifestyle 178 , such as eating higher-calorie foods, maintaining more sedentary lifestyles and sleeping fewer hours. Here, obesity manifests due to a ‘mismatch’ between the genotype and a rapidly changing environment. Genotypes often have opposing effects on different traits. This evolutionary pattern, called antagonistic pleiotropy, often leads to disease 179 . A canonical example is balancing selection to maintain variation at the haemoglobin subunit-β ( HBB ) locus that protects against malarial disease but recessively leads to sickle cell anaemia. Antagonistic pleiotropy has also been detected in complex genetic traits, such as heart disease where alleles that increase lifetime reproductive success also increase the risk for heart disease 180 . As these examples illustrate, many modern human diseases exist because populations have not adapted to changing environments or previous adaptations lead to trade-offs between health and fitness. However, disease is not just a product of the modern world. As long as there is phenotypic variation, disease is inevitable; some individuals will be better suited to some environments (and thus healthier) than others.
Box 2 Evolutionary medicine
Evolutionary medicine is the study of how evolutionary processes have produced human traits/disease and how evolutionary principles can be applied in medicine. This Review focuses on recent advances in evolutionary genomics as they relate to our understanding of the origins and genetic basis for disease. Evolutionary medicine is a larger field that has been extensively reviewed elsewhere 12 , 26 , 181 . For context, we introduce major principles of evolutionary medicine here. Evolutionary perspectives on medicine are predicated on the idea that human diseases emerge out of the constraints, trade-offs, mismatches and conflicts inherent to complex biological systems interacting (via natural selection) with diverse and shifting environments (Box 1 ).
Evolutionary medicine has identified several categories of explanation for complex genetic diseases. The first category of evolutionary explanation is that natural selection does not result in perfect bodies but operates on relative reproductive fitness constrained by the laws of physics and the role, availability and interactions of pre-existing biological variation that shapes or constrains the subsequent course of evolution 182 , 183 . A second explanation is mismatch between our biological legacy and our modern environments 184 . Mismatch between our biological adaptations to ancestral environments and modern lifestyles contributes to many common diseases, such as obesity, diabetes and heart disease, that are promoted by sedentary lifestyles and poor nutrition 185 , 186 . For example, past exposure to calorie-poor conditions may promote metabolically efficient ‘thrifty’ gene variants that may contribute to increased obesity in calorie-rich environments. A third explanation is that of trade-offs, the idea that there are combinations of traits that cannot be simultaneously optimized by natural selection 50 , 51 . The trade-off concept is related to evolutionary constraint, but encompasses a large set of phenomena that shape trait evolution. For example, many fitness-related traits draw on common energetic reserves, and investment in one comes at the expense of another 52 . Likewise, pleiotropic genetic variants that influence multiple systems create potential for trade-offs. Furthermore, symptoms that are interpreted as disease may actually represent conditionally adaptive responses. Finally, evolutionary conflicts provide a fourth possible explanation. All multicellular organisms are aggregates of genes and genomes with different evolutionary histories and with diverse strategic interests. This means that all traits expressed by complex metazoans are a balanced compromise between different genetic elements and bodily systems 187 . Pathology can emerge out of conflict when conditions perturb these compromises.
Macroevolutionary imprints on human disease
Systems involved in disease have ancient origins.
Many of cellular life’s essential biological systems and processes, such as DNA replication, transcription and translation, represent ancient evolutionary innovations shared by all living organisms. Although essential, each of these ancient innovations generated the conditions for modern disease (Fig. 1 ). In this section, we provide examples of how several ancient innovations have created substrates for dysfunction and disease, and how considering these histories contributes to understanding the biology of disease and extrapolating results from model systems to humans.
A timeline of evolutionary events (top) in the deep evolutionary past and on the human lineage that are relevant to patterns of human disease risk (bottom). The ancient innovations on this timeline (left) formed biological systems that are essential, but are also foundations for disease. During recent human evolution (right), the development of new traits and recent rapid demographic and environmental changes have created the potential for mismatches between genotypes and modern environments that can cause disease. The timeline is schematic and not shown to scale. bya, billion years ago; kya, thousand years ago; mya, million years ago.
As a foundational (if obvious) example, the origin of self-replicating molecules 4 billion years ago formed the basis of life, but also the root of genetic diseases 12 , 14 , 15 . Similarly, asymmetric cell division may have evolved as an efficient way to handle cellular damage, but it also established the basis for ageing in multicellular organisms 16 , 17 . Myriad age-related diseases in humans, and many other multicellular organisms, are a manifestation of this first evolutionary trade-off .
The evolution of multicellularity, which has occurred many times across the tree of life, illustrates the interplay between evolutionary innovation and disease 18 . The origin of multicellularity enabled complex body plans with trillions of cells, involving innovations associated with the ability of cells to regulate their cell cycles, modulate their growth and form intricate networks of communication. But multicellularity also established the foundation for cancer 19 , 20 . Genes that regulate cell cycle control are often divided into two groups: caretakers and gatekeepers 21 , 22 . The caretakers are involved in basic control of the cell cycle and DNA repair, and mutations in these genes often lead to increased mutation rates or genomic instability, both of which increase cancer risk. Caretaker genes are enriched for functions with origins dating back to the first cells 23 . The gatekeepers appeared later, at the genesis of metazoan multicellularity 23 . The gatekeepers are directly linked to tumorigenesis through their roles in regulating cell growth, death and communication. The progression of individual tumours in a given patient is likewise informed by an evolutionary perspective. Designing treatments that account for the evolution of drug resistance and heterogeneity in tumours is a tenet of modern cancer therapy 24 , 25 , 26 , 27 , 28 , 29 .
Like multicellularity, the evolution of immune systems also set the stage for dysregulation and disease. Mammalian innate and adaptive immune systems are both ancient. Components of the innate immune system are present across metazoans and even some plants 30 , 31 , whereas the adaptive immune system is present across jawed vertebrates 32 . These systems provided molecular mechanisms for self-/non-self-recognition and response to pathogens, but they evolved in a piecemeal fashion, using many different, pre-existing genes and processes. For example, co-option of endogenous retroviruses provided novel regulatory elements for interferon response 33 . As well, it is clear that the human immune system has co-evolved with parasites, such as helminths, over millions of years. Helminth infection both induces and modulates an immune response in humans 34 .
Evolutionary analyses of development have revealed that new anatomical structures often arise by co-opting existing structures and molecular pathways that were established earlier in the history of life. For example, animal eyes, limb structure in tetrapods and pregnancy in mammals (Box 3 ) each evolved by adapting and integrating ancient genes and regulatory circuits in new ways 35 , 36 , 37 , 38 . This integration of novel traits into the existing network of biological systems gives rise to links between diverse traits via the shared genes that underlie their development and function 36 . As a result, many genes are pleiotropic — they have effects on multiple, seemingly unrelated, traits. We do not have space here to cover the full evolutionary scope of these innovations and their legacies, but just as in each of the cases described above, innovations and adaptations spanning from the origin of metazoans to modern human populations shape the substrate upon which disease appears.
Box 3 Pregnancy as a case study in evolutionary medicine
Mammalian pregnancy illustrates how consideration of a trait’s history across evolutionary time can inform our understanding of disease. Every human who ever lived experienced pregnancy, but its complexity is remarkable — it involves coordination between multiple genomes and physiological integration between individuals, and is administered by a transient organ, the placenta 188 . Furthermore, by ensuring the generational transmission of genetic information, it provides the substrate for all evolution and renewal of life itself 189 .
Pregnancy in placental mammals, which appeared ~170 million years ago, involves physiological integration of fetal and maternal tissues via the placenta, a transient fetal-derived, extra-embryonic organ. Live birth and placentation open the door to interplay between mother and fetus over resource provisioning, with the potential for the mother to provide less than fetal demands because of other energetic needs, such as caring for other offspring. In some mammals, including humans, placentation is highly invasive, setting up a physiological tug of war between mother and fetus over provisioning. When this precarious balance is disrupted, diseases of pregnancy can occur. Poor maternal arterial remodelling during placentation limits placental invasion, which invokes a compensatory response by the distressed fetus. This imbalance results in inflammation, hypertension, kidney damage and proteinuria in the mother, and an increase in oxidative stress and spontaneous preterm birth in the fetus 190 . Pregnancy-associated maternal hypertension with proteinuria is clinically defined as pre-eclampsia with vascular aetiologies, with a poor prognosis for both mother and fetus if untreated. Understanding pre-eclampsia as the result of an evolutionary tug of war between mother and the fetus has medical implications 191 , 192 , 193 , 194 .
Timing of birth is key to a successful, healthy pregnancy, but little is known about the mechanisms governing the initiation of parturition. The steroid hormone progesterone and its receptors are involved in parturition in all viviparous species; however, how progesterone regulates parturition is likely to be species-specific. For example, the human progesterone receptor (PGR) exhibited rapid evolution after divergence from the last common ancestor with chimpanzees 195 , 196 . There are functional differences between the human and Neanderthal versions of the progesterone receptor 197 . The human-specific changes in the PGR influence its transcription and probably its phosphorylation 198 , 199 . Similarly, loci associated with human preterm birth have experienced diverse evolutionary forces, including balancing selection, positive selection and population differentiation 200 . The rapid and diverse types of evolutionary change observed in the PGR and some of the loci associated with preterm birth make it challenging to extrapolate analyses of their molecular functions in animal models, such as mice. In addition, humans and mice differ in reproductive strategies, morphology of the uterus, placentation, hormone production and the drivers of uterine activation 201 . For example, progesterone is produced maternally in mice throughout pregnancy, whereas in humans its production shifts to the placenta after the early stages of pregnancy. Given the unique evolutionary history of human pregnancy, many molecular aspects of pregnancy may be better studied in other model organisms or human cell-based systems.
Human population level
A central enigma of mammalian pregnancy is that the maternal immune system does not reject the foreign fetus; rather, it has not only evolved to accept the fetus but is also critical in the process of placentation 202 , 203 . The centrality of the maternal immune system in pregnancy has important medical implications. The modulation of the maternal immune system during pregnancy results in a lowered ability to clear certain infections 204 , 205 . Uterine natural killer (uNK) cells and their killer cell inhibitory receptors (KIRs) cooperate with fetal trophoblasts to regulate the maternal immune response. In addition, uNK cells are also involved in immune response to pathogens, and this dual role provides the substrate for evolutionary trade-offs. For example, the human-specific KIR AA haplotype is associated with lower birthweight and pre-eclampsia as well as with a more effective defence against Ebola virus and hepatitis 206 , 207 (Fig. 4a ). Modern human populations have variation in the diversity and identity of KIR haplotypes, probably due to selection on both placentation and host defence 208 . Infectious disease outbreaks, therefore, place a unique selective pressure on pregnancy. Severe outbreaks of infectious diseases, such as malaria, often produce significant shifts in population-level allele frequencies in pregnancy-related genes, such as FLT1 in malaria-endemic populations of Tanzania 209 . The varying pressures from infectious disease are likely to contribute to variation in risk of pregnancy-related diseases between modern populations.
Although ancient macroevolutionary innovations may seem far removed from modern human phenotypes, their imprint remains on the human body and genome. Understanding the constraints they impose can provide insight into mechanisms of disease.
Mapping the origins and evolution of traits and identifying the genetic networks that underlie them are critical to the accurate selection of model systems and extrapolation to human populations. Failure to consider the evolutionary history of homologous systems, their phylogenetic relationships and their functional contexts in different organisms can lead to inaccurate generalization. Instead, when considering a model system, key evolutionary questions about both the organism and the trait of interest can indicate how translatable the research will be to humans 39 , 40 . For example, is the similarity between the trait in humans and the trait in the model system due to shared ancestry, that is, homology ? The presence of homology in a human gene or system of study suggests potential as a model system; however, homology alone is not sufficient justification. Environmental and life history factors shape traits, and divergence between species complicates the simple assumption that homology provides genetic or mechanistic similarity. Thus, homology must be supplemented by understanding of whether the evolutionary divergence between humans and the proposed model led to functional divergence. For example, the rapid evolution of the placenta and variation in reproductive strategy across mammals have made it challenging to extrapolate results about the regulation of birth timing from model organisms, such as mouse, to humans (Box 3 ). More broadly, differences in genetic networks that underlie the development of homologous traits across mammals explain why the majority of successful animal trials fail to translate to human clinical trials 41 , 42 . Molecular mechanisms of ancient systems, such as DNA replication, can be studied using phylogenetically distant species; however, ‘humanizing’ these models to research human-specific aspects of traits may not be possible and comparative studies of closely related species may be required 40 .
