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• W2922963777 abstract "Pathogen-imposed selection pressures have been paramount during human evolution. Detecting such selection signatures in ancient and modern human genomes can thus help us to identify genes of temporal and spatial immunological relevance. Admixture with ancient hominins and between human populations has been a source of genetic diversity open to selection by infections. Furthermore, cultural transitions, such as the advent of agriculture, have exposed humans to new microbial threats, with impacts on host defense mechanisms. The integration of population genetics and systems immunology holds great promise for the increased understanding of the factors driving immune response variation between individuals and populations. Pathogen-imposed selection pressures have been paramount during human evolution. Detecting such selection signatures in ancient and modern human genomes can thus help us to identify genes of temporal and spatial immunological relevance. Admixture with ancient hominins and between human populations has been a source of genetic diversity open to selection by infections. Furthermore, cultural transitions, such as the advent of agriculture, have exposed humans to new microbial threats, with impacts on host defense mechanisms. The integration of population genetics and systems immunology holds great promise for the increased understanding of the factors driving immune response variation between individuals and populations. Humans and microbes have a long-standing, double-edged relationship. They can complement each other, as for the mutualist gut microbiota, but in other situations, microorganisms can be pathogenic, causing disease in the human host. Like famines and wars, which have continually inflicted a massive mortality burden on humans, the threat of pathogenic infections has had an overwhelming effect (Cairns, 1997Cairns J. Matters of Life and Death. Princeton University Press, Princeton, NJ1997Crossref Google Scholar). Pathogens have accompanied humans since their emergence in Africa ∼200,000–300,000 years ago (ya), through subsequent dispersals across continents over the last ∼60,000–100,000 years and through major cultural transitions, such as the emergence of agriculture and sedentarism ∼10,000 ya, until more recent migratory events, including the European colonization of the Americas and contemporary globalization (see Karlsson et al., 2014Karlsson E.K. Kwiatkowski D.P. Sabeti P.C. Natural selection and infectious disease in human populations.Nat. Rev. Genet. 2014; 15: 379-393Crossref PubMed Scopus (149) Google Scholar and references). Ancient diseases, such as malaria and tuberculosis, the causal agents of which emerged ∼100,000–70,000 ya, and more recent diseases, such as Black Death and Spanish flu, have wiped out hundreds of millions of people during human history (Comas et al., 2013Comas I. Coscolla M. Luo T. Borrell S. Holt K.E. Kato-Maeda M. Parkhill J. Malla B. Berg S. Thwaites G. et al.Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans.Nat. Genet. 2013; 45: 1176-1182Crossref PubMed Scopus (400) Google Scholar, Fumagalli and Sironi, 2014Fumagalli M. Sironi M. Human genome variability, natural selection and infectious diseases.Curr. Opin. Immunol. 2014; 30: 9-16Crossref PubMed Scopus (36) Google Scholar, Morens et al., 2008Morens D.M. Folkers G.K. Fauci A.S. Emerging infections: a perpetual challenge.Lancet Infect. Dis. 2008; 8: 710-719Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Mortality rates from infection remained high until the late 19th and early 20th century, when hygiene improved and vaccines and antibiotics began to be developed, and they remain high in many developing countries. Infectious diseases have been, and still are, a major cause of human mortality, and thus, they represent a strong selection pressure. For example, at the end of the 19th century, only 35% of Europeans reached the age of 40 years, highlighting the high infectious burden and illustrating what must have been the rule during most of our history as a species (Cairns, 1997Cairns J. Matters of Life and Death. Princeton University Press, Princeton, NJ1997Crossref Google Scholar, Casanova and