Key Points
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Pathogens and infectious diseases have been, and still are, paramount among the threats to human health and survival. Exposure to infection has therefore imposed strong selective pressures on the evolution of the human genome.
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The field of evolutionary genetics of immunity searches the genome of present-day human populations for molecular 'footprints' of natural selection that have been exerted by past infections.
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Some of the strongest evidence of selection in the human genome has been obtained for genes involved in immunity and host defence, as revealed by genome-wide scans for selection among primate species and within human populations.
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Evolutionary genetics reveal genes that have a redundant role in host defence and show how, in certain circumstances, recent gene loss can represent a selective advantage for the host.
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The signatures of positive selection observed at some disease-associated SNPs suggest that the increasing prevalence of autoimmune disorders in modern societies might, at least partially, be the consequence of past selective events to combat infection.
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Characterizing how natural selection has targeted immunity-related genes provides important clues for delineating human genes and immunological pathways that have major roles in host defence and for predicting which regions of the genome are associated with susceptibility to infection or disease outcome.
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Integrative approaches that combine evolutionary genetics data with immunological phenotypes will help to elucidate more precisely the immunological mechanisms that have been targeted by natural selection in humans.
Abstract
Pathogens have always been a major cause of human mortality, so they impose strong selective pressure on the human genome. Data from population genetic studies, including genome-wide scans for selection, are providing important insights into how natural selection has shaped immunity and host defence genes in specific human populations and in the human species as a whole. These findings are helping to delineate genes that are important for host defence and to increase our understanding of how past selection has had an impact on disease susceptibility in modern populations. A tighter integration between population genetic studies and immunological phenotype studies is now necessary to reveal the mechanisms that have been crucial for our past and present survival against infection.
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References
Casanova, J. L. & Abel, L. Inborn errors of immunity to infection: the rule rather than the exception. J. Exp. Med. 202, 197–201 (2005).
Haldane, J. B. S. Disease and evolution. Ric. Sci. 19 (Suppl. A), 68–76 (1949).
Ausubel, F. M. Are innate immune signaling pathways in plants and animals conserved? Nature Immunol. 6, 973–979 (2005).
Cooper, M. D. & Alder, M. N. The evolution of adaptive immune systems. Cell 124, 815–822 (2006).
Flajnik, M. F. & Du Pasquier, L. Evolution of innate and adaptive immunity: can we draw a line? Trends Immunol. 25, 640–644 (2004).
Kimbrell, D. A. & Beutler, B. The evolution and genetics of innate immunity. Nature Rev. Genet. 2, 256–267 (2001).
Lazzaro, B. P. & Little, T. J. Immunity in a variable world. Phil. Trans. R. Soc. Lond. B 364, 15–26 (2009).
Schulenburg, H., Kurtz, J., Moret, Y. & Siva-Jothy, M. T. Introduction. Ecological immunology. Phil. Trans. R. Soc. Lond. B 364, 3–14 (2009).
Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).
Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007). An integrated view of the innate and adaptive components of the immune system, how they work and interact, and their role in host defence.
Allison, A. C. Protection afforded by sickle-cell trait against subtertian malareal infection. BMJ 1, 290–294 (1954). The seminal paper that showed that 'sickle-cell' heterozygotes have increased protection against malaria.
Nielsen, R., Hellmann, I., Hubisz, M., Bustamante, C. & Clark, A. G. Recent and ongoing selection in the human genome. Nature Rev. Genet. 8, 857–868 (2007).
Sabeti, P. C. et al. Positive natural selection in the human lineage. Science 312, 1614–1620 (2006).
Akey, J. M. Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res. 19, 711–722 (2009). References 12–14 are excellent reviews on how recent positive selection has targeted the human genome. They discuss the major findings of genome-wide scans for selection and their strengths and weaknesses.
Trowsdale, J. & Parham, P. Mini-review: defense strategies and immunity-related genes. Eur. J. Immunol. 34, 7–17 (2004).
Varki, A. A chimpanzee genome project is a biomedical imperative. Genome Res. 10, 1065–1070 (2000).
Varki, A. & Altheide, T. K. Comparing the human and chimpanzee genomes: searching for needles in a haystack. Genome Res. 15, 1746–1758 (2005).
Yang, Z. Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution. Mol. Biol. Evol. 15, 568–573 (1998).