Although evolutionary divergence in homologous traits is an impediment to the direct translation of findings from a model system to humans, understanding how these evolutionary differences came about can also yield insights into disease mechanisms. For example, intuition would suggest that large animals (many cells and cell divisions) with long lifespans (many ageing cells), such as elephants and whales, would be at increased risk for developing cancer. However, size and lifespan are not significantly correlated with cancer risk across species; despite their large size, elephants and whales do not have a higher risk of developing cancer 43 , 44 . Why is this so? Recent studies of the evolution of genes involved in the DNA damage response in elephants have revealed mechanisms that may contribute to cancer resistance. An ancient leukaemia inhibiting factor pseudogene ( LIF6 ) regained its function in the ancestor of modern elephants. This gene works in conjunction with the tumour suppressor gene TP53 , which has increased in copy number in elephants, to reduce elephants’ risk for cancer despite their large body size 45 , 46 . This illustrates a basic life history trade-off: selection has created mechanisms for cancer suppression and somatic maintenance in large vertebrates that are not needed in small short-lived vertebrates. Studying such seeming paradoxes, especially those with clear contrasts to human disease risk, will shed light on broader disease mechanisms and suggest targets for functional interventions with translation potential.
Human adaptation, trade-offs and disease.
The macroevolutionary events described above created the foundation of genetic disease, but considering the more recent changes that occurred during the evolutionary history of the human lineage is necessary to illuminate the full context of human disease. Comparisons between humans and their closest living primate relatives, such as chimpanzees, have revealed diseases that either do not appear in other species or take very different courses 47 . We are beginning to understand the genetic differences underlying some of these human-specific conditions, with particular insights into infectious diseases.
The last common ancestors of humans and chimpanzees underwent a complex speciation event that is likely to have involved multiple rounds of gene flow between ~12 and 6 million years ago (mya) 48 . Over the millions of years after this divergence, climatic, demographic and social pressures drove the evolution of many physical and behavioural traits unique to the human lineage, including bipedalism (~7 mya), lack of body hair (~2–3 mya) and larger brain volume relative to body size (~2 mya) 12 , 47 . These traits evolved in a diverse array of hominin groups, mainly in Africa, although some of these species, such as Homo erectus , ventured into Europe and Asia.
These human adaptations developed on the substrate of tightly integrated systems shaped by billions of years of evolution, and thus beneficial adaptations with respect to one system often incurred trade-offs in the form of costs on other linked systems 49 . The trade-off concept derives from a branch of evolutionary biology known as life history theory. It is based on the observation that organisms contain combinations of traits that cannot be simultaneously optimized by natural selection 50 , 51 . For example, many fitness-related traits draw on common energetic reserves, and investment in one comes at the expense of another 52 . Large body size may improve survival in certain environments, but it comes at the expense of longer development and lower numerical investment in reproduction.
The trade-off concept is clinically relevant because it dispenses with the notion of a single ‘optimal’ phenotype or fitness state for an individual 49 , 53 , 54 . Given the interconnected deep evolution of the human body, many diseases are tightly linked, in the sense that decreasing the risk for one increases the risk for the other. Such diametric diseases and the trade-offs that produce them are the starkest when there is competition within the body for limited resources; for example, energy used for reproduction cannot be used for growth, immune function or other energy-consuming survival processes 54 . The molecular basis for diametric diseases often results from antagonistic pleiotropy at the genetic level — when a variant has contrasting effects on multiple bodily systems. In extreme cases, some diseases that manifest well after reproductive age, for example, Alzheimer disease, have been less visible to selection and, thus, potentially more susceptible to trade-offs. Cancer and neurodegenerative disorders also exhibit this diametric pattern, where cancer risk is inversely associated with Alzheimer disease, Parkinson disease and Huntington disease. This association is hypothesized to be mediated by differences in the neuronal energy use and trade-offs in cell proliferation and apoptosis pathways 49 . Similarly, osteoarthritis (breakdown of cartilage in joints often accompanied by high bone mineral density) and osteoporosis (low bone mineral density) rarely co-occur. Their diametric pattern reflects, at least in part, different probabilities across individuals of mesenchymal stem cells within bone marrow to develop into osteoblasts versus non-bone cells such as adipocytes 49 , 55 . In another example, a history of selection for a robust immune response can now lead to an increased risk for autoimmune and inflammatory diseases, especially when coupled with new environmental mismatches 49 , 54 . Other examples of trade-offs are found throughout the human body, manifesting in risk for diverse diseases, including psychiatric and rheumatoid disorders 49 , 56 .
Just as adaptations in deep evolutionary time created new substrates for disease, evolutionary pressures exerted on the human lineage established the foundation for complex cognitive capabilities, but they also established the potential for many neuropsychiatric or neurodevelopmental diseases. For example, genomic structural variants enabled functional innovation in the brain through the emergence of novel genes 57 , 58 , 59 , 60 . Many human-specific segmental duplications influence genes that are essential to the development of the human brain, such as SRGAP2C and ARHGAP11B . Both of these genes function in cortical development and may be involved in the expansion of human brain size 61 , 62 , 63 . The human-specific NOTCH2NL is also hypothesized to have evolved from a partial duplication event, and is implicated in increased output during human corticogenesis, another potential key contributor to human brain size 59 , 60 . Although these structural variants were probably adaptive 58 , they may have also predisposed humans to neuropsychiatric diseases and developmental disorders. Copy number variation in the region flanking ARHGAP11B , specifically a microdeletion at 15q13.3, is associated with risk for intellectual disability, autism spectrum disorder (ASD), schizophrenia and epilepsy 58 , 64 . Duplications and deletions of NOTCH2NL and surrounding regions are implicated in macrocephaly and ASD or microcephaly and schizophrenia, respectively 59 . These trade-offs also play out at the protein domain level. For example, the Olduvai domain (previously known as DUF1220) is a 1.4-kb sequence that appears in ~300 copies in the human genome; this domain has experienced a large human-specific increase in copy number. These domains appear in tandem arrays in neuroblastoma breakpoint family ( NBPF ) genes, and have been associated with both increased brain size and neuropsychiatric diseases, including autism and schizophrenia 65 . These examples suggest that the genomic organization of these human-specific duplications may have enabled human-specific changes in brain development while also increasing the likelihood of detrimental rearrangements that cause human disease 59 , 64 . Furthermore, genomic regions associated with neuropsychiatric diseases have experienced human-specific accelerated evolution and recent positive selection, providing additional evidence for the role of recent evolutionary pressures on human disease risk 66 , 67 . Schizophrenia-associated loci, for example, are enriched near human accelerated regions (HARs) that are conserved in non-human primates 68 . Variation in HARs has also been associated with risk for ASD, possibly through perturbations of gene regulatory architecture 69 .
Human immune systems have adapted in response to changes in environment and lifestyles over the past few million years; however, the rapid evolution of the immune system may have left humans vulnerable to certain diseases, such as HIV-1 infection. A similar virus, simian immunodeficiency virus (SIV), is found in chimpanzees and other primates, and studies in the early 2000s found evidence of AIDS-like symptoms (primarily a reduction in CD4 + T cells) in chimpanzees infected with SIV. Although the effects of SIV in chimpanzees mirror some of the effects of HIV in humans 70 , captive chimpanzees infected with HIV-1 do not typically develop AIDS and have better clinical outcomes. The differences in outcome are influenced by human-specific immune evolution. For example, humans have lost expression of several Siglecs, cell surface proteins that binds sialic acids, in T lymphocytes compared with great apes 71 . In support of this hypothesis, human T cells with high Siglec-5 expression survive longer after HIV-1 infection 72 . Moreover, there is a possible role for the rapidly evolving Siglecs in other diseases, such as epithelial cancers, that differentially affect humans relative to closely related primates 73 , 74 .
Another human-specific immune change is the deletion of an exon of CMP- N -acetylneuraminic acid hydroxylase ( CMAH ) leading to a difference in human cell surface sialoglycans compared with other great apes 75 , 76 , 77 . The change in human sialic acid to an N -acetylneuraminic acid (Neu5Ac) termination, rather than N -glycolylneuraminic acid (Neu5Gc), may have been driven by pressure to escape infection by Plasmodium reichenowi , a parasite that binds Neu5Gc and causes malaria in chimpanzees. Conversely, the prevalence of Neu5Ac probably made humans more susceptible to infection by the malaria parasite Plasmodium falciparum , which binds to Neu5Ac 78 , 79 , and another human-specific pathology: typhoid fever 80 . Typhoid toxin binds specifically and is cytotoxic to cells expressing Neu5Ac glycans. Thus, the deletion of CMAH was likely to have been selected for by pressure from pathogens, but has in turn enabled other human-specific diseases such as malaria and typhoid fever 81 . The rapid evolution of the human immune system creates the potential for human-specific disease. As a result, human-specific variation in many other human immune genes influences human-specific disease risk 82 , 83 .
These examples from recent human evolution highlight the ongoing interplay of genetic variation, adaptation and disease. Understanding the evolutionary history of traits along with the aetiology of related diseases can help identify and evaluate risks for unintended consequences of treatments due to trade-offs. For example, ovarian steroids have pleiotropic effects stimulating both bone growth and mitosis in breast tissues to mobilize calcium stores during lactation 54 . However, later in life this link gives rise to a clinical trade-off. Hormone replacement therapy in postmenopausal women reduces the risk for osteoporosis and ovarian cancer, but also, as a result of its effects on breast tissue, increases the risk for breast cancer. Given the commonality of the trade-off between maintenance and proliferation, this is just one of many examples of cancer risk emerging as a result of trade-offs in immune, reproductive and metabolic systems 56 , 84 . Pregnancy is also rife with clinically relevant trade-offs given the interaction between multiple individuals and genomes (mother, father and fetus) with different objectives (Box 3 ). Trade-offs at the cellular level also have medical implications. For example, cellular senescence is a necessary and beneficial part of many basic bodily responses, but the accumulation of senescent cells underlies many ageing-related disorders. Thus, individuals with different solutions to this trade-off may have very different ‘molecular’ versus ‘chronological’ ages 85 .
Identifying such trade-offs by studying disease and treatment response is of great interest, but is challenging for several reasons: the number of possible combinations of traits to consider is large; many humans must have experienced the negative effects; and data must be available on both traits in the same individuals. Here, evolution paired with massive electronic health record (EHR)-linked biobanks 5 , 86 , 87 provides a possible solution. By considering the evolutionary context and potential linkages between traits, the search space of possible trade-offs can be constrained. Then, diametric traits can be tested for among individuals in the EHRs by performing phenome-wide association studies (PheWAS) either on traits or genetic loci of interest and looking for inverse relationships 88 . The mechanisms underlying the observed associations could then be evaluated in model systems and, if validated, anticipated in future human treatments.
In addition to trade-offs, evolutionary analyses can help us identify therapeutic targets for uniquely human diseases. A small subset of humans infected with HIV never progress to AIDS — a resistance phenotype that has been generally attributed to host genomics 89 , 90 , 91 . Identifying and understanding the genes that contribute to non-progression is of great interest in the development of vaccines and treatments for HIV infection. Genome-wide association studies (GWAS) and functional studies have supported the role of the MHC class I region, specifically the HLA-B*27/B*57 molecules, in HIV non-progression 92 , 93 , 94 . Comparative genomics with chimpanzees identified a chimpanzee MHC class I molecule functionally analogous to that of the non-progressors that contains amino acid substitutions that change binding affinity for conserved areas of the HIV-1 and SIV viruses. Evolutionary analysis of this region suggests that these substitutions are the result of an ancient selective sweep in chimpanzee genomes that did not occur in humans 95 . This analysis not only helps us understand how humans are uniquely susceptible to HIV progression but also highlights functional variation in the MHC that are potential targets of medical intervention.
Recent human demographic history
Most genetic variants are young, but have diverse histories.
The complex demographic history of modern humans in the past 200,000 years has created differences in the genetic architecture of and risk for specific diseases among human populations. With genomic sequences of thousands of humans from diverse locations, we can compare genetic information over time and geography to better understand the origins and evolution of both individual genetic variants and human populations 96 , 97 , 98 . The vast majority of human genetic variants are not shared with other species 99 . Demographic events such as bottlenecks , introgression and population expansion shaped the genetic composition of human populations, whereas rapid introduction of humans into new environments and the subsequent adaptations created potential for evolutionary mismatches (Figs 2 , 3 ).
Representative genes that have experienced local adaptive evolution over the past 100,000 years as humans moved across the globe. We focus on adaptations that also produced the potential for disease due to trade-offs or mismatches with modern environments. For each, we list the evolutionary pressure, the trait(s) influenced and the associated disease(s). The approximate regions where the adaptations occurred are indicated by blue circles. Arrows represent the expansion of human populations, and purple shading represents introgression events with archaic hominins. Supplementary Table S1 presents more details and references. COVID-19, coronavirus disease 2019; G6PD, glucose-6-phosphate dehydrogenase; UV, ultraviolet.
Ancient human migrations, introgression events with other archaic hominins and recent population expansions have all contributed to the introduction of variants associated with human disease. Schematic of human evolutionary history, where the branches represent different human populations and the branch widths represent population size (top left). Letter labels refer to the processes illustrated in parts a – d . a | Human populations migrating out of Africa maintained only a subset of genetic diversity present in African populations. The resulting out-of-Africa bottleneck is likely to have increased the fraction of deleterious, disease-associated variants in non-African populations. Coloured circles represent different genetic variants. Circles marked with X denote deleterious, disease-associated variants. b | When anatomically modern humans left Africa, they encountered other archaic hominin populations. Haplotypes introduced by archaic introgression events (illustrated in grey) contained Neanderthal-derived variants (denoted by red circles) associated with increased disease risk in modern populations. c | In the last 10,000 years, the burden of rare disease-associated variants (denoted by yellow circles) has increased due to rapid population expansion. d | Modern human individuals with admixture in their recent ancestry, such as African Americans, can have differences in genetic risk for disease, because of each individual’s unique mix of genomic regions with African and European evolutionary ancestry. For example, each of the three admixed individuals depicted have the same proportions of African and European ancestry, but do not all carry the disease-associated variant found at higher frequency in European populations (illustrated by yellow circles). Summarizing clinical risk for a patient requires a higher resolution view of evolutionary ancestry along the genome and improved representation of genetic variation from diverse human populations.