Abel, 2005Casanova J.L. Abel L. Inborn errors of immunity to infection: the rule rather than the exception.J. Exp. Med. 2005; 202: 197-201Crossref PubMed Scopus (127) Google Scholar). John B.S. Haldane and Anthony Allison were the first to establish a formal link between infectious diseases and natural selection, with the suggestion that red blood-cell disorders, such as thalassemia and sickle-cell disease, can provide protection against malaria (Allison, 1954Allison A.C. Protection afforded by sickle-cell trait against subtertian malareal infection.BMJ. 1954; 1: 290-294Crossref PubMed Google Scholar, Haldane, 1949Haldane J.B.S. Disease and Evolution.Ric. Sci. 1949; 19: 68-76Google Scholar). Strong evidence concerning the genetic determinants of infectious, inflammatory, and autoimmune disorders has since accumulated (Abel et al., 2014Abel L. Alcaïs A. Schurr E. The dissection of complex susceptibility to infectious disease: bacterial, viral and parasitic infections.Curr. Opin. Immunol. 2014; 30: 72-78Crossref PubMed Scopus (15) Google Scholar, Parkes et al., 2013Parkes M. Cortes A. van Heel D.A. Brown M.A. Genetic insights into common pathways and complex relationships among immune-mediated diseases.Nat. Rev. Genet. 2013; 14: 661-673Crossref PubMed Scopus (280) Google Scholar). The genome-wide approaches developed over the last decade, in particular, have revealed that the observed inter-individual heterogeneity in infection outcome is due, in many cases, to differences in the genetic make-up of the human host, resulting in rare, Mendelian diseases or altering the individual susceptibility to complex immune-related phenotypes (Casanova and Abel, 2018Casanova J.L. Abel L. Human genetics of infectious diseases: Unique insights into immunological redundancy.Semin. Immunol. 2018; 36: 1-12Crossref PubMed Scopus (5) Google Scholar). Population genetic studies have shown that genes involved in immune function present strong selection signatures, have helped to delineate genes and pathways of major importance in host defense, and have provided support for the notion that microbes have had an overwhelming impact on human evolution (Barreiro and Quintana-Murci, 2010Barreiro L.B. Quintana-Murci L. From evolutionary genetics to human immunology: how selection shapes host defence genes.Nat. Rev. Genet. 2010; 11: 17-30Crossref PubMed Scopus (266) Google Scholar, Fumagalli and Sironi, 2014Fumagalli M. Sironi M. Human genome variability, natural selection and infectious diseases.Curr. Opin. Immunol. 2014; 30: 9-16Crossref PubMed Scopus (36) Google Scholar, Karlsson et al., 2013Karlsson E.K. Harris J.B. Tabrizi S. Rahman A. Shlyakhter I. Patterson N. O’Dushlaine C. Schaffner S.F. Gupta S. Chowdhury F. et al.Natural selection in a bangladeshi population from the cholera-endemic ganges river delta.Sci. Transl. Med. 2013; 5: 192ra86Crossref PubMed Scopus (37) Google Scholar, Quintana-Murci and Clark, 2013Quintana-Murci L. Clark A.G. Population genetic tools for dissecting innate immunity in humans.Nat. Rev. Immunol. 2013; 13: 280-293Crossref PubMed Scopus (64) Google Scholar). This Review does not attempt to provide a comprehensive view of the effects of different types of selection on genome diversity or the statistical methods available to detect them, which have already been dealt with in outstanding reviews (Fan et al., 2016Fan S. Hansen M.E. Lo Y. Tishkoff S.A. Going global by adapting local: A review of recent human adaptation.Science. 2016; 354: 54-59Crossref PubMed Scopus (45) Google Scholar, Vitti et al., 2013Vitti J.J. Grossman S.R. Sabeti P.C. Detecting natural selection in genomic data.Annu. Rev. Genet. 2013; 47: 97-120Crossref PubMed Scopus (210) Google Scholar). Likewise, much of the excellent work on the population genetics of immune system genes in humans will not be reviewed here, as this work has already been extensively reviewed elsewhere (Barreiro and Quintana-Murci, 2010Barreiro L.B. Quintana-Murci L. From evolutionary genetics to human immunology: how selection shapes host defence genes.Nat. Rev. Genet. 2010; 11: 17-30Crossref PubMed Scopus (266) Google Scholar, Fumagalli and Sironi, 2014Fumagalli M. Sironi M. Human genome variability, natural selection and infectious diseases.Curr. Opin. Immunol. 