Arbiza, L., Dopazo, J. & Dopazo, H. Positive selection, relaxation, and acceleration in the evolution of the human and chimp genome. PLoS Comput. Biol. 2, e38 (2006).
Bustamante, C. D. et al. Natural selection on protein-coding genes in the human genome. Nature 437, 1153–1157 (2005). This paper assesses the genome-wide impact of weak negative and positive selection on protein-coding regions since humans and chimpanzees started to diverge.
The Chimpanzee Sequencing and Analysis Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).
Gibbs, R. A. et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science 316, 222–234 (2007).
Nielsen, R. et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol. 3, e170 (2005).
Kosiol, C. et al. Patterns of positive selection in six mammalian genomes. PLoS Genet. 4, e1000144 (2008).
International Chicken Genome Sequencing Consortium. Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. Nature 432, 695–716 (2004).
Clark, A. G. et al. Inferring nonneutral evolution from human–chimp–mouse orthologous gene trios. Science 302, 1960–1963 (2003). The first genome-wide analysis of genes evolving under positive selection in the human evolutionary lineage.
Bakewell, M. A., Shi, P. & Zhang, J. More genes underwent positive selection in chimpanzee evolution than in human evolution. Proc. Natl Acad. Sci. USA 104, 7489–7494 (2007).
Vamathevan, J. J. et al. The role of positive selection in determining the molecular cause of species differences in disease. BMC Evol. Biol. 8, 273 (2008).
Sharp, P. M., Shaw, G. M. & Hahn, B. H. Simian immunodeficiency virus infection of chimpanzees. J. Virol. 79, 3891–3902 (2005).
Silvestri, G. Immunity in natural SIV infections. J. Intern. Med. 265, 97–109 (2009).
Keele, B. F. et al. Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz. Nature 460, 515–519 (2009).
Seeler, J. S., Muchardt, C., Suessle, A. & Gaynor, R. B. Transcription factor PRDII-BF1 activates human immunodeficiency virus type 1 gene expression. J. Virol. 68, 1002–1009 (1994).
Gonzalez, E. et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science 307, 1434–1440 (2005).
Degenhardt, J. D. et al. Copy number variation of CCL3-like genes affects rate of progression to simian-AIDS in rhesus macaques (Macaca mulatta). PLoS Genet. 5, e1000346 (2009).
Baum, J., Ward, R. H. & Conway, D. J. Natural selection on the erythrocyte surface. Mol. Biol. Evol. 19, 223–229 (2002).
Wang, H. Y., Tang, H., Shen, C. K. & Wu, C. I. Rapidly evolving genes in human. I. The glycophorins and their possible role in evading malaria parasites. Mol. Biol. Evol. 20, 1795–1804 (2003).
Wilder, J. A., Hewett, E. K. & Gansner, M. E. Molecular evolution of GYPC: evidence for recent structural innovation and positive selection in humans. Mol. Biol. Evol. 13 Aug 2009 (doi:10.1093/molbev/msp183).
Maier, A. G. et al. Plasmodium falciparum erythrocyte invasion through glycophorin C and selection for Gerbich negativity in human populations. Nature Med. 9, 87–92 (2003).
Sim, B. K., Chitnis, C. E., Wasniowska, K., Hadley, T. J. & Miller, L. H. Receptor and ligand domains for invasion of erythrocytes by Plasmodium falciparum. Science 264, 1941–1944 (1994).
Martin, M. J., Rayner, J. C., Gagneux, P., Barnwell, J. W. & Varki, A. Evolution of human–chimpanzee differences in malaria susceptibility: relationship to human genetic loss of N-glycolylneuraminic acid. Proc. Natl Acad. Sci. USA 102, 12819–12824 (2005).
King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975).
Blekhman, R., Oshlack, A., Chabot, A. E., Smyth, G. K. & Gilad, Y. Gene regulation in primates evolves under tissue-specific selection pressures. PLoS Genet. 4, e1000271 (2008).
Hahn, M. W., Demuth, J. P. & Han, S. G. Accelerated rate of gene gain and loss in primates. Genetics 177, 1941–1949 (2007).
Wang, X., Grus, W. E. & Zhang, J. Gene losses during human origins. PLoS Biol. 4, e52 (2006).
Dumas, L. et al. Gene copy number variation spanning 60 million years of human and primate evolution. Genome Res. 17, 1266–1277 (2007).