Approximately 200,000 years ago, ‘ anatomically modern humans ’ (AMHs) first appeared in Africa. This group had the key physical characteristics of modern human groups and exhibited unique behavioural and cognitive abilities that enabled rapid improvements in tool development, art and material culture. Approximately 100,000 years ago, AMH groups began to migrate out of Africa. The populations ancestral to all modern Eurasians are likely to have left Africa tens of thousands of years later 98 , but quickly spread across Eurasia. Expansions into the Americas and further bottlenecks are thought to have occurred between 35,000 and 15,000 years ago. The details and uncertainties surrounding these origin and migration events are more extensively reviewed elsewhere 98 .
Populations that experience bottlenecks and founder effects have a higher mutation load than populations that do not, largely due to their lower effective population sizes reducing the efficacy of selection 100 (Fig. 3a ). During this dispersal, the migrant human populations harboured less genetic variation than was present in Africa. The reduction in diversity caused by the out-of-Africa and subsequent bottlenecks shaped the genetic landscape of all populations outside Africa.
AMHs did not live in isolation after migration out of Africa. Instead, there is evidence of multiple admixture events with other archaic hominin groups, namely Neanderthals and Denisovans 101 , 102 . Modern non-African populations derive approximately 2% of their ancestry from Neanderthals, with some Asian populations having an even higher proportion of archaic hominin ancestry (Fig. 3b ). African populations have only a small amount of Neanderthal and Denisovan ancestry, largely from back migration from European populations with archaic ancestry 103 . However, there is evidence of admixture with other, as yet unknown, archaic hominins in the genomes of modern African populations 104 , 105 , 106 .
Following their expansion around the globe, humans have experienced explosive growth over the past 10,000 years, in particular in modern Eurasian populations 107 , 108 (Fig. 3c ). Growth in population size modifies the genetic architecture of traits by increasing the efficacy of selection and generating many more low-frequency genetic variants. Although the impact of rare alleles is not completely understood, they often have a deleterious role in variation in traits in modern populations 109 . Although there is still debate about the combined effects of these recent demographic differences, a consensus is emerging that they are likely to have only minor effects on the efficacy of selection and the mutation load between human populations 100 , 110 , 111 , 112 , 113 , 114 . Nonetheless, there are substantial differences in allele frequency between populations that are relevant to disease risk 115 .
The exposure of humans to new environments and major lifestyle shifts, such as agriculture and urbanization, created the opportunity for adaptation 96 , 116 . Ancient DNA sequencing efforts coupled with recent statistical advances are beginning to enable the linking of human adaptations to specific environmental shifts in the recent past 96 , 117 , 118 . However, these rapid environmental changes also created new patterns of complex disease. Mismatch between our biological suitability for ancestral environments and modern environments accounts for the prevalence of many common diseases, such as obesity, diabetes or heart disease that derive from sedentary lifestyles and poor nutrition. The ancestral susceptibility model proposes that ancestral alleles that were adapted to ancient environments can, in modern populations, increase the risk for disease 119 , 120 . Supporting this hypothesis, both ancestral and derived alleles increase disease risk in modern humans 121 , 122 . However, underscoring the importance of recent demographic history, patterns of risk for ancestral and derived alleles differ in African and European populations, with ancestral risk alleles at higher frequencies in African populations 115 .
The different evolutionary histories of modern human individuals and populations described in the previous section influence disease susceptibilities and outcomes. Perhaps most striking are the mismatches and trade-offs resulting from recent immune system adaptations. Classic examples include genetic variants conferring resistance to malaria also causing sickle cell-related diseases in homozygotes 96 , 123 , or the predominantly African G1 and G2 variants in APOL1 protecting against trypanosomes and ‘sleeping sickness’ but leading to chronic kidney disease in individuals with these genotypes 96 . Similarly, a variant in CREBRF that is thought to have improved survival for people in times of starvation is now linked to obesity and type 2 diabetes 124 . In a study of ancient European populations, a variant in SLC22A4 , the ergothioneine transporter, that may have been selected for to protect against deficiency of ergothioneine (an antioxidant) is also associated with gastrointestinal problems such as coeliac disease, ulcerative colitis and irritable bowel syndrome 118 . The variant responsible did not reach high frequency in European populations until relatively recently, and current disease associations are likely to be new, perhaps as a result of mismatches with the current environment 118 . The possibility of mismatch is further supported by the varying prevalence of coeliac disease between human populations related to population-specific selection for several risk alleles 82 . Indeed, recent studies suggest that there is a relationship between ancestry and immune response, with individuals of African ancestry demonstrating stronger responses. This could be the result of selective processes in response to new environments for European populations, or a larger pathogen burden in Africa now leading to a higher instance of inflammatory and autoimmune disorders. This is still an open area of research, and more evidence is needed before strong conclusions can be drawn 125 .
In modern human environments, there is also a mismatch between the current low parasite infection levels and the immune system that evolved under higher parasite load. This mismatch is hypothesized to contribute to the increase in inflammatory and autoimmune diseases seen in modern humans 34 . For example, loci associated with ten different inflammatory diseases, including Crohn’s disease and multiple sclerosis, show evidence of selection consistent with the hygiene hypothesis 126 . Furthermore, recent positive selection on variants in the type 2 immune response pathway favoured alleles associated with susceptibility to asthma 127 . This suggests that recent evolutionary processes may have led to elevated or altered immune responses at the expense of increased susceptibility to inflammatory and autoimmune diseases. This insight has broad clinical implications, including the potential targeted use of helminths and natural products for immune modulation in patients with chronic inflammatory disease 128 , 129 .
Archaic introgression is relevant to modern medicine because alleles introduced by these evolutionary events continue to have an impact on modern populations even though the archaic hominin lineages are now extinct (Fig. 3b ). Archaic hominins had considerably lower effective population sizes than AMHs, and thus they probably carried a larger fraction of weakly deleterious mutations than AMHs 101 . As a result, Neanderthal introgression is predicted to have substantially increased the genetic load of non-African AMHs 130 , 131 . Large-scale sequencing efforts, in combination with analysis of clinical biobanks and improved computational methods, have revealed the potential impacts of introgressed DNA on modern human genomes. Several recent studies link regions of archaic admixture in modern populations with a range of diseases, including immunological, neuropsychiatric and dermatological phenotypes 102 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 . This demonstrates the functional impact of introgressed sequence on disease risk in non-African humans today. However, some of these associations may be influenced by linked non-Neanderthal alleles 140 . For example, in addition to alleles of Neanderthal origin, introgression also reintroduced ancestral alleles that were lost in modern Eurasian populations prior to interbreeding (for example, in the out-of-Africa bottleneck) 141 . Some introgressed alleles may have initially lessened adverse effects from migration to northern climates, dietary changes and introduction to novel pathogens 117 , 142 , 143 . For example, Neanderthal alleles contribute to variation in innate immune response across populations 125 , 132 , 134 , 144 and probably helped AMHs adapt to new viruses, in particular RNA viruses in Europe 145 . However, due to recent demographic and environmental changes, some previously adaptive Neanderthal alleles may no longer provide the same benefits 146 . For example, there is evidence that an introgressed Neanderthal haplotype increases risk for SARS-CoV-2 (ref. 147 ).
Physicians regularly rely on proxies for our more recent evolutionary history in the form of self-reported ancestry in their clinical practice; however, these measures fail to capture the complex evolutionary ancestry of each individual patient. For example, two individuals who identify as African Americans may both have 15% European ancestry, but this ancestry will be at different genomic loci and from different ancestral European and African populations (Fig. 3d ). Thus, one may carry a disease-increasing European ancestry allele whereas the other does not. Mapping fine-scale genetic ancestry across patients’ genomes can improve our ability to summarize clinically relevant risk 148 , but such approaches require broad sampling across populations and awareness of human diversity (Box 4 ). The profound need to increase the sampling of diverse groups is demonstrated by the lack of diversity in genomic studies, and the potential for health disparities caused by the over-representation of European-ancestry populations 149 , 150 , 151 (Fig. 4 ). In 2016, 81% of GWAS data were from studies conducted on European populations 149 . Although this is an improvement from 96% in 2009, most non-European populations still lack appropriate representation. The problem is more extreme for many phenotypes or traits of interest. For example, only 1.2% of the studies in a survey of 569 GWAS on neurological phenotypes included individuals of African ancestry 150 , 152 .
a | Interactions between the maternal killer cell inhibitory receptor (KIR) genotype and the fetal trophoblasts illustrate evolutionary trade-offs in pregnancy. Birthweight is under stabilizing selection in human populations. The interaction between maternal KIR genotypes (a diversity of which are maintained in the population) and the fetal trophoblasts influence birthweight. African (AFR) populations, relative to European (EUR) populations, maintain larger proportions of the KIR AA haplotype 176 , which is associated with improved maternal immune response to some viral challenges; however, it is also associated with low birthweight. Alternatively, the KIR BB haplotype is associated with higher birthweight but increased risk of pre-eclampsia. b | Current strategies for predicting genetic risk are confounded by a lack of inclusion of diverse human populations. Thus, they are more likely to fail in genetic risk prediction in populations that are under-represented in genetic databases. For example, polygenic risk score (PRS) models trained on European populations often perform poorly when applied to African populations. This poor performance stems from the fact that the genetic diversity of African populations, differences in effect sizes between populations and differential evolutionary pressures are not taken into account. The weights for each variant (blue circles) in the PRS derived from genome-wide association studies are signified by w1, w2 and w3. c | Population-specific adaptation and genetic hitch-hiking can produce different disease risk between populations. Haplotypes with protective effects against disease may rise to high frequency in specific populations through genetic hitch-hiking with nearby alleles under selection for a different trait. For example, selection for lighter skin pigmentation caused a haplotype that carried a variant associated with lighter skin (blue circle) to increase in frequency in European populations compared with African populations. This haplotype also carried a variant protective against prostate cancer (blue triangle).
Ancestry biases in genomic databases and GWAS propagate through other strategies that are designed to translate population genetic insights to the clinic, such as polygenic risk scores (PRSs) 153 , 154 (Fig. 4b ). PRSs hold the promise of predicting medical outcomes from genomic data alone. However, the evolutionary perspective suggests that the genetic architecture of diseases should differ between populations due to the effects of the demographic and environmental differences discussed above. Indeed, many PRSs generalize poorly across populations and are subject to biases 155 , 156 . Prioritization of Mendelian disease genes is also challenging in under-represented populations. Generally, African-ancestry individuals have significantly more variants, yet we know less about the pathogenicity of variants that are absent from or less frequent in European populations 157 . Patients of African and Asian ancestry are currently more likely than those of European ancestry to receive ambiguous genetic test results after exome sequencing or be told that they have variants of uncertain significance (VUS) 158 . Indeed, disease-causing variants of African origin are under-represented in common databases 159 . This under-representation covers a range of phenotypic traits and outcomes, including interpreting the effects of CYP2D6 variants on drug response 160 , 161 , risk identification and classification for breast cancer across populations 162 , and disparate effects of GWAS associations for traits including body mass index (BMI) and type 2 diabetes in non-European populations 163 . In a study on hypertrophic cardiomyopathy, benign variants in African Americans were incorrectly classified as pathogenic on the basis of GWAS results from a European ancestry cohort. Inclusion of individuals of African descent in the initial GWAS could have prevented these errors 164 .
Box 4 Evolutionary medicine in clinical practice
Evolutionary perspectives have yet to be integrated into most areas of clinical practice. Notable exceptions involve diseases in which evolutionary processes act over short timescales to drive the progression of disease. For example, knowledge of the intense selective pressures underlying the evolution of drug resistance of microorganisms and the growth of tumours now guides the application of precise therapies and drug delivery strategies 210 , 211 , 212 , 213 . These examples illustrate how an evolutionary perspective can improve patient outcomes. However, they differ from the main focus of this article — the influence of human evolution on common genetic disease — where the relevant evolutionary processes have acted over thousands or millions of years.