2014; 30: 9-16Crossref PubMed Scopus (36) Google Scholar, Karlsson et al., 2014Karlsson E.K. Kwiatkowski D.P. Sabeti P.C. Natural selection and infectious disease in human populations.Nat. Rev. Genet. 2014; 15: 379-393Crossref PubMed Scopus (149) Google Scholar, Quintana-Murci and Clark, 2013Quintana-Murci L. Clark A.G. Population genetic tools for dissecting innate immunity in humans.Nat. Rev. Immunol. 2013; 13: 280-293Crossref PubMed Scopus (64) Google Scholar). Instead, I will first provide an overview of the way in which the detection of different selection regimes, from maintenance of the status quo to the benefits of diversity, can provide us with information about the immunological relevance of host genes in natural settings, stressing the value of studies of ancient DNA time transects for the direct detection of natural selection. I will also provide an extensive review of how admixture at different timescales—from archaic admixture with ancient hominins such as Neanderthals to more recent historical gene flow between human populations—can provide an additional source of advantageous immune variation. In addition, I will describe how changes in subsistence patterns, such as the transition from nomadic hunting and gathering to a sedentary farming-based lifestyle, may have modified the way humans interact with pathogens. Finally, I will highlight the ways in which the integration of population genetics and systems immunology can help us to tackle questions of major fundamental and public health importance, such as the delineation of the evolutionary determinants of human immune responsiveness, and the various sources of immune response variation between both individuals and populations. A dissection of the molecular signatures left by natural selection in genomic regions involved in immune responses, or the absence of such signatures (i.e., neutrality), can be used to assess the biological relevance of the corresponding genes in natura, determining whether they are essential, redundant, or adaptable (Figure 1). Two main forms of selection occur, according to whether the alleles concerned are deleterious or advantageous. Purifying selection, or negative selection, involves the removal of deleterious alleles from the population. Its pace depends on how deleterious the alleles are (i.e., the selective coefficient s) and on effective population size (i.e., Ne). This selection regime is the most widespread throughout the genome. Conversely, adaptation can occur through positive selection, which increases the frequency of an advantageous allele according to various evolutionary models such as the classic sweep (strong selection on a new mutation), standing variation (selection on a pre-existing mutation), or polygenic adaptation (selection acting simultaneously on multiple loci) (Figure 2A), or through other forms, such as balancing selection or adaptation through admixture (Figures 2B and 2C), which we will discuss in detail later in this Review.Figure 2Different Forms of Genetic Adaptation following Various Evolutionary ModelsShow full caption(A) Different models of positive selection are represented: the classic sweep, where a new mutation rapidly increases in frequency until fixation (red dots); selection on standing variation, where selection acts on a pre-existing, neutrally evolving genetic variant in the population (orange dots); and polygenic adaptation, where multiple genetic variants located in different genomic regions simultaneously increase in frequency (green dots).(B) Balancing selection is represented here by heterozygote advantage (colored arrows). The preservation of immune diversity can be achieved through long-lived, trans-species balancing selection (represented by red and blue arrows), in which genetic diversity is maintained at selected loci, such as the ABO blood group, over long periods of time (e.g., since the separation of the ancestors of modern humans and chimpanzees). Balancing selection can also be more recent, and population specific (represented here by the yellow and green arrows), as illustrated by the textbook example of HbA/HbS in Africa.