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The Influence of Evolutionary History on Human Health and Disease

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The Influence of Evolutionary History on Human Health and Disease REVIEWS The influence of evolutionary history on human health and disease Mary Lauren Benton 1,2, Abin Abraham3,4, Abigail L. LaBella 5, Patrick Abbot5, Antonis Rokas 1,3,5 and John A. Capra 1,5,6 ✉ Abstract | 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 These studies are radically changing our understanding (BOx 1). Fundamental biological systems, such as DNA of the genetic architecture of disease8. It is also now possi- replication, transcription and translation, evolved very ble to extract and sequence ancient DNA from remains early in the history of life. Although these ancient evo- of organisms that are thousands of years old, enabling 1Department of Biomedical lutionary innovations gave rise to cellular life, they also scientists to reconstruct the history of recent human Informatics, Vanderbilt created the potential for disease. Subsequent innovations adaptation with unprecedented resolution9,10. These University School of Medicine, along life’s long evolutionary history have similarly ena- breakthroughs have revealed the recent, often compli- Nashville, TN, USA. bled both adaptation and the potential for dysfunction. cated, history of our species and how it influences the 2Department of Computer Against this ancient background, young genetic vari- genetic architecture of disease8,11. With the expansion Science, Baylor University, Waco, TX, USA. ants specific to the human lineage interact with modern of clinical whole- genome sequencing and personal- environments to produce human disease phenotypes. ized medicine, the influence of our evolutionary past 3Vanderbilt Genetics Institute, Vanderbilt University, Consequently, the substrates for genetic disease in mod- and its implications for understanding human disease Nashville, TN, USA. ern humans are often far older than the human lineage can no longer remain overlooked by medical practice; 12,13 4Vanderbilt University itself, but the genetic variants that cause them are usually evolutionary perspectives must inform medicine . Medical Center, Vanderbilt unique to humans. Much like a family’s medical history over genera- University, Nashville, The advent of high-throughput genomic technologies tions, the genome is fundamentally a historical record. TN, USA. has enabled the sequencing of the genomes of diverse Decoding the evolution of the human genome provides 5 Department of Biological species from across the tree of life1. Analysis of these valuable context for interpreting and modelling disease. Sciences, Vanderbilt University, Nashville, genomes has, in turn, revealed the striking conservation This context is not limited to recent human evolution TN, USA. of many of the molecular pathways that underlie the but also includes more ancient events that span life’s his- 6Bakar Computational Health function of biological systems that are essential for cel- tory. In this Review, we trace the 4 billion- year interplay Sciences Institute and lular life2. The same technologies have also spearheaded between evolution and disease by illustrating how inno- Department of Epidemiology a revolution in human genomics3; currently, more than vations during the course of life’s history have established and Biostatistics, University 120,000 individual whole human genome sequences the potential for, and inevitability of, disease. Beginning of California, San Francisco, CA, USA. are publicly available, and genome- scale data from with events in the very deep past, where most genes ✉e- mail: tony.capra@ hundreds of thousands more have been generated by and pathways involved in human disease originate, we 4 ucsf.edu consumer genomics companies . Huge nationwide bio- explain how ancient biological systems, recent genetic https://doi.org/10.1038/ banks are also characterizing the genotypes and pheno- variants and dynamic environments interact to produce s41576-020-00305-9 types of millions of people from around the world5–7. both adaptation and disease risk in human populations. NATURE REVIEWS | GENETICS VOLUME 22 | MAY 2021 | 269 REVIEWS Box 1 | The evolutionary necessity of disease Myriad age- related diseases in humans, and many other multicellular organisms, are a manifestation The definition of disease of this first evolutionary trade- off. varies across biological, A The evolution of multicellularity, which has occurred medical and evolutionary B many times across the tree of life, illustrates the inter- perspectives. Viewing C 18 disease through the lens of play between evolutionary innovation and disease . evolution provides a flexible D The origin of multicellularity enabled complex body and powerful framework for Disease risk plans with trillions of cells, involving innovations defining and classifying associated with the ability of cells to regulate their cell disease12. As illustrated in cycles, modulate their growth and form intricate net- the reaction norms plotted Environment works of communication. But multicellularity also estab- in the figure, disease risk lished the foundation for cancer19,20. Genes that regulate (y axis) is a function of both genotype (coloured lines) and environment (x axis). cell cycle control are often divided into two groups: care- Some genotypes lead to disease in all environments (line A); high-penetrance Mendelian takers and gatekeepers21,22. The caretakers are involved in disorders fall into this group. At the other extreme, disease risk may only occur in the case of basic control of the cell cycle and DNA repair, and muta- 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 tions in these genes often lead to increased mutation rates hydroxylase enzyme non- functional and a diet that includes phenylalanine, illustrates this or genomic instability, both of which increase cancer risk. case. Most diseases fall between these extremes (lines B and C). Disease often arises from Caretaker genes are enriched for functions with origins fundamental evolutionary ‘mismatches’ between genotype and environment. For example, dating back to the first cells23. The gatekeepers appeared the high risk for obesity, a chronic disease with substantial heritability (30–40%)177, in many later, at the genesis of metazoan multicellularity23. modern populations is due (at least in part) to rapid and recent changes in human lifestyle178, The gatekeepers are directly linked to tumorigenesis such as eating higher- calorie foods, maintaining more sedentary lifestyles and sleeping through their roles in regulating cell growth, death and fewer hours. Here, obesity manifests due to a ‘mismatch’ between the genotype and a communication. The progression of individual tumours rapidly changing environment. Genotypes often have opposing effects on different in a given patient is likewise informed by an evolutionary traits. This evolutionary pattern, called antagonistic pleiotropy, often leads to disease179. perspective. Designing treatments that account for A canonical example is balancing selection to maintain variation at the haemoglobin subunit- (HBB) locus that protects against malarial disease but recessively leads to sickle the evolution of drug resistance and heterogeneity in β 24–29 cell anaemia. Antagonistic pleiotropy has also been detected in complex genetic traits, such tumours is a tenet of modern cancer therapy . as heart disease where alleles that increase lifetime reproductive success also increase the Like multicellularity, the evolution of immune risk for heart disease180. As these examples illustrate, many modern human diseases exist systems also set the stage for dysregulation and dis- because populations have not adapted to changing environments or previous adaptations ease. Mammalian innate and adaptive immune systems lead to trade- offs between health and fitness. However, disease is not just a product of are both ancient. Components of the innate immune the modern world. As long as there is phenotypic variation, disease is inevitable; some system are present across metazoans and even some individuals will be better suited to some environments (and thus healthier) than others. plants30,31, whereas the adaptive immune system is pres- ent across jawed vertebrates32. These systems provided Given this scope, we cannot provide a comprehensive molecular mechanisms for self-/non- self- recognition account of
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