Nonetheless, accounting for the innovations, adaptations and trade-offs that have shaped human populations should be considered in the clinical application of precision medicine to complex disease. For example, polygenic risk scores (PRSs) are a burgeoning technology with great clinical potential to stratify individuals by risk and enable preventative care 154 , 214 , but they have a fundamental dependence on underlying evolutionary processes. Individuals have different genetic backgrounds based on their ancestry, and these different histories alter the relationships between genotypes, environmental factors and risk of disease (Fig. 4 ). From this evolutionary perspective, PRSs should not be expected to generalize across populations and environments given the varied demographic histories of human populations that shape genetic variation 155 , 156 , 215 . Indeed, failure to account for this diversity in the application of PRSs and other genetics-based prediction methods can cause substantial harm and contribute to health disparities by producing misdiagnosis, improper drug dosing and inaccurate risk predictions 149 , 150 , 151 , 158 , 160 , 161 , 162 , 163 , 164 . An evolutionary approach is integral to solving this problem. PRSs must be developed and critically evaluated across the full range of human diversity to determine when genetic factors can provide an accurate risk profile for individuals. This is crucial in individuals with recent admixture in their ancestry, as risk profiles can vary based on the unique patterns of ancestry in each individual (Fig. 3 ). If genetic information is to inform personalized predictions about disease risk, explicitly considering evolution by quantifying genetic ancestry must be a critical component of this process.
The development of PRSs provides a timely and illustrative case study of how evolutionary perspectives can move from research contexts to inform clinical application. It also highlights the pitfalls of ignoring the implications of human evolutionary history when generalizing findings across populations. The establishment of a new technology (genome sequencing) enabled the measurement of a signal that is informative about disease risk (genetic variation) but is also influenced by evolutionary history. The knowledge gained from 100 years of basic research in population genetics about how human populations have evolved provides the context for these new technologies and the path towards ensuring that new treatments are not biased against specific populations.
Beyond providing context for existing analyses and treatments, new approaches are needed to translate our understanding of the history of human evolution from basic research to clinical relevance. In the main text, we highlight examples of how trade-offs, caused by competition for resources or antagonistic pleiotropy, may produce contrasting effects on disease risk within an individual. Similarly, new environmental conditions, such as a new pathogen, may rapidly create genetic mismatches in some populations. We propose that evolution-guided analysis of large-scale phenotype databases, such as those in electronic health record (EHR)-linked biobanks, are a promising approach for identifying novel patterns of diametric disease or mismatches in patient populations. For example, if a gene with pleiotropic functions is targeted by a treatment, such as a drug, knowledge of the gene’s evolution and functions can suggest specific phenotypes to test for diametric occurrence in the biobank. Given the overlapping evolutionary histories of molecular pathways involved in most traits, we anticipate that many clinically relevant trade-offs are waiting to be discovered.
Conclusions and future perspectives
All diseases have evolutionary histories, and the signatures of those histories are archived in our genomes. Recent advances in genomics are enabling us to read these histories with high accuracy, resolution and depth. Insights from evolutionary genomics reveal that there is not one answer to the question of why we get sick. Rather, diseases affect patchworks of ancient biological systems that evolved over millennia, and although the systems involved are ancient, the variation that is relevant for human disease is recent. Furthermore, evolutionary genomics approaches have the power to identify potential mechanisms, pathways and networks and to suggest clinical targets. In this context, we argue that an evolutionary perspective can aid the implementation of precision medicine in the era of genome sequencing and editing 165 (Box 4 ).
Combining knowledge of evolutionary events along the human lineage with results from recent genomic studies provides an explanatory framework beyond descriptions of disease risk or association. For example, a recent analysis of the higher incidence of prostate cancer among men of African ancestry not only discovered a set of genetic variants associated with increased risk, but also used measures of selection to propose an evolutionary explanation of genetic hitch-hiking for the lower incidence in non-African populations 166 . Haplotypes with protective effects against prostate cancer may have risen to higher frequency in non-African populations because of selection on the nearby variants associated with skin pigmentation (Fig. 4c ). Thus, evolutionary perspectives not only help answer the question of how we get sick but also why we get sick.
As the genetic information available from diverse populations increases, we can specifically map the genetics of traits in different populations and more precisely define disease risk on an individual basis 167 , 168 . However, we emphasize that environmental and social factors are major determinants of disease risk that often contribute more than genetics, and thus must be prioritized. Studying diverse human populations will provide additional power to discover trait-associated loci and understand genetic architecture across different environmental exposures and evolutionary histories 150 , 169 . For example, a GWAS with small sample size in a Greenlandic Inuit population found a variant in a fatty-acid enzyme that affects height in both this population and European populations 170 . Previous GWAS probably missed this variant due to its low frequency in European populations (0.017 compared with 0.98 in the Inuit); nevertheless, it has a much greater effect on height than other variants previously identified through GWAS 170 . Similarly, a recent study of height in 3,000 Peruvians identified another variant with an even greater influence on height 171 . The growth of large DNA biobanks in which hundreds of thousands of patients’ EHRs are linked to DNA samples represents a substantial untapped resource for evolutionary medicine 5 , 86 , 87 . These data enable testing of the functional effects of genetic variants on diverse traits at minimal additional cost. Shifting from single-ancestry GWAS to trans-ethnic or multi-ethnic GWAS will capitalize on the benefits of both a larger sample size and the inherent diversity of human populations for replication of established signals and discovery of new ones 172 , 173 , 174 , 175 .
Although evolutionary assumptions are tacit in medical practice, until recently self-reported family history remained the best representation of our evolutionary ancestry’s imprint on our disease risk. However, a family history cannot fully capture the complex evolutionary and demographic history of each individual. New technologies now enable the collection and interpretation of an individual’s family history in a much longer and complementary form — their genome. New data and methods are substantially increasing the resolution and depth with which these histories can be quantified, providing opportunities for evolution to inform medical practice.
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The authors thank L. Muglia and members of the Capra, Rokas and Abbot laboratories for helpful discussions. They also thank the National Institutes of Health (NIH) (T32LM012412 to M.L.B. and R35GM127087 to J.A.C.), the Burroughs Wellcome Fund Preterm Birth Initiative (A.R. and J.A.C.), the March of Dimes Prematurity Research Center Ohio Collaborative (P.A., A.R. and J.A.C.) and the American Heart Association (A.A.) for support.
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Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA
Mary Lauren Benton, Antonis Rokas & John A. Capra
Department of Computer Science, Baylor University, Waco, TX, USA
Mary Lauren Benton
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
Abin Abraham & Antonis Rokas
Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA
Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA
Abigail L. LaBella, Patrick Abbot, Antonis Rokas & John A. Capra
Bakar Computational Health Sciences Institute and Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
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Supplementary table s1.
All aspects of the genetic variants that influence variation of a trait in a population. Commonly studied attributes of genetic architecture include the number of genetic loci that influence a trait, the frequency of these variants, the magnitudes of their effects and how they interact with one another and the environment. The genetic architectures of traits vary along these axes; for example, some traits are influenced by many common variants of small effect, whereas others are driven by a few rare variants of large effect.
Representations of how the expressed phenotype for a genotype varies in response to a range of environments. Reaction norms can be used to illustrate many of the concepts described in this Review, including evolutionary mismatches and antagonistic pleiotropy.
Adaptations that are advantageous for one phenotype have costs for others. Evolutionary trade-offs often result when genes influence multiple phenotypes (pleiotropy) or when there is a limited resource that must be apportioned to different functions. Because of trade-offs, there is not an optimal genotype across all environments.
Pertaining to pleiotropy, which is when a genetic locus (for example, a gene or regulatory element) has effects on multiple unrelated phenotypes. Antagonistic pleiotropy results when a locus has a beneficial effect on one trait and a detrimental effect on another.
Similarity in traits, bodily structures or genomic sequences due to shared ancestry between two species. Homology is considered when selecting model systems to study a particular phenotype; however, it does not guarantee underlying functional or mechanistic similarity.
Linked diseases for which decreasing the risk for one increases the risk for the other, such as protection from infectious disease increasing risk for autoimmune disease. Diametric disorders result from evolutionary trade-offs.
An animal that gives birth to live young, rather than laying eggs.
(HARs). Genomic loci conserved across mammalian species that experienced an increase in substitution rate specific to the human lineage. Genetic changes in HARs are responsible for some attributes of human-specific biology.
Rapid decreases in the size of populations that lead to a decrease in genetic diversity. Genetic bottlenecks can be caused by environmental factors (such as famine or disease) or demographic factors (such as migration). The ancestors of most modern non-African populations experienced a bottleneck as they left Africa, which is often referred to as the out-of-Africa bottleneck.
The flow of genetic material between two species through interbreeding followed by backcrossing. Analyses of ancient DNA have revealed that introgression was common in human history over the past several hundred thousand years.
(AMHs). Individuals, both modern and ancient, with the physical characteristics of humans ( Homo sapiens ) living today.
Reduced genetic diversity as a result of a small number of individuals establishing a new population from a larger original population. Founder effects can lead to genetic conditions that were rare in the original population becoming common in the new population. Serial founder effects occurred as anatomically modern humans spread out of Africa and colonized the world.
The component of the genetic load contributed by recent deleterious variants; other factors that contribute to the overall genetic load include the amount of heterozygote advantage and inbreeding.
The creation of novel genotypes from interbreeding between two genetically differentiated populations.
Ancient individuals on the human lineage, such as Neanderthals and Denisovans, that diverged before the origin of anatomically modern humans. Use of this terminology is established in human evolutionary genetics, but is not consistent across fields due to historical differences in the use of taxonomic terms and the fluidity of the species concept in the presence of substantial introgression.
A model proposing that ancestral alleles adapted to ancient environments can increase disease risk in modern environments due to evolutionary mismatches. Many human populations are likely to be subject to such mismatches due to rapidly changing environments.
A hypothesis proposing that immune systems adapted for environments with a high pathogen load are now mismatched to current environments with low pathogen load. This mismatch is further hypothesized to contribute to the higher incidence of autoimmune and inflammatory diseases.
The decrease in population fitness caused by the presence of non-optimal alleles compared with the most fit genotype: ( W max – W mean ) / W max , where W max is the maximum possible fitness and W mean is the average fitness over all observed genotypes.
(PRSs). Results of a mathematical model to estimate the genetic risk of a disease for an individual based on the sum of the effects of all their genetic variants as estimated in a genome-wide association study. The clinical utility of PRSs is a topic of current debate (Box 4 ).
A disease caused by a variant in a single gene, such as sickle cell anaemia, cystic fibrosis and phenylketonuria. Mendelian (also known as monogenic) disorders are usually rare and follow simple dominant or recessive inheritance patterns.
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Benton, M.L., Abraham, A., LaBella, A.L. et al. The influence of evolutionary history on human health and disease. Nat Rev Genet 22 , 269–283 (2021). https://doi.org/10.1038/s41576-020-00305-9
Accepted : 26 October 2020
Published : 06 January 2021
Issue Date : May 2021
DOI : https://doi.org/10.1038/s41576-020-00305-9
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Understanding human genetic variation.
Genetics is the scientific study of inherited variation. Human genetics , then, is the scientific study of inherited human variation.
Why study human genetics? One reason is simply an interest in better understanding ourselves. As a branch of genetics, human genetics concerns itself with what most of us consider to be the most interesting species on earth: Homo sapiens . But our interest in human genetics does not stop at the boundaries of the species, for what we learn about human genetic variation and its sources and transmission inevitably contributes to our understanding of genetics in general, just as the study of variation in other species informs our understanding of our own.
A second reason for studying human genetics is its practical value for human welfare. In this sense, human genetics is more an applied science than a fundamental science. One benefit of studying human genetic variation is the discovery and description of the genetic contribution to many human diseases. This is an increasingly powerful motivation in light of our growing understanding of the contribution that genes make to the development of diseases such as cancer, heart disease, and diabetes. In fact, society has been willing in the past and continues to be willing to pay significant amounts of money for research in this area, primarily because of its perception that such study has enormous potential to improve human health. This perception, and its realization in the discoveries of the past 20 years, have led to a marked increase in the number of people and organizations involved in human genetics.
This second reason for studying human genetics is related to the first. The desire to develop medical practices that can alleviate the suffering associated with human disease has provided strong support to basic research. Many basic biological phenomena have been discovered and described during the course of investigations into particular disease conditions. A classic example is the knowledge about human sex chromosomes that was gained through the study of patients with sex chromosome abnormalities. A more current example is our rapidly increasing understanding of the mechanisms that regulate cell growth and reproduction, understanding that we have gained primarily through a study of genes that, when mutated, increase the risk of cancer.
Likewise, the results of basic research inform and stimulate research into human disease. For example, the development of recombinant DNA techniques ( Figure 3 ) rapidly transformed the study of human genetics, ultimately allowing scientists to study the detailed structure and functions of individual human genes, as well as to manipulate these genes in a variety of previously unimaginable ways.
Recombinant techniques have transformed the study of human genetics.
A third reason for studying human genetics is that it gives us a powerful tool for understanding and describing human evolution. At one time, data from physical anthropology (including information about skin color, body build, and facial traits) were the only source of information available to scholars interested in tracing human evolutionary history. Today, however, researchers have a wealth of genetic data, including molecular data, to call upon in their work.
- How Do Scientists Study Human Genetic Variation?
Two research approaches were historically important in helping investigators understand the biological basis of heredity. The first of these approaches, transmission genetics, involved crossing organisms and studying the offsprings' traits to develop hypotheses about the mechanisms of inheritance. This work demonstrated that in some organisms at least, heredity seems to follow a few definite and rather simple rules.