Carlson, C. S. et al. Genomic regions exhibiting positive selection identified from dense genotype data. Genome Res. 15, 1553–1565 (2005).
Kelley, J. L., Madeoy, J., Calhoun, J. C., Swanson, W. & Akey, J. M. Genomic signatures of positive selection in humans and the limits of outlier approaches. Genome Res. 16, 980–989 (2006).
Williamson, S. H. et al. Localizing recent adaptive evolution in the human genome. PLoS Genet. 3, e90 (2007).
Barreiro, L. B., Laval, G., Quach, H., Patin, E. & Quintana-Murci, L. Natural selection has driven population differentiation in modern humans. Nature Genet. 40, 340–345 (2008).
Kimura, R., Fujimoto, A., Tokunaga, K. & Ohashi, J. A practical genome scan for population-specific strong selective sweeps that have reached fixation. PLoS ONE 2, e286 (2007).
Sabeti, P. C. et al. Genome-wide detection and characterization of positive selection in human populations. Nature 449, 913–918 (2007).
Tang, K., Thornton, K. R. & Stoneking, M. A new approach for using genome scans to detect recent positive selection in the human genome. PLoS Biol. 5, e171 (2007).
Voight, B. F., Kudaravalli, S., Wen, X. & Pritchard, J. K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006). This paper reports a genome-wide scan, based on haplotype structure information, for recent and ongoing positive selection in human populations.
Wang, E. T., Kodama, G., Baldi, P. & Moyzis, R. K. Global landscape of recent inferred Darwinian selection for Homo sapiens. Proc. Natl Acad. Sci. USA 103, 135–140 (2006).
Wolfe, N. D., Dunavan, C. P. & Diamond, J. Origins of major human infectious diseases. Nature 447, 279–283 (2007).
Anderson, R. M. & May, R. M. Infectious Diseases of Humans: Dynamics and Control (Oxford Univ. Press, 1991).
Fumagalli, M. et al. Widespread balancing selection and pathogen-driven selection at blood group antigen genes. Genome Res. 19, 199–212 (2009).
Fumagalli, M. et al. Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. J. Exp. Med. 206, 1395–1408 (2009).
Prugnolle, F. et al. Pathogen-driven selection and worldwide HLA class I diversity. Curr. Biol. 15, 1022–1027 (2005). The first study to correlate the worldwide genetic diversity at HLA class I genes with pathogen presence.
Hughes, A. L. & Nei, M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature 335, 167–170 (1988).
Hedrick, P. W., Whittam, T. S. & Parham, P. Heterozygosity at individual amino acid sites: extremely high levels for HLA-A and -B genes. Proc. Natl Acad. Sci. USA 88, 5897–5901 (1991).
Takahata, N., Satta, Y. & Klein, J. Polymorphism and balancing selection at major histocompatibility complex loci. Genetics 130, 925–938 (1992). References 60–62 describe how the extraordinary levels of genetic diversity observed at the major histocompatibility complex may result from the action of balancing selection.
Bamshad, M. J. et al. A strong signature of balancing selection in the 5′ cis-regulatory region of CCR5. Proc. Natl Acad. Sci. USA 99, 10539–10544 (2002).
Novembre, J., Galvani, A. P. & Slatkin, M. The geographic spread of the CCR5 Δ32 HIV-resistance allele. PLoS Biol. 3, e339 (2005).
Stephens, J. C. et al. Dating the origin of the CCR5-Δ32 AIDS-resistance allele by the coalescence of haplotypes. Am. J. Hum. Genet. 62, 1507–1515 (1998).
Sabeti, P. C. et al. The case for selection at CCR5-Δ32. PLoS Biol. 3, e378 (2005).
Arenzana-Seisdedos, F. & Parmentier, M. Genetics of resistance to HIV infection: role of co-receptors and co-receptor ligands. Semin. Immunol. 18, 387–403 (2006).
Gonzalez, E. et al. Race-specific HIV-1 disease-modifying effects associated with CCR5 haplotypes. Proc. Natl Acad. Sci. USA 96, 12004–12009 (1999).
Lalani, A. S. et al. Use of chemokine receptors by poxviruses. Science 286, 1968–1971 (1999).