(C) Beneficial genetic variation can be acquired from other species or populations through admixture. Adaptive introgression from archaic humans is represented by blue arrows, while adaptive admixture between modern human populations is represented by ochre arrows.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) Different models of positive selection are represented: the classic sweep, where a new mutation rapidly increases in frequency until fixation (red dots); selection on standing variation, where selection acts on a pre-existing, neutrally evolving genetic variant in the population (orange dots); and polygenic adaptation, where multiple genetic variants located in different genomic regions simultaneously increase in frequency (green dots). (B) Balancing selection is represented here by heterozygote advantage (colored arrows). The preservation of immune diversity can be achieved through long-lived, trans-species balancing selection (represented by red and blue arrows), in which genetic diversity is maintained at selected loci, such as the ABO blood group, over long periods of time (e.g., since the separation of the ancestors of modern humans and chimpanzees). Balancing selection can also be more recent, and population specific (represented here by the yellow and green arrows), as illustrated by the textbook example of HbA/HbS in Africa. (C) Beneficial genetic variation can be acquired from other species or populations through admixture. Adaptive introgression from archaic humans is represented by blue arrows, while adaptive admixture between modern human populations is represented by ochre arrows. The genes evolving under strong purifying selection are those for which functional variation cannot be tolerated. These genes thus encode products with essential, non-redundant functions, and their mutations may underlie severe disorders. Innate immunity genes are generally constrained by selection, particularly those associated with autosomal dominant primary immunodeficiencies, such as STAT1 and TRAF3 (Deschamps et al., 2016Deschamps M. Laval G. Fagny M. Itan Y. Abel L. Casanova J.L. Patin E. Quintana-Murci L. Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes.Am. J. Hum. Genet. 2016; 98: 5-21Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Classical examples of highly constrained immune genes include the genes encoding endosomal Toll-like receptors (TLRs) (Barreiro et al., 2009Barreiro L.B. Ben-Ali M. Quach H. Laval G. Patin E. Pickrell J.K. Bouchier C. Tichit M. Neyrolles O. Gicquel B. et al.Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense.PLoS Genet. 2009; 5: e1000562Crossref PubMed Scopus (0) Google Scholar), most NALP members of the NOD-like receptor (NLR) family (Vasseur et al., 2012Vasseur E. Boniotto M. Patin E. Laval G. Quach H. Manry J. Crouau-Roy B. Quintana-Murci L. The evolutionary landscape of cytosolic microbial sensors in humans.Am. J. Hum. Genet. 2012; 91: 27-37Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), IFN-γ (Manry et al., 2011Manry J. Laval G. Patin E. Fornarino S. Itan Y. Fumagalli M. Sironi M. Tichit M. Bouchier C. Casanova J.L. et al.Evolutionary genetic dissection of human interferons.J. Exp. Med. 2011; 208: 2747-2759Crossref PubMed Scopus (75) Google Scholar), and many others (Quintana-Murci and Clark, 2013Quintana-Murci L. Clark A.G. Population genetic tools for dissecting innate immunity in humans.Nat. Rev. Immunol. 2013; 13: 280-293Crossref PubMed Scopus (64) Google Scholar). Mutations occurring in some of these genes or affecting the pathways they trigger (e.g., TLR3-TRIF, TIR-MYD88, IFN-γ, NALP3) have been associated with life-threatening phenotypes, such as HSV-1 encephalitis, pyogenic bacterial infections, Mendelian susceptibility to mycobacterial disease, and severe inflammatory diseases (for an extensive review, see Casanova and Abel, 2013Casanova J.L. Abel L. The genetic theory of infectious diseases: a brief history and selected illustrations.Annu. Rev. Genomics Hum. Genet. 2013; 14: 215-243Crossref PubMed Scopus (67) Google Scholar). Strong or complete redundancy can also be deduced from population genetics data. Redundant genes often display profiles of genetic diversity that are consistent with relaxed selective constraints. This is the case for the three members of the RIG-I-like receptor (RLR) family, suggesting some degree of redundancy in immunity to viruses (Barreiro et al., 2009Barreiro L.B. Ben-Ali M. Quach H. Laval G. Patin E. Pickrell J.K. Bouchier C. Tichit M. Neyrolles O. Gicquel B. et al.Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense.PLoS Genet. 2009; 5: e1000562Crossref PubMed Scopus (0) Google Scholar, Vasseur et al., 2012Vasseur E. Boniotto M. Patin E. Laval G. Quach H. Manry J. Crouau-Roy B. Quintana-Murci L. The evolutionary landscape of cytosolic microbial sensors in humans.Am. J. Hum. Genet. 2012; 91: 27-37Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). High redundancy is illustrated by cases of apparent “knockouts” in humans, as reported for IFNA10, IFNE, MBL2, and TLR5, loss-of-function variants of which can reach high frequencies in the healthy general population (Quintana-Murci and Clark, 2013Quintana-Murci L. Clark A.G. Population genetic tools for dissecting innate immunity in humans.Nat. Rev. Immunol. 2013; 13: 280-293Crossref PubMed Scopus (64) Google Scholar). In rare cases, loss of function may not only be tolerated, but may actually prove beneficial, with disruptive variants increasing to high population frequencies through positive selection. This situation has been reported for CASP12, ACKR1 (also known as DARC), and FUT2, among other genes, possibly because they provide protection against sepsis, vivax malaria, and noroviruses, respectively (Casanova and Abel, 2018Casanova J.L. Abel L. Human genetics of infectious diseases: Unique insights into immunological redundancy.Semin. Immunol. 2018; 36: 1-12Crossref PubMed Scopus (5) Google Scholar, Quintana-Murci and Barreiro, 2010Quintana-Murci L. Barreiro L.B. The role played by natural selection on Mendelian traits in humans.Ann. N Y Acad. Sci. 2010; 1214: 1-17Crossref PubMed Scopus (16) Google Scholar). The detection of different forms of adaptive evolution (Figure 2) makes it possible to identify genes and functions for which novelty or diversity has been beneficial to the host (Karlsson et al., 2014Karlsson E.K. Kwiatkowski D.P. Sabeti P.C. Natural selection and infectious disease in human populations.Nat. Rev. Genet. 2014; 15: 379-393Crossref PubMed Scopus (149) Google Scholar, Key et al., 2014Key F.M. Teixeira J.C. de Filippo C. Andrés A.M. Advantageous diversity maintained by balancing selection in humans.Curr. Opin. Genet. Dev. 2014; 29: 45-51Crossref PubMed Scopus (0) Google Scholar, Quintana-Murci and Clark, 2013Quintana-Murci L. Clark A.G. Population genetic tools for dissecting innate immunity in humans.Nat. Rev. Immunol. 2013; 13: 280-293Crossref PubMed Scopus (64) Google Scholar). In particular, there is growing evidence confirming that the diversity of immune genes is driven by human exposure to pathogens. For example, significant correlations have been detected between the genetic variability of HLA class I genes, blood group antigens, and interleukin genes and pathogen diversity worldwide (Fumagalli et al., 2009aFumagalli M. Cagliani R. Pozzoli U. Riva S. Comi G.P. Menozzi G. Bresolin N. Sironi M. Widespread balancing selection and pathogen-driven selection at blood group antigen genes.Genome Res. 2009; 19: 199-212Crossref PubMed Scopus (101) Google Scholar, Fumagalli et al., 2009bFumagalli M. Pozzoli U. Cagliani R. Comi G.P. Riva S. Clerici M. Bresolin N. Sironi M. Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions.J. Exp. Med. 2009; 206: 1395-1408Crossref PubMed Scopus (161) Google Scholar, Prugnolle et al., 2005Prugnolle F. Manica A. Charpentier M. Guégan J.F. Guernier V. Balloux F. Pathogen-driven selection and worldwide HLA class I diversity.Curr. Biol. 2005; 15: 1022-1027Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Some of these correlations may be due to confounding with variables such as climate, diet, or lifestyle, but the primary drivers of local adaptation have been shown to be pathogens, the diversity of which is correlated with that of the inflammatory response and innate immunity genes (Fumagalli et al., 2011Fumagalli M. Sironi M. Pozzoli U. Ferrer-Admetlla A. Pattini L. Nielsen R. Signatures of environmental genetic adaptation pinpoint pathogens as the main selective pressure through human evolution.PLoS Genet. 