The second approach involved using cytologic techniques to study the machinery and processes of cellular reproduction. This approach laid a solid foundation for the more conceptual understanding of inheritance that developed as a result of transmission genetics. By the early 1900s, cytologists had demonstrated that heredity is the consequence of the genetic continuity of cells by cell division, had identified the gametes as the vehicles that transmit genetic information from one generation to another, and had collected strong evidence for the central role of the nucleus and the chromosomes in heredity.
As important as they were, the techniques of transmission genetics and cytology were not enough to help scientists understand human genetic variation at the level of detail that is now possible. The central advantage that today's molecular techniques offer is that they allow researchers to study DNA directly. Before the development of these techniques, scientists studying human genetic variation were forced to make inferences about molecular differences from the phenotypes produced by mutant genes. Furthermore, because the genes associated with most single-gene disorders are relatively rare, they could be studied in only a small number of families. Many of the traits associated with these genes also are recessive and so could not be detected in people with heterozygous genotypes. Unlike researchers working with other species, human geneticists are restricted by ethical considerations from performing experimental, "at-will" crosses on human subjects. In addition, human generations are on the order of 20 to 40 years, much too slow to be useful in classic breeding experiments. All of these limitations made identifying and studying genes in humans both tedious and slow.
In the last 50 years, however, beginning with the discovery of the structure of DNA and accelerating significantly with the development of recombinant DNA techniques in the mid-1970s, a growing battery of molecular techniques has made direct study of human DNA a reality. Key among these techniques are restriction analysis and molecular recombination, which allow researchers to cut and rejoin DNA molecules in highly specific and predictable ways; amplification techniques, such as the polymerase chain reaction (PCR), which make it possible to make unlimited copies of any fragment of DNA; hybridization techniques, such as fluorescence in situ hybridization, which allow scientists to compare DNA samples from different sources and to locate specific base sequences within samples; and the automated sequencing techniques that today are allowing workers to sequence the human genome at an unprecedented rate.
On the immediate horizon are even more powerful techniques, techniques that scientists expect will have a formidable impact on the future of both research and clinical genetics. One such technique, DNA chip technology (also called DNA microarray technology), is a revolutionary new tool designed to identify mutations in genes or survey expression of tens of thousands of genes in one experiment.
In one application of this technology, the chip is designed to detect mutations in a particular gene. The DNA microchip consists of a small glass plate encased in plastic. It is manufactured using a process similar to the process used to make computer microchips. On its surface, it contains synthetic single-stranded DNA sequences identical to that of the normal gene and all possible mutations of that gene. To determine whether an individual possesses a mutation in the gene, a scientist first obtains a sample of DNA from the person's blood, as well as a sample of DNA that does not contain a mutation in that gene. After denaturing, or separating, the DNA samples into single strands and cutting them into smaller, more manageable fragments, the scientist labels the fragments with fluorescent dyes: the person's DNA with red dye and the normal DNA with green dye. Both sets of labeled DNA are allowed to hybridize, or bind, to the synthetic DNA on the chip. If the person does not have a mutation in the gene, both DNA samples will hybridize equivalently to the chip and the chip will appear uniformly yellow. However, if the person does possess a mutation, the mutant sequence on the chip will hybridize to the patient's sample, but not to the normal DNA, causing it (the chip) to appear red in that area. The scientist can then examine this area more closely to confirm that a mutation is present.
DNA microarray technology is also allowing scientists to investigate the activity in different cell types of thousands of genes at the same time, an advance that will help researchers determine the complex functional relationships that exist between individual genes. This type of analysis involves placing small snippets of DNA from hundreds or thousands of genes on a single microscope slide, then allowing fluorescently labeled mRNA molecules from a particular cell type to hybridize to them. By measuring the fluorescence of each spot on the slide, scientists can determine how active various genes are in that cell type. Strong fluorescence indicates that many mRNA molecules hybridized to the gene and, therefore, that the gene is very active in that cell type. Conversely, no fluorescence indicates that none of the cell's mRNA molecules hybridized to the gene and that the gene is inactive in that cell type.
Although these technologies are still relatively new and are being used primarily for research, scientists expect that one day they will have significant clinical applications. For example, DNA chip technology has the potential to significantly reduce the time and expense involved in genetic testing. This technology or others like it may one day help make it possible to define an individual's risk of developing many types of hereditary cancer as well as other common disorders, such as heart disease and diabetes. Likewise, scientists may one day be able to classify human cancers based on the patterns of gene activity in the tumor cells and then be able to design treatment strategies that are targeted directly to each specific type of cancer.
- How Much Genetic Variation Exists Among Humans?
Homo sapiens is a relatively young species and has not had as much time to accumulate genetic variation as have the vast majority of species on earth, most of which predate humans by enormous expanses of time. Nonetheless, there is considerable genetic variation in our species. The human genome comprises about 3 × 10 9 base pairs of DNA, and the extent of human genetic variation is such that no two humans, save identical twins, ever have been or will be genetically identical. Between any two humans, the amount of genetic variation—biochemical individuality—is about .1 percent. This means that about one base pair out of every 1,000 will be different between any two individuals. Any two (diploid) people have about 6 × 10 6 base pairs that are different, an important reason for the development of automated procedures to analyze genetic variation.
The most common polymorphisms (or genetic differences) in the human genome are single base-pair differences. Scientists call these differences SNPs, for single-nucleotide polymorphisms. When two different haploid genomes are compared, SNPs occur, on average, about every 1,000 bases. Other types of polymorphisms—for example, differences in copy number, insertions, deletions, duplications, and rearrangements—also occur, but much less frequently.
Notwithstanding the genetic differences between individuals, all humans have a great deal of their genetic information in common. These similarities help define us as a species. Furthermore, genetic variation around the world is distributed in a rather continuous manner; there are no sharp, discontinuous boundaries between human population groups. In fact, research results consistently demonstrate that about 85 percent of all human genetic variation exists within human populations, whereas about only 15 percent of variation exists between populations ( Figure 4 ). That is, research reveals that Homo sapiens is one continuously variable, interbreeding species. Ongoing investigation of human genetic variation has even led biologists and physical anthropologists to rethink traditional notions of human racial groups. The amount of genetic variation between these traditional classifications actually falls below the level that taxonomists use to designate subspecies, the taxonomic category for other species that corresponds to the designation of race in Homo sapiens . This finding has caused some biologists to call the validity of race as a biological construct into serious question.
Most variation occurs within populations.
Analysis of human genetic variation also confirms that humans share much of their genetic information with the rest of the natural world—an indication of the relatedness of all life by descent with modification from common ancestors. The highly conserved nature of many genetic regions across considerable evolutionary distance is especially obvious in genes related to development. For example, mutations in the patched gene produce developmental abnormalities in Drosophila , and mutations in the patched homolog in humans produce analogous structural deformities in the developing human embryo.
Geneticists have used the reality of evolutionary conservation to detect genetic variations associated with some cancers. For example, mutations in the genes responsible for repair of DNA mismatches that arise during DNA replication are associated with one form of colon cancer. These mismatched repair genes are conserved in evolutionary history all the way back to the bacterium Escherichia coli , where the genes are designated Mut l and Mut s. Geneticists suspected that this form of colon cancer was associated with a failure of mismatch repair, and they used the known sequences from the E. coli genes to probe the human genome for homologous sequences. This work led ultimately to the identification of a gene that is associated with increased risk for colon cancer.
- What Is the Significance of Human Genetic Variation?
Almost all human genetic variation is relatively insignificant biologically; that is, it has no adaptive significance. Some variation (for example, a neutral mutation) alters the amino acid sequence of the resulting protein but produces no detectable change in its function. Other variation (for example, a silent mutation) does not even change the amino acid sequence. Furthermore, only a small percentage of the DNA sequences in the human genome are coding sequences (sequences that are ultimately translated into protein) or regulatory sequences (sequences that can influence the level, timing, and tissue specificity of gene expression). Differences that occur elsewhere in the DNA—in the vast majority of the DNA that has no known function—have no impact.
Some genetic variation, however, can be positive, providing an advantage in changing environments. The classic example from the high school biology curriculum is the mutation for sickle hemoglobin, which in the heterozygous state provides a selective advantage in areas where malaria is endemic.
More recent examples include mutations in the CCR5 gene that appear to provide protection against AIDS. The CCR5 gene encodes a protein on the surface of human immune cells. HIV, the virus that causes AIDS, infects immune cells by binding to this protein and another protein on the surface of those cells. Mutations in the CCR5 gene that alter its level of expression or the structure of the resulting protein can decrease HIV infection. Early research on one genetic variant indicates that it may have risen to high frequency in Northern Europe about 700 years ago, at about the time of the European epidemic of bubonic plague. This finding has led some scientists to hypothesize that the CCR5 mutation may have provided protection against infection by Yersinia pestis , the bacterium that causes plague. The fact that HIV and Y. pestis both infect macrophages supports the argument for selective advantage of this genetic variant.
The sickle cell and AIDS/plague stories remind us that the biological significance of genetic variation depends on the environment in which genes are expressed. It also reminds us that differential selection and evolution would not proceed in the absence of genetic variation within a species.
Some genetic variation, of course, is associated with disease, as classic single-gene disorders such as sickle cell disease, cystic fibrosis, and Duchenne muscular dystrophy remind us. Increasingly, research also is uncovering genetic variations associated with the more common diseases that are among the major causes of sickness and death in developed countries—diseases such as heart disease, cancer, diabetes, and psychiatric disorders such as schizophrenia and bipolar disease (manic-depression). Whereas disorders such as cystic fibrosis or Huntington disease result from the effects of mutation in a single gene and are evident in virtually all environments, the more common diseases result from the interaction of multiple genes and environmental variables. Such diseases therefore are termed polygenic and multifactorial . In fact, the vast majority of human traits, diseases or otherwise, are multifactorial.
The genetic distinctions between relatively rare single-gene disorders and the more common multifactorial diseases are significant. Genetic variations that underlie single-gene disorders generally are relatively recent, and they often have a major, detrimental impact, disrupting homeostasis in significant ways. Such disorders also generally exact their toll early in life, often before the end of childhood. In contrast, the genetic variations that underlie common, multifactorial diseases generally are of older origin and have a smaller, more gradual effect on homeostasis. They also generally have their onset in adulthood. The last two characteristics make the ability to detect genetic variations that predispose/increase risk of common diseases especially valuable because people have time to modify their behavior in ways that can reduce the likelihood that the disease will develop, even against a background of genetic predisposition.
- How Is Our Understanding of Human Genetic Variation Affecting Medicine?
As noted earlier, one of the benefits of understanding human genetic variation is its practical value for understanding and promoting health and for understanding and combating disease. We probably cannot overestimate the importance of this benefit. First, as Figure 5 shows, virtually every human disease has a genetic component. In some diseases, such as Huntington disease, Tay-Sachs disease, and cystic fibrosis, this component is very large. In other diseases, such as cancer, diabetes, and heart disease, the genetic component is more modest. In fact, we do not typically think of these diseases as "genetic diseases," because we inherit not the certainty of developing a disease, but only a predisposition to developing it.
Virtually all human diseases, except perhaps trauma, have a genetic component.
In still other diseases, the genetic component is very small. The crucial point, however, is that it is there. Even infectious diseases, diseases that we have traditionally placed in a completely different category than genetic disorders, have a real, albeit small, genetic component. For example, as the CCR5 example described earlier illustrates, even AIDS is influenced by a person's genotype. In fact, some people appear to have genetic resistance to HIV infection as a result of carrying a variant of the CCR5 gene.
Second, each of us is at some genetic risk, and therefore can benefit, at least theoretically, from the progress scientists are making in understanding and learning how to respond to these risks. Scientists estimate that each of us carries between 5 and 50 mutations that carry some risk for disease or disability. Some of us may not experience negative consequences from the mutations we carry, either because we do not live long enough for it to happen or because we may not be exposed to the relevant environmental triggers. The reality, however, is that the potential for negative consequences from our genes exists for each of us.
How is modern genetics helping us address the challenge of human disease? As Figure 6 shows, modern genetic analysis of a human disease begins with mapping and cloning the associated gene or genes. Some of the earliest disease genes to be mapped and cloned were the genes associated with Duchenne muscular dystrophy, retinoblastoma, and cystic fibrosis. More recently, scientists have announced the cloning of genes for breast cancer, diabetes, and Parkinson disease.
Mapping and cloning a gene can lead to strategies that reduce the risk of disease (preventive medicine); guidelines for prescribing drugs based on a person's genotype (pharmacogenomics); procedures that alter the affected gene (gene therapy); or drugs (more...)
As Figure 6 also shows, mapping and cloning a disease-related gene opens the way for the development of a variety of new health care strategies. At one end of the spectrum are genetic tests intended to identify people at increased risk for the disease and recognize genotypic differences that have implications for effective treatment. At the other end are new drug and gene therapies that specifically target the biochemical mechanisms that underlie the disease symptoms or even replace, manipulate, or supplement nonfunctional genes with functional ones. Indeed, as Figure 6 suggests, we are entering the era of molecular medicine.
Genetic testing is not a new health care strategy. Newborn screening for diseases like PKU has been going on for 30 years in many states. Nevertheless, the remarkable progress scientists are making in mapping and cloning human disease genes brings with it the prospect for the development of more genetic tests in the future. The availability of such tests can have a significant impact on the way the public perceives a particular disease and can also change the pattern of care that people in affected families might seek and receive. For example, the identification of the BRCA1 and BRCA2 genes and the demonstration that particular variants of these genes are associated with an increased risk of breast and ovarian cancer have paved the way for the development of guidelines and protocols for testing individuals with a family history of these diseases. BRCA1 , located on the long arm of chromosome 17, was the first to be isolated, and variants of this gene account for about 50 percent of all inherited breast cancer, or about 5 percent of all breast cancer. Variants of BRCA2 , located on the long arm of chromosome 13, appear to account for about 30 to 40 percent of all inherited breast cancer. Variants of these genes also increase slightly the risk for men of developing breast, prostate, or possibly other cancers.
Scientists estimate that hundreds of thousands of women in the United States have 1 of hundreds of significant mutations already detected in the BRCA1 gene. For a woman with a family history of breast cancer, the knowledge that she carries one of the variants of BRCA1 or BRCA2 associated with increased risk can be important information. If she does carry one of these variants, she and her physician can consider several changes in her health care, such as increasing the frequency of physical examinations; introducing mammography at an earlier age; and even having prophylactic mastectomy. In the future, drugs may also be available that decrease the risk of developing breast cancer.
The ability to test for the presence in individuals of particular gene variants is also changing the way drugs are prescribed and developed. A rapidly growing field known as pharmacogenomics focuses on crucial genetic differences that cause drugs to work well in some people and less well, or with dangerous adverse reactions, in others. For example, researchers investigating Alzheimer disease have found that the way patients respond to drug treatment can depend on which of three genetic variants of the ApoE (Apolipoprotein E) gene a person carries. Likewise, some of the variability in children's responses to therapeutic doses of albuterol, a drug used to treat asthma, was recently linked to genotypic differences in the beta-2-adrenergic receptor. Because beta-2-adrenergic receptor agonists (of which albuterol is one) are the most widely used agents in the treatment of asthma, these results may have profound implications for understanding the genetic factors that determine an individual's response to asthma therapy.
Experts predict that increasingly in the future, physicians will use genetic tests to match drugs to an individual patient's body chemistry, so that the safest and most effective drugs and dosages can be prescribed. After identifying the genotypes that determine individual responses to particular drugs, pharmaceutical companies also likely will set out to develop new, highly specific drugs and revive older ones whose effects seemed in the past too unpredictable to be of clinical value.
Knowledge of the molecular structure of disease-related genes also is changing the way researchers approach developing new drugs. A striking example followed the discovery in 1989 of the gene associated with cystic fibrosis (CF). Researchers began to study the function of the normal and defective proteins involved in order to understand the biochemical consequences of the gene's variant forms and to develop new treatment strategies based on that knowledge. The normal protein, called CFTR for cystic fibrosis transmembrane conductance regulator, is embedded in the membranes of several cell types in the body, where it serves as a channel, transporting chloride ions out of the cells. In CF patients, depending on the particular mutation the individual carries, the CFTR protein may be reduced or missing from the cell membrane, or may be present but not function properly. In some mutations, synthesis of CFTR protein is interrupted, and the cells produce no CFTR molecules at all.
Although all of the mutations associated with CF impair chloride transport, the consequences for patients with different mutations vary. For example, patients with mutations causing absent or markedly reduced CFTR protein may have more severe disease than patients with mutations in which CFTR is present but has altered function. The different mutations also suggest different treatment strategies. For example, the most common CF-related mutation (called delta F508) leads to the production of protein molecules (called delta F508 CFTR) that are misprocessed and are degraded prematurely before they reach the cell membrane. This finding suggests that drug treatments that would enhance transport of the defective delta F508 protein to the cell membrane or prevent its degradation could yield important benefits for patients with delta F508 CFTR.
Finally, the identification, cloning, and sequencing of a disease-related gene can open the door to the development of strategies for treating the disease using the instructions encoded in the gene itself. Collectively referred to as gene therapy , these strategies typically involve adding a copy of the normal variant of a disease-related gene to a patient's cells. The most familiar examples of this type of gene therapy are cases in which researchers use a vector to introduce the normal variant of a disease-related gene into a patient's cells and then return those cells to the patient's body to provide the function that was missing. This strategy was first used in the early 1990s to introduce the normal allele of the adenosine deaminase (ADA) gene into the body of a little girl who had been born with ADA deficiency. In this disease, an abnormal variant of the ADA gene fails to make adenosine deaminase, a protein that is required for the correct functioning of T-lymphocytes.
Although researchers are continuing to refine this general approach to gene therapy, they also are developing new approaches. For example, scientists hope that one very new strategy, called chimeraplasty, may one day be used to actually correct genetic defects that involve only a single base change. Chimeraplasty uses specially synthesized molecules that base pair with a patient's DNA and stimulate the cell's normal DNA repair mechanisms to remove the incorrect base and substitute the correct one. At this point, chimeraplasty is still in early development and the first clinical trials are about to get underway.
Yet another approach to gene therapy involves providing new or altered functions to a cell through the introduction of new genetic information. For example, recent experiments have demonstrated that it is possible, under carefully controlled experimental conditions, to introduce genetic information into cancer cells that will alter their metabolism so that they commit suicide when exposed to a normally innocuous environmental trigger. Researchers are also using similar experiments to investigate the feasibility of introducing genetic changes into cells that will make them immune to infection by HIV. Although this research is currently being done only in nonhuman primates, it may eventually benefit patients infected with HIV.
As Figure 6 indicates, the Human Genome Project (HGP) has significantly accelerated the pace of both the discovery of human genes and the development of new health care strategies based on a knowledge of a gene's structure and function. The new knowledge and technologies emerging from HGP-related research also are reducing the cost of finding human genes. For example, the search for the gene associated with cystic fibrosis, which ended in 1989, before the inception of the HGP, required more than eight years and $50 million. In contrast, finding a gene associated with a Mendelian disorder now can be accomplished in less than a year at a cost of approximately $100,000.
The last few years of research into human genetic variation also have seen a gradual transition from a primary focus on genes associated with single-gene disorders, which are relatively rare in the human population, to an increasing focus on genes associated with multifactorial diseases. Because these diseases are not rare, we can expect that this work will affect many more people. Understanding the genetic and environmental bases for these multifactorial diseases also will lead to increased testing and the development of new interventions that likely will have an enormous effect on the practice of medicine in the next century.
- Genetics, Ethics, and Society
What are the implications of using our growing knowledge of human genetic variation to improve personal and public health? As noted earlier, the rapid pace of the discovery of genetic factors in disease has improved our ability to predict the risk of disease in asymptomatic individuals. We have learned how to prevent the manifestations of some of these diseases, and we are developing the capacity to treat others.
Yet, much remains unknown about the benefits and risks of building an understanding of human genetic variation at the molecular level. While this information would have the potential to dramatically improve human health, the architects of the HGP realized that it also would raise a number of complex ethical, legal, and social issues. Thus, in 1990 they established the Ethical, Legal, and Social Implications (ELSI) program to anticipate and address the ethical, legal, and social issues that arise from human genetic research. This program, perhaps more than any other, has focused public attention, as well as the attention of educators, on the increasing importance of preparing citizens to understand and contribute to the ongoing public dialogue related to advances in genetics.
Ethics is the study of right and wrong, good and bad. It has to do with the actions and character of individuals, families, communities, institutions, and societies. During the last two and one-half millennia, Western philosophy has developed a variety of powerful methods and a reliable set of concepts and technical terms for studying and talking about the ethical life. Generally speaking, we apply the terms "right" and "good" to those actions and qualities that foster the interests of individuals, families, communities, institutions, and society. Here, an "interest" refers to a participant's share or participation in a situation. The terms "wrong" or "bad" apply to those actions and qualities that impair interests.
Ethical considerations are complex, multifaceted, and raise many questions. Often, there are competing, well-reasoned answers to questions about what is right and wrong, and good and bad, about an individual's or group's conduct or actions. Typically, these answers all involve appeals to values. A value is something that has significance or worth in a given situation. One of the exciting events to witness in any discussion in ethics is the varying ways in which the individuals involved assign values to things, persons, and states of affairs. Examples of values that students may appeal to in a discussion about ethics include autonomy, freedom, privacy, sanctity of life, religion, protecting another from harm, promoting another's good, justice, fairness, relationships, scientific knowledge, and technological progress.
Acknowledging the complex, multifaceted nature of ethical discussions is not to suggest that "anything goes." Experts generally agree on the following features of ethics. First, ethics is a process of rational inquiry. It involves posing clearly formulated questions and seeking well-reasoned answers to those questions. For example, we can ask questions about an individual's right to privacy regarding personal genetic information; we also can ask questions about the appropriateness of particular uses of gene therapy. Well-reasoned answers to such questions constitute arguments . Ethical analysis and argument, then, result from successful ethical inquiry.
Second, ethics requires a solid foundation of information and rigorous interpretation of that information. For example, one must have a solid understanding of biology to evaluate the recent decision by the Icelandic government to create a database that will contain extensive genetic and medical information about the country's citizens. A knowledge of science also is needed to discuss the ethics of genetic screening or of germ-line gene therapy. Ethics is not strictly a theoretical discipline but is concerned in vital ways with practical matters.
Third, discussions of ethical issues often lead to the identification of very different answers to questions about what is right and wrong and good and bad. This is especially true in a society such as our own, which is characterized by a diversity of perspectives and values. Consider, for example, the question of whether adolescents should be tested for late-onset genetic conditions. Genetic testing centers routinely withhold genetic tests for Huntington disease (HD) from asymptomatic patients under the age of 18. The rationale is that the condition expresses itself later in life and, at present, treatment is unavailable. Therefore, there is no immediate, physical health benefit for a minor from a specific diagnosis based on genetic testing. In addition, there is concern about the psychological effects of knowing that later in life one will get a debilitating, life-threatening condition. Teenagers can wait until they are adults to decide what and when they would like to know. In response, some argue that many adolescents and young children do have sufficient autonomy in consent and decision making and may wish to know their future. Others argue that parents should have the right to have their children tested, because parents make many other medical decisions on behalf of their children. This example illustrates how the tools of ethics can bring clarity and rigor to discussions involving values.
One of the goals of this module is to help students see how understanding science can help individuals and society make reasoned decisions about issues related to genetics and health. Activity 5, Making Decisions in the Face of Uncertainty , presents students with a case of a woman who is concerned that she may carry an altered gene that predisposes her to breast and ovarian cancer. The woman is faced with numerous decisions, which students also consider. Thus, the focus of Activity 5 is prudential decision making, which involves the ability to avoid unnecessary risk when it is uncertain whether an event actually will occur. By completing the activity, students understand that uncertainty is often a feature of questions related to genetics and health, because our knowledge of genetics is incomplete and constantly changing. In addition, students see that making decisions about an uncertain future is complex. In simple terms, students have to ask themselves, "How bad is the outcome and how likely is it to occur?" When the issues are weighed, different outcomes are possible, depending on one's estimate of the incidence of the occurrence and how much burden one attaches to the risk.
Clearly, science as well as ethics play important roles in helping individuals make choices about individual and public health. Science provides evidence that can help us understand and treat human disease, illness, deformity, and dysfunction. And ethics provides a framework for identifying and clarifying values and the choices that flow from these values. But the relationships between scientific information and human choices, and between choices and behaviors, are not straightforward. In other words, human choice allows individuals to choose against sound knowledge, and choice does not require action.
Nevertheless, it is increasingly difficult to deny the claims of science. We are continually presented with great amounts of relevant scientific and medical knowledge that is publicly accessible. As a consequence, we can think about the relationships between knowledge, choice, behavior, and human welfare in the following ways:
One of the goals of this module is to encourage students to think in terms of these relationships, now and as they grow older.
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The following glossary was modified from the glossary on the National Human Genome Research Institute's Web site, available at http://www.nhgri.nih.gov .
One of the variant forms of a gene at a particular locus, or location, on a chromosome. Different alleles produce variation in inherited characteristics such as hair color or blood type. In an individual, one form of the allele (the dominant one) may be expressed more than another form (the recessive one).
One of 20 different kinds of small molecules that link together in long chains to form proteins. Amino acids are referred to as the "building blocks" of proteins.
Gene on one of the autosomes that, if present, will almost always produce a specific trait or disease. The chance of passing the gene (and therefore the disease) to children is 50-50 in each pregnancy.
Chromosome other than a sex chromosome. Humans have 22 pairs of autosomes.
Two bases that form a "rung of the DNA ladder." The bases are the "letters" that spell out the genetic code. In DNA, the code letters are A, T, G, and C, which stand for the chemicals adenine, thymine, guanine, and cytosine, respectively. In base pairing, adenine always pairs with thymine, and guanine always pairs with cytosine.
Defect present at birth, whether caused by mutant genes or by prenatal events that are not genetic.
First breast cancer genes to be identified. Mutated forms of these genes are believed to be responsible for about one-half the cases of inherited breast cancer, especially those that occur in younger women, and also to increase a woman's risk for ovarian cancer. Both are tumor suppressor genes.
Diseases in which abnormal cells divide and grow unchecked. Cancer can spread from its original site to other parts of the body and can be fatal if not treated adequately.