Single, R. M. et al. Global diversity and evidence for coevolution of KIR and HLA. Nature Genet. 39, 1114–1119 (2007).
Chaix, R., Cao, C. & Donnelly, P. Is mate choice in humans MHC-dependent? PLoS Genet. 4, e1000184 (2008).
Ober, C. et al. HLA and mate choice in humans. Am. J. Hum. Genet. 61, 497–504 (1997).
Parham, P. & Ohta, T. Population biology of antigen presentation by MHC class I molecules. Science 272, 67–74 (1996).
Snow, R. W., Guerra, C. A., Noor, A. M., Myint, H. Y. & Hay, S. I. The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434, 214–217 (2005).
Kwiatkowski, D. P. How malaria has affected the human genome and what human genetics can teach us about malaria. Am. J. Hum. Genet. 77, 171–192 (2005). The most comprehensive review of the genetic basis of resistance to malaria in humans and the selective pressures that are exerted by malaria in the human genome.
Flint, J., Harding, R. M., Boyce, A. J. & Clegg, J. B. The population genetics of the haemoglobinopathies. Baillieres Clin. Haematol. 11, 1–51 (1998).
Agarwal, A. et al. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 96, 2358–2363 (2000).
Modiano, D. et al. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414, 305–308 (2001).
Chotivanich, K. et al. Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P. falciparum malaria. Blood 100, 1172–1176 (2002).
Ohashi, J. et al. Extended linkage disequilibrium surrounding the hemoglobin E variant due to malarial selection. Am. J. Hum. Genet. 74, 1198–1208 (2004).
Chitnis, C. E. & Miller, L. H. Identification of the erythrocyte binding domains of Plasmodium vivax and Plasmodium knowlesi proteins involved in erythrocyte invasion. J. Exp. Med. 180, 497–506 (1994).
Tournamille, C., Colin, Y., Cartron, J. P. & Le Van Kim, C. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nature Genet. 10, 224–228 (1995).
Cavalli-Sforza, L. L., Menozzi, P. & Piazza, A. The History and Geography of Human Genes (Princeton Univ. Press, 1994).
Hamblin, M. T. & Di Rienzo, A. Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am. J. Hum. Genet. 66, 1669–1679 (2000).
Hamblin, M. T., Thompson, E. E. & Di Rienzo, A. Complex signatures of natural selection at the Duffy blood group locus. Am. J. Hum. Genet. 70, 369–383 (2002).
Aitman, T. J. et al. Malaria susceptibility and CD36 mutation. Nature 405, 1015–1016 (2000).
Ruwende, C. & Hill, A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J. Mol. Med. 76, 581–588 (1998).
Sabeti, P. et al. CD40L association with protection from severe malaria. Genes Immun. 3, 286–291 (2002).
The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Sabeti, P. C. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).
Currat, M. et al. Molecular analysis of the β-globin gene cluster in the Niokholo Mandenka population reveals a recent origin of the βS Senegal mutation. Am. J. Hum. Genet. 70, 207–223 (2002).
Saunders, M. A., Hammer, M. F. & Nachman, M. W. Nucleotide variability at G6pd and the signature of malarial selection in humans. Genetics 162, 1849–1861 (2002).
Tishkoff, S. A. et al. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293, 455–462 (2001).
Joy, D. A. et al. Early origin and recent expansion of Plasmodium falciparum. Science 300, 318–321 (2003).
Coluzzi, M., Sabatini, A., della Torre, A., Di Deco, M. A. & Petrarca, V. A polytene chromosome analysis of the Anopheles gambiae species complex. Science 298, 1415–1418 (2002).
Barreiro, L. B. et al. Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense. PLoS Genet. 5, e1000562 (2009). The first evolutionary dissection of how natural selection has targeted the TLR family members in humans.
Dobson, A. in The Cambridge Encyclopedia of Human Evolution (eds Jones, S., Martin, R. & Pilbeam, D.) 411–420 (Cambridge Univ. Press, 1992).
Quintana-Murci, L., Alcais, A., Abel, L. & Casanova, J. L. Immunology in natura: clinical, epidemiological and evolutionary genetics of infectious diseases. Nature Immunol. 8, 1165–1171 (2007).
Garred, P., Larsen, F., Seyfarth, J., Fujita, R. & Madsen, H. O. Mannose-binding lectin and its genetic variants. Genes Immun. 7, 85–94 (2006).