2011; 7: e1002355Crossref PubMed Scopus (252) Google Scholar). It has recently been suggested that viruses have been the most pervasive agents driving mammalian evolution, with 30% of all amino-acid changes in the human proteome due to selection pressures imposed by viruses (Enard et al., 2016Enard D. Cai L. Gwennap C. Petrov D.A. Viruses are a dominant driver of protein adaptation in mammals.eLife. 2016; 5: 5Crossref Scopus (45) Google Scholar). Adaptation to pathogens may in some cases cause collateral damage. There is increasing evidence to suggest that past selection for higher resistance to infection may result—following the decreasing incidence of infections—in present-day susceptibility to autoimmune, inflammatory, or allergic diseases (Sironi and Clerici, 2010Sironi M. Clerici M. The hygiene hypothesis: an evolutionary perspective.Microbes Infect. 2010; 12: 421-427Crossref PubMed Scopus (0) Google Scholar), as predicted by the hygiene hypothesis (Strachan, 1989Strachan D.P. Hay fever, hygiene, and household size.BMJ. 1989; 299: 1259-1260Crossref PubMed Google Scholar). Signatures of positive selection have been reported for genetic variants that are associated with increased risk of inflammatory bowel disease, type 1 diabetes, celiac disease, multiple sclerosis, and psoriasis among others (see Brinkworth and Barreiro, 2014Brinkworth J.F. Barreiro L.B. The contribution of natural selection to present-day susceptibility to chronic inflammatory and autoimmune disease.Curr. Opin. Immunol. 2014; 31: 66-78Crossref PubMed Scopus (24) Google Scholar and references therein). However, because the genetic architecture of polygenic traits, such as immunity to infection, is likely to be dominated by the effects of long-term stabilizing selection (Simons et al., 2018Simons Y.B. Bullaughey K. Hudson R.R. Sella G. A population genetic interpretation of GWAS findings for human quantitative traits.PLoS Biol. 2018; 16: e2002985Crossref PubMed Scopus (4) Google Scholar) and pleiotropy is pervasive among immune genes (Brinkworth and Barreiro, 2014Brinkworth J.F. Barreiro L.B. The contribution of natural selection to present-day susceptibility to chronic inflammatory and autoimmune disease.Curr. Opin. Immunol. 2014; 31: 66-78Crossref PubMed Scopus (24) Google Scholar), establishing a direct link between past selection favoring a specific phenotype and present-day maladaptation is far from straight-forward. Balancing selection may take various forms and acts to preserve functional, beneficial genetic diversity. The mechanisms of balancing selection include overdominance (i.e., heterozygote advantage), frequency-dependent selection (i.e., rare allele advantage), and selection fluctuating over time and space (Key et al., 2014Key F.M. Teixeira J.C. de Filippo C. Andrés A.M. Advantageous diversity maintained by balancing selection in humans.Curr. Opin. Genet. Dev. 2014; 29: 45-51Crossref PubMed Scopus (0) Google Scholar). There is increasing evidence for long-lived balancing selection, a selective regime allowing polymorphisms to survive over long time periods and during speciation (trans-species polymorphism) (Figure 2B). Textbook examples of balancing selection can again be found in the immunological literature, in the form of the extraordinarily high levels of genetic diversity reported for the vertebrate major histocompatibility complex (MHC, referred to as HLA in humans), genetic variation in which has been maintained and inherited from distant ancestors in primates, but also in other mammals, birds, and fish species (Klein et al., 2007Klein J. Sato A. Nikolaidis N. MHC, TSP, and the origin of species: from immunogenetics to evolutionary genetics.Annu. Rev. Genet. 2007; 41: 281-304Crossref PubMed Scopus (99) Google Scholar, Lawlor et al., 1988Lawlor D.A. Ward F.E. Ennis P.D. Jackson A.P. Parham P. HLA-A and B polymorphisms predate the divergence of humans and chimpanzees.Nature. 