Gene, located in a chromosome region suspected of being involved in a disease, whose protein product suggests that it could be the disease gene in question.
Mutation that confers immunity to infection by HIV. The mutation alters the structure of a receptor on the surface of macrophages such that HIV cannot enter the cell.
Collection of DNA sequences generated from mRNA sequences. This type of library contains only protein-coding DNA (genes) and does not include any noncoding DNA.
Basic unit of any living organism. It is a small, watery, compartment filled with chemicals and a complete copy of the organism's genome.
One of the thread like "packages" of genes and other DNA in the nucleus of a cell. Different kinds of organisms have different numbers of chromosomes. Humans have 23 pairs of chromosomes, 46 in all: 44 autosomes and two sex chromosomes. Each parent contributes one chromosome to each pair, so children get one-half of their chromosomes from their mothers and one-half from their fathers.
Process of making copies of a specific piece of DNA, usually a gene. When geneticists speak of cloning, they do not mean the process of making genetically identical copies of an entire organism.
Three bases in a DNA or RNA sequence that specify a single amino acid.
Hereditary disease whose symptoms usually appear shortly after birth. They include faulty digestion, breathing difficulties and respiratory infections due to mucus accumulation, and excessive loss of salt in sweat. In the past, cystic fibrosis was almost always fatal in childhood, but treatment is now so improved that patients commonly live to their 20s and beyond.
Visual appearance of a chromo some when stained and examined under a microscope. Particularly important are visually distinct regions, called light and dark bands, that give each of the chromosomes a unique appearance. This feature allows a person's chromosomes to be studied in a clinical test known as a karyotype, which allows scientists to look for chromosomal alterations.
Particular kind of mutation: loss of a piece of DNA from a chromosome. Deletion of a gene or part of a gene can lead to a disease or abnormality.
Chemical inside the nucleus of a cell that carries the genetic instructions for making living organisms.
Number of chromosomes in most cells except the gametes. In humans, the diploid number is 46.
Technology that identifies mutations in genes. It uses small glass plates that contain synthetic single-stranded DNA sequences identical to those of a normal gene.
Process by which the DNA double helix unwinds and makes an exact copy of itself.
Determining the exact order of the base pairs in a segment of DNA.
Gene that almost always results in a specific physical characteristic (for example, a disease) even though the patient's genome possesses only one copy. With a dominant gene, the chance of passing on the gene (and therefore the disease) to children is 50-50 in each pregnancy.
Structural arrangement of DNA, which looks something like an immensely long ladder twisted into a helix, or coil. The sides of the "ladder" are formed by a backbone of sugar and phosphate molecules, and the "rungs" consist of nucleotide bases joined weakly in the middle by hydrogen bonds.
Particular kind of mutation: production of one or more copies of any piece of DNA, including a gene or even an entire chromosome.
Process in which molecules (such as proteins, DNA, or RNA fragments) can be separated according to size and electrical charge by applying an electric current to them. The current forces the molecules through pores in a thin layer of gel, a firm, jellylike substance. The gel can be made so that its pores are just the right dimensions for separating molecules within a specific range of sizes and shapes. Smaller fragments usually travel further than large ones. The process is sometimes called gel electrophoresis.
Protein that encourages a specific biochemical reaction, usually speeding it up. Organisms could not function if they had no enzymes.
Region of a gene that contains the code for producing the gene's protein. Each exon codes for a specific portion of the complete protein. In some species (including humans), a gene's exons are separated by long regions of DNA (called "introns" or sometimes "junk DNA") that have no apparent function.
Process that vividly paints chromosomes or portions of chromosomes with fluorescent molecules. This technique is useful for identifying chromosomal abnormalities and gene mapping.
Functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein.
Increase in the number of copies of any particular piece of DNA. A tumor cell amplifies, or copies, DNA segments naturally as a result of cell signals and sometimes environmental events.
Highly specific process in which a gene is switched on at a certain time and begins production of its protein.
Determining the relative positions of genes on a chromosome and the distance between them.
Sum total of genes, with all their variations, possessed by a particular species at a particular time.
Evolving technique used to treat inherited diseases. The medical procedure involves either replacing, manipulating, or supplementing nonfunctional genes with healthy genes.
Insertion of unrelated DNA into the cells of an organism. There are many different reasons for gene transfer, for example, attempting to treat disease by supplying patients with therapeutic genes. There are also many possible ways to trans fer genes. Most involve the use of a vector, such as a specially modified virus that can take the gene along when it enters the cell.
Instructions in a gene that tell the cell how to make a specific protein. A, T, G, and C are the "letters" of the DNA code; they stand for the chemicals adenine, thymine, guanine, and cytosine, respectively, that make up the nucleotide bases of DNA. Each gene's code combines the four chemicals in various ways to spell out three-letter "words" that specify which amino acid is needed at every step in making a protein.
Short-term educational counseling process for individuals and families who have a genetic disease or who are at risk for such a disease. Genetic counseling provides patients with information about their condition and helps them make informed decisions.
Chromosome map of a species that shows the position of its known genes and/or markers relative to each other, rather than as specific physical points on each chromosome.
Segment of DNA with an identifiable physical location on a chromosome and whose inheritance can be followed. A marker can be a gene, or it can be some section of DNA with no known function. Because DNA segments that lie near each other on a chromosome tend to be inherited together, markers are often used as indirect ways of tracking the inheritance pattern of a gene that has not yet been identified, but whose approximate or exact location is known.
Testing a population group to identify a subset of individuals at high risk for having or transmitting a specific genetic disorder.
Study of inherited variation.
All the DNA contained in an organism or a cell, which includes both the chromosomes within the nucleus and the DNA in mitochondria.
Genetic identity of an individual that does not show as outward characteristics.
Sequence of cells, each descended from earlier cells in the lineage, that will develop into new sperm and egg cells for the subsequent generation.
Number of chromosomes in a sperm or egg cell; one-half the diploid number.
Possessing two different forms of a particular gene, one inherited from each parent.
DNA sequence that is very similar in several different kinds of organisms. Scientists regard these cross species' similarities as evidence that a specific gene performs some basic function essential to many forms of life and that evolution has therefore conserved its structure by permitting few mutations to accumulate in it.
Possessing two identical forms of a particular gene, one inherited from each parent.
International research project to map each human gene and to completely sequence human DNA.
Base pairing of two single strands of DNA or RNA.
Base pairing of a sequence of DNA to metaphase chromosomes on a microscope slide.
Transmitted through genes from parents to offspring.
Type of chromosomal abnormality in which a DNAsequence is inserted into a gene, disrupting the normal structure and function of that gene.
Collection of cloned DNA, usually from a specific organism.
Association of genes and/or markers that lie near each other on a chromosome. Linked genes and markers tend to be inherited together.
Place on a chromosome where a specific gene is located; a kind of address for the gene.
Process of deducing schematic representations of DNA. Three types of DNA maps can be constructed: physical maps, genetic maps, and cytogenetic maps; the key distinguishing feature among these three types is the landmarks on which they are based.
Also known as a genetic marker, a segment of DNA with an identifiable physical location on a chromosome whose inheritance can be followed. A marker can be a gene, or it can be some section of DNA with no known function. Because DNA segments that lie near each other on a chromosome tend to be inherited together, markers are often used as indirect ways of tracking the inheritance pattern of genes that have not yet been identified, but whose approximate locations are known.
Manner in which genes and traits are passed from parents to children. Examples of Mendelian inheritance include autosomal dominant, autosomal recessive, and sex-linked genes.
Template for protein synthesis. Each set of three bases, called a codon, specifies a certain amino acid in the sequence of amino acids that compose the protein. The sequence of a strand of mRNA is based on the sequence of a complementary strand of DNA.
Phase of mitosis, or cell division, when the chromosomes align along the center of the cell. Because metaphase chromosomes are highly condensed, scientists use these chromosomes for gene mapping and identifying chromosomal aberrations.
New way of studying how large numbers of genes interact with each other and how a cell's regulatory networks control vast batteries of genes simultaneously. The method uses a robot to precisely apply tiny droplets containing functional DNA to glass slides. Researchers then attach fluorescent labels to DNA from the cell they are studying. The labeled probes are allowed to bind to complementary DNA strands on the slides. The slides are put into a scanning microscope that can measure the brightness of each fluorescent dot; brightness reveals how much of a specific DNA fragment is present, an indicator of how active it is.
Genetic material of the mitochondria, the organelles that generate energy for the cell.
Trait that is controlled by many genes and is also influenced by the environment.
Permanent structural alteration in DNA. In most cases, such DNA changes either have no effect or cause harm, but occasionally a mutation can improve an organism's chance of surviving and passing the beneficial change on to its descendants.
Mutation that results in a changed amino acid sequence, but does not alter the protein's function.
One of the structural components, or building blocks, of DNA and RNA. A nucleotide consists of a base (one of four chemicals: adenine, thymine, guanine, and cytosine) plus a molecule of sugar and one of phosphoric acid.
Central cell structure that houses the chromosomes.
Oligonucleotide, short sequence of single-stranded DNA or RNA. Oligos are often used as probes for detecting complementary DNA or RNA because they bind readily to their complements.
Gene that is capable of causing the transformation of normal cells into cancer cells.
Simplified diagram of a family's genealogy that shows family members' relationships to each other and how a particular trait or disease has been inherited.
Study of genetic variation underlying differential response to drugs.
Observable traits or characteristics of an organism, for example, hair color, weight, or the presence or absence of a disease. Phenotypic traits are not necessarily genetic.
Chromosome map of a species that shows the specific physical locations of its genes and/or markers on each chromosome. Physical maps are particularly important when searching for disease genes by positional cloning strategies and for DNA sequencing.
Fast, inexpensive technique for making an unlimited number of copies of any piece of DNA. Sometimes called "molecular photocopying," PCR has had an immense impact on biology and medicine, especially genetic research.
Gene that exists in more than one version (allele), and where the rare allele can be found in more than 2 percent of the population.
Genetic trait that appears only in people who have received two copies of a mutant gene, one from each parent.
Enzyme that recognizes specific nucleotide sequences in DNA and cuts the DNA molecule at these points.
Chemical similar to a single strand of DNA. In RNA, the letter U, which stands for uracil, is substituted for T (thymine) in the genetic code. RNA delivers DNA's genetic message to the cytoplasm of a cell where proteins are made.
Cellular organelle that is the site of protein synthesis.
Short DNA segment that occurs only once in the human genome and whose exact location and order of bases are known. Because each is unique, STSs are helpful for chromosome placement of mapping and sequencing data from many different laboratories. STSs serve as landmarks on the physical map of the human genome.
One of the two chromosomes that specify an organism's genetic sex. Humans have two kinds of sex chromosomes, one called X and the other Y. Normal females possess two X chromosomes and normal males one X and one Y.
Located on the X chromosome. Sex-linked (or X-linked) diseases are generally seen only in males.
Mutation that results in an unchanged amino acid sequence and thus in a protein with normal function.
Difference in a single base of DNA.
Any of the body's cells, except the reproductive cells.
Strategy for making cancer cells more vulnerable to chemotherapy. One approach has been to link parts of genes expressed in cancer cells to other genes for enzymes not found in mammals that can convert a harmless substance into one that is toxic to the tumor.
Drug that, when tested in clinical trials, reduced by about half the development of breast cancer in women taking the drug as compared with women taking a placebo.
Experimentally produced organism in which DNA has been artificially introduced and incorporated into the organism's germ line, usually by injecting the foreign DNA into the nucleus of a fertilized embryo.
Breakage and removal of a large segment of DNA from one chromosome, followed by the segment's attachment to a different chromo some.
Possessing three copies of a particular chromosome instead of the normal two copies.
Protective gene that normally limits the growth of tumors. When a tumor suppressor is mutated, it may fail to keep a cancer from growing. BRCA1 and p53 are well-known tumor suppressor genes.
Agent that transfers material from one organism to another. For example, a virus can be a vector for the transfer of a gene.
- Cite this Page National Institutes of Health (US); Biological Sciences Curriculum Study. NIH Curriculum Supplement Series [Internet]. Bethesda (MD): National Institutes of Health (US); 2007. Understanding Human Genetic Variation.
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Written by the educator who created What Makes Us Human?, a brief look at the key facts, tough questions and big ideas in his field. Begin this TED Study with a fascinating read that gives context and clarity to the material.
As a biological anthropologist, I never liked drawing sharp distinctions between human and non-human. Such boundaries make little evolutionary sense, as they ignore or grossly underestimate what we humans have in common with our ancestors and other primates. What's more, it's impossible to make sharp distinctions between human and non-human in the paleoanthropological record. Even with a time machine, we couldn't go back to identify one generation of humans and say that the previous generation contained none: one's biological parents, by definition, must be in the same species as their offspring. This notion of continuity is inherent to most evolutionary perspectives and it's reflected in the similarities (homologies) shared among very different species. As a result, I've always been more interested in what makes us similar to, not different from, non-humans.
Evolutionary research has clearly revealed that we share great biological continuity with others in the animal kingdom. Yet humans are truly unique in ways that have not only shaped our own evolution, but have altered the entire planet. Despite great continuity and similarity with our fellow primates, our biocultural evolution has produced significant, profound discontinuities in how we interact with each other and in our environment, where no precedent exists in other animals. Although we share similar underlying evolved traits with other species, we also display uses of those traits that are so novel and extraordinary that they often make us forget about our commonalities. Preparing a twig to fish for termites may seem comparable to preparing a stone to produce a sharp flake—but landing on the moon and being able to return to tell the story is truly out of this non-human world.
Humans are the sole hominin species in existence today. Thus, it's easier than it would have been in the ancient past to distinguish ourselves from our closest living relatives in the animal kingdom. Primatologists such as Jane Goodall and Frans de Waal, however, continue to clarify why the lines dividing human from non-human aren't as distinct as we might think. Goodall's classic observations of chimpanzee behaviors like tool use, warfare and even cannibalism demolished once-cherished views of what separates us from other primates. de Waal has done exceptional work illustrating some continuity in reciprocity and fairness, and in empathy and compassion, with other species. With evolution, it seems, we are always standing on the shoulders of others, our common ancestors.
Primatology—the study of living primates—is only one of several approaches that biological anthropologists use to understand what makes us human. Two others, paleoanthropology (which studies human origins through the fossil record) and molecular anthropology (which studies human origins through genetic analysis), also yield some surprising insights about our hominin relatives. For example, Zeresenay Alemsegad's painstaking field work and analysis of Selam, a 3.3 million-year old fossil of a 3-year-old australopithecine infant from Ethiopia, exemplifies how paleoanthropologists can blur boundaries between living humans and apes.
Selam, if alive today, would not be confused with a three-year-old human—but neither would we mistake her for a living ape. Selam's chimpanzee-like hyoid bone suggests a more ape-like form of vocal communication, rather than human language capability. Overall, she would look chimp-like in many respects—until she walked past you on two feet. In addition, based on Selam's brain development, Alemseged theorizes that Selam and her contemporaries experienced a human-like extended childhood with a complex social organization.
Fast-forward to the time when Neanderthals lived, about 130,000 – 30,000 years ago, and most paleoanthropologists would agree that language capacity among the Neanderthals was far more human-like than ape-like; in the Neanderthal fossil record, hyoids and other possible evidence of language can be found. Moreover, paleogeneticist Svante Pääbo's groundbreaking research in molecular anthropology strongly suggests that Neanderthals interbred with modern humans. Paabo's work informs our genetic understanding of relationships to ancient hominins in ways that one could hardly imagine not long ago—by extracting and comparing DNA from fossils comprised largely of rock in the shape of bones and teeth—and emphasizes the great biological continuity we see, not only within our own species, but with other hominins sometimes classified as different species.
Though genetics has made truly astounding and vital contributions toward biological anthropology by this work, it's important to acknowledge the equally pivotal role paleoanthropology continues to play in its tandem effort to flesh out humanity's roots. Paleoanthropologists like Alemsegad draw on every available source of information to both physically reconstruct hominin bodies and, perhaps more importantly, develop our understanding of how they may have lived, communicated, sustained themselves, and interacted with their environment and with each other. The work of Pääbo and others in his field offers powerful affirmations of paleoanthropological studies that have long investigated the contributions of Neanderthals and other hominins to the lineage of modern humans. Importantly, without paleoanthropology, the continued discovery and recovery of fossil specimens to later undergo genetic analysis would be greatly diminished.
Molecular anthropology and paleoanthropology, though often at odds with each other in the past regarding modern human evolution, now seem to be working together to chip away at theories that portray Neanderthals as inferior offshoots of humanity. Molecular anthropologists and paleoanthropologists also concur that that human evolution did not occur in ladder-like form, with one species leading to the next. Instead, the fossil evidence clearly reveals an evolutionary bush, with numerous hominin species existing at the same time and interacting through migration, some leading to modern humans and others going extinct.
Molecular anthropologist Spencer Wells uses DNA analysis to understand how our biological diversity correlates with ancient migration patterns from Africa into other continents. The study of our genetic evolution reveals that as humans migrated from Africa to all continents of the globe, they developed biological and cultural adaptations that allowed for survival in a variety of new environments. One example is skin color. Biological anthropologist Nina Jablonski uses satellite data to investigate the evolution of skin color, an aspect of human biological variation carrying tremendous social consequences. Jablonski underscores the importance of trying to understand skin color as a single trait affected by natural selection with its own evolutionary history and pressures, not as a tool to grouping humans into artificial races.
For Pääbo, Wells, Jablonski and others, technology affords the chance to investigate our origins in exciting new ways, adding pieces into the human puzzle at a record pace. At the same time, our technologies may well be changing who we are as a species and propelling us into an era of "neo-evolution."
Increasingly over time, human adaptations have been less related to predators, resources, or natural disasters, and more related to environmental and social pressures produced by other humans. Indeed, biological anthropologists have no choice but to consider the cultural components related to human evolutionary changes over time. Hominins have been constructing their own niches for a very long time, and when we make significant changes (such as agricultural subsistence), we must adapt to those changes. Classic examples of this include increases in sickle-cell anemia in new malarial environments, and greater lactose tolerance in regions with a long history of dairy farming.
Today we can, in some ways, evolve ourselves. We can enact biological change through genetic engineering, which operates at an astonishing pace in comparison to natural selection. Medical ethicist Harvey Fineberg calls this "neo-evolution". Fineberg goes beyond asking who we are as a species, to ask who we want to become and what genes we want our offspring to inherit. Depending on one's point of view, the future he envisions is both tantalizing and frightening: to some, it shows the promise of science to eradicate genetic abnormalities, while for others it raises the specter of eugenics. It's also worth remembering that while we may have the potential to influence certain genetic predispositions, changes in genotypes do not guarantee the desired results. Environmental and social pressures like pollution, nutrition or discrimination can trigger "epigenetic" changes which can turn genes on or off, or make them less or more active. This is important to factor in as we consider possible medical benefits from efforts in self-directed evolution. We must also ask: In an era of human-engineered, rapid-rate neo-evolution, who decides what the new human blueprints should be?
Technology figures in our evolutionary future in other ways as well. According to anthropologist Amber Case, many of our modern technologies are changing us into cyborgs: our smart phones, tablets and other tools are "exogenous components" that afford us astonishing and unsettling capabilities. They allow us to travel instantly through time and space and to create second, "digital selves" that represent our "analog selves" and interact with others in virtual environments. This has psychological implications for our analog selves that worry Case: a loss of mental reflection, the "ambient intimacy" of knowing that we can connect to anyone we want to at any time, and the "panic architecture" of managing endless information across multiple devices in virtual and real-world environments.
Despite her concerns, Case believes that our technological future is essentially positive. She suggests that at a fundamental level, much of this technology is focused on the basic concerns all humans share: who am I, where and how do I fit in, what do others think of me, who can I trust, who should I fear? Indeed, I would argue that we've evolved to be obsessed with what other humans are thinking—to be mind-readers in a sense—in a way that most would agree is uniquely human. For even though a baboon can assess those baboons it fears and those it can dominate, it cannot say something to a second baboon about a third baboon in order to trick that baboon into telling a fourth baboon to gang up on a fifth baboon. I think Facebook is a brilliant example of tapping into our evolved human psychology. We can have friends we've never met and let them know who we think we are—while we hope they like us and we try to assess what they're actually thinking and if they can be trusted. It's as if technology has provided an online supply of an addictive drug for a social mind evolved to crave that specific stimulant!
Yet our heightened concern for fairness in reciprocal relationships, in combination with our elevated sense of empathy and compassion, have led to something far greater than online chats: humanism itself. As Jane Goodall notes, chimps and baboons cannot rally together to save themselves from extinction; instead, they must rely on what she references as the "indomitable human spirit" to lessen harm done to the planet and all the living things that share it. As Goodall and other TED speakers in this course ask: will we use our highly evolved capabilities to secure a better future for ourselves and other species?
I hope those reading this essay, watching the TED Talks, and further exploring evolutionary perspectives on what makes us human, will view the continuities and discontinuities of our species as cause for celebration and less discrimination. Our social dependency and our prosocial need to identify ourselves, our friends, and our foes make us human. As a species, we clearly have major relationship problems, ranging from personal to global scales. Yet whenever we expand our levels of compassion and understanding, whenever we increase our feelings of empathy across cultural and even species boundaries, we benefit individually and as a species.
The search for humanity's roots, relevant talks.
A family tree for humanity.
Dna clues to our inner neanderthal.
Skin color is an illusion.
We are all cyborgs now
Are we ready for neo-evolution.
Frans de Waal
Moral behavior in animals.
What separates us from chimpanzees.
Evolution: Changing Species Over Time
Evolution is the process by which species adapt over time in response to their changing environment. Use these ideas to teach about the water cycle in your classroom.
Biology, Ecology, Genetics
Photograph by James L. Amos
Evolution is an important field of study for scientists. It covers the study of changes organisms have undergone over time in response to different factors in their environment. All organisms, including humans, evolve over time. Evolution occurs through natural selection, and is a force that has shaped every organism living today.
Have the students read about and research the finches Darwin studied on the Galapagos Islands . Darwin noticed that different finches had differently shaped beaks. He also noticed that the various beak shapes were each best suited for handling certain types of food. Darwin knew that the finches had come from continental South America originally, but those that he saw on the islands were unlike the ones on the mainland. Darwin wondered what caused these finches to change when they made it to the Galapagos Islands. Have students test the ability of different beaks to get different types of food. Provide students with spoons, forks, metal binders clip, and tweezers to represent different types of beaks and food bowl with foam packing peanuts, small bird seed, large bird seed (sunflower seeds), and toothpicks. Have student try the different tools and identify which tool works best with which foods.
National Geographic Explorer Jingchun Li: Evolution of “Living Solar Panels”
The first thing you notice when visiting a healthy marine coral reef is the number of different fishes and the many bright colors of both the fishes and the corals. Marine biodiversity refers to the richness of different species living together in a community. Have the students read about National Geographic Explorer Jingchun Li and her research on marine biodiversity and biologically productive coral reef ecosystems . Li is studying how coral reefs and other organisms are undergoing macroevolution to cope with the stresses created by human disturbances to their ecosystem.
Divide students into groups. Ask the students what stresses are taking place in the marine environment that coral reefs and other marine organisms need to adapt to. Have them divide into small groups and research these changes and design solutions to address these disturbances.
Scientists who study early humans depend on fossil evidence to help them sort out how our ancestors evolved over time. When looking at the fossils, scientists look for clues to changes in different characteristics such as brain size, skull shape, locomotion, and jaw size. Have the students learn about human evolution , then have them work through the Mystery Skull Interactive to use clues to identify fossils.
Evolution in Isolation
Have the students watch the video about the birds living on the island of Papua in Indonesia. This isolated island is a paradise with a lush and resource-rich habitat. Male birds of many different species have evolved elaborate ways of attracting mates. Ask the students, why is it important for a species to have the strongest males mate with the females and how does this affect the species?
National Geographic Explorer Jeremy Emiland Martin: Evolution of Crocodiles
Have the students read about Jeremy Emiland Martin’s work on the evolution of crocodiles and then have them research how modern crocodiles have been evolving since the time of the dinosaurs. Because crocodiles are found in so many different areas of the world, it is important to go back to where they first emerged to learn about their evolutionary beginnings. Ask the students, how have crocodiles evolved since the Cretaceous Period? What might have caused crocodiles to evolve? Why were these traits favorable in this particular environment?
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September 5, 2023
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- Bivalve Introduction
- Defining "Science"
- Defining "Evolution"
- Teaching It with Confidence
- How the Theory Developed
- How Evolution Works
- The Evidence for Evolution
- Evolution in Everyday Life
- Suggested Classroom Activities
Why Study Evolution?
A caricature of Charles Darwin from the London Sketchbook (1874).
We study evolution for the same reasons that we study any subject — the thirst for knowledge, to understand the past and predict the future, and to organize our world. But the subject of evolution also has huge relevance to our world and current issues that concern all of us. Evolution was happening 150 million years ago when dinosaurs dominated the Earth, was happening in the 1830s when Charles Darwin landed on the Galapagos Islands during the voyage of the HMS Beagle , and it is happening today. It is occurring in every living species on the planet, right now.
Evolution is not just about fossils. It is also about molecules, genes, mutations, populations, and sex in living organisms. All of these things are primary sources of data about evolutionary processes that occur when organisms try to survive and reproduce. Evolution also is about rigorous analyses — what we must do with the data to say something that is scientifically defendable. So if you thought that evolutionary biology was limited to dusty old curators in dusty old museums, think again. Scientists at universities, research centers, and museums are conducting some of the most sophistocated analyses of any kind today, using some of the best prepared specimens, most advanced techniques, and fastest computers available. Nothing in biology can be truly understood without first understanding evolution.
The Paleontological Research Institution and its Museum of the Earth 1259 Trumansburg Road • Ithaca, NY 14850 USA phone: 607-273-6623 • fax: 607-273-6620
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Relevance of Evolution
The relevance of evolution.
Explore just a few of the real world applications of evolutionary theory in:
- Relevance of evolution: agriculture
- Relevance of evolution: conservation
- Relevance of evolution: medicine
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