Casanova, J. L. & Abel, L. Human mannose-binding lectin in immunity: friend, foe, or both? J. Exp. Med. 199, 1295–1299 (2004).
Eisen, D. P. & Minchinton, R. M. Impact of mannose-binding lectin on susceptibility to infectious diseases. Clin. Infect. Dis. 37, 1496–1505 (2003).
Verdu, P. et al. Evolutionary insights into the high worldwide prevalence of MBL2 deficiency alleles. Hum. Mol. Genet. 15, 2650–2658 (2006).
Bernig, T. et al. Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection. Genes Immun. 5, 461–476 (2004).
Mukherjee, S., Sarkar-Roy, N., Wagener, D. K. & Majumder, P. P. Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature. Proc. Natl Acad. Sci. USA 106, 7073–7078 (2009).
Walsh, E. C. et al. Searching for signals of evolutionary selection in 168 genes related to immune function. Hum. Genet. 119, 92–102 (2006).
Lynch, N. J. et al. L-ficolin specifically binds to lipoteichoic acid, a cell wall constituent of Gram-positive bacteria, and activates the lectin pathway of complement. J. Immunol. 172, 1198–1202 (2004).
Roos, A. et al. Antibody-mediated activation of the classical pathway of complement may compensate for mannose-binding lectin deficiency. Eur. J. Immunol. 34, 2589–2598 (2004).
Hayashi, F. et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 410, 1099–1103 (2001).
Hawn, T. R. et al. A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease. J. Exp. Med. 198, 1563–1572 (2003).
Wlasiuk, G., Khan, S., Switzer, W. M. & Nachman, M. W. A history of recurrent positive selection at the Toll-like receptor 5 in primates. Mol. Biol. Evol. 26, 937–949 (2009).
Hawn, T. R. et al. A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc. Natl Acad. Sci. USA 102, 10593–10597 (2005).
Franchi, L. et al. Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1β in salmonella-infected macrophages. Nature Immunol. 7, 576–582 (2006).
Miao, E. A., Andersen-Nissen, E., Warren, S. E. & Aderem, A. TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin. Immunopathol. 29, 275–288 (2007).
Olson, M. V. When less is more: gene loss as an engine of evolutionary change. Am. J. Hum. Genet. 64, 18–23 (1999).
Hirayasu, K. et al. Evidence for natural selection on leukocyte immunoglobulin-like receptors for HLA class I in Northeast Asians. Am. J. Hum. Genet. 82, 1075–1083 (2008).
Seixas, S. et al. Sequence diversity at the proximal 14q32.1 SERPIN subcluster: evidence for natural selection favoring the pseudogenization of SERPINA2. Mol. Biol. Evol. 24, 587–598 (2007).
Xue, Y. et al. Spread of an inactive form of caspase-12 in humans is due to recent positive selection. Am. J. Hum. Genet. 78, 659–670 (2006). An intriguing example of how the loss of an immunity-related gene can represent a selective advantage in humans.
Yngvadottir, B. et al. A genome-wide survey of the prevalence and evolutionary forces acting on human nonsense SNPs. Am. J. Hum. Genet. 84, 224–234 (2009).
Saleh, M. et al. Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms. Nature 429, 75–79 (2004).
Scott, A. M. & Saleh, M. The inflammatory caspases: guardians against infections and sepsis. Cell Death Differ. 14, 23–31 (2007).
Perry, G. H. et al. Copy number variation and evolution in humans and chimpanzees. Genome Res. 18, 1698–1710 (2008).
Blekhman, R. et al. Natural selection on genes that underlie human disease susceptibility. Curr. Biol. 18, 883–889 (2008).
Nielsen, R. et al. Darwinian and demographic forces affecting human protein coding genes. Genome Res. 19, 838–849 (2009).
Picard, C. et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 299, 2076–2079 (2003).
von Bernuth, H. et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321, 691–696 (2008).
Zhang, S. Y. et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science 317, 1522–1527 (2007).
Casanova, J. L. & Abel, L. Human genetics of infectious diseases: a unified theory. EMBO J. 26, 915–922 (2007). An important review of the genetic basis of infectious diseases in humans, bridging the dysfunctional gap between Mendelian genetics and population-based complex genetics.
Di Rienzo, A. Population genetics models of