1988; 335: 268-271Crossref PubMed Google Scholar). Likewise, the ABO histoblood group was recently shown to be a trans-species polymorphism, identical by descent in various primate species, including humans and gibbons in particular (Ségurel et al., 2012Ségurel L. Thompson E.E. Flutre T. Lovstad J. Venkat A. Margulis S.W. Moyse J. Ross S. Gamble K. Sella G. et al.The ABO blood group is a trans-species polymorphism in primates.Proc. Natl. Acad. Sci. USA. 2012; 109: 18493-18498Crossref PubMed Scopus (54) Google Scholar). Other factors have helped to maintain high levels of diversity and trans-species polymorphism at the HLA and ABO loci, including sexual selection in the case of HLA (Ober et al., 1997Ober C. Weitkamp L.R. Cox N. Dytch H. Kostyu D. Elias S. HLA and mate choice in humans.Am. J. Hum. Genet. 1997; 61: 497-504Abstract Full Text PDF PubMed Google Scholar), but the selection signals observed are probably pathogen driven (Prugnolle et al., 2005Prugnolle F. Manica A. Charpentier M. Guégan J.F. Guernier V. Balloux F. Pathogen-driven selection and worldwide HLA class I diversity.Curr. Biol. 2005; 15: 1022-1027Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Other immune genes have been shown to evolve through the action of balancing selection on functions relating to cell migration and β-defensins (Cagliani et al., 2008Cagliani R. Fumagalli M. Riva S. Pozzoli U. Comi G.P. Menozzi G. Bresolin N. Sironi M. The signature of long-standing balancing selection at the human defensin beta-1 promoter.Genome Biol. 2008; 9: R143Crossref PubMed Scopus (45) Google Scholar). That this selective regime is particularly pervasive in the context of immune function is supported by genome-wide studies, which have explored the extent of balancing selection long-lived and trans-species (Leffler et al., 2013Leffler E.M. Gao Z. Pfeifer S. Ségurel L. Auton A. Venn O. Bowden R. Bontrop R. Wall J.D. Sella G. et al.Multiple instances of ancient balancing selection shared between humans and chimpanzees.Science. 2013; 339: 1578-1582Crossref PubMed Scopus (131) Google Scholar, Teixeira et al., 2015Teixeira J.C. de Filippo C. Weihmann A. Meneu J.R. Racimo F. Dannemann M. Nickel B. Fischer A. Halbwax M. Andre C. et al.Long-Term Balancing Selection in LAD1 Maintains a Missense Trans-Species Polymorphism in Humans, Chimpanzees, and Bonobos.Mol. Biol. Evol. 2015; 32: 1186-1196Crossref PubMed Scopus (17) Google Scholar) within humans (Andrés et al., 2009Andrés A.M. Hubisz M.J. Indap A. Torgerson D.G. Degenhardt J.D. Boyko A.R. Gutenkunst R.N. White T.J. Green E.D. Bustamante C.D. et al.Targets of balancing selection in the human genome.Mol. Biol. Evol. 2009; 26: 2755-2764Crossref PubMed Scopus (149) Google Scholar, DeGiorgio et al., 2014DeGiorgio M. Lohmueller K.E. Nielsen R. A model-based approach for identifying signatures of ancient balancing selection in genetic data.PLoS Genet. 2014; 10: e1004561Crossref PubMed Scopus (57) Google Scholar, Siewert and Voight, 2017Siewert K.M. Voight B.F. Detecting Long-Term Balancing Selection Using Allele Frequency Correlation.Mol. Biol. Evol. 2017; 34: 2996-3005Crossref PubMed Scopus (5) Google Scholar), as well as more complex models of balancing selection turning into positive selection (de Filippo et al., 2016de Filippo C. Key F.M. Ghirotto S. Benazzo A. Meneu J.R. Weihmann A. Parra G. Green E.D. Andrés A.M. Andres A.M. NISC Comparative Sequence ProgramRecent Selection Changes in Human Genes under Long-Term Balancing Selection.Mol. Biol. Evol. 2016; 33: 1435-1447Crossref PubMed Scopus (5) Google Scholar). Several immune functions involving genes encoding membrane glycoproteins, such as GYPE, and innate immunity proteins, such as IGFBP7, present strong signals of trans-species polymorphism between humans and chimpanzees (Leffler et al., 2013Leffler E.M. Gao Z. Pfeifer S. Ségurel L. Auton A. Venn O. Bowden R. Bontrop R. Wall J.D. Sella G. et al.Multiple instances of ancient balancing selection shared between humans and chimpanzees.Science. 2013; 339: 1578-1582Crossref PubMed Scopus (131) Google Scholar). Within humans, genes subject to balancing selection include not only HLA, but also BTN1A1, NALP13, TRIM22, and FUT2, for example (Andrés et al., 2009Andrés A.M. Hubisz M.J. Indap A. Torgerson D.G. Degenhardt J.D. Bo" @default.
• W2922963777 created "2019-04-01" @default.
• W2922963777 creator A5012236358 @default.
• W2922963777 date "2019-03-01" @default.
• W2922963777 modified "2023-10-17" @default.
• W2922963777 title "Human Immunology through the Lens of Evolutionary Genetics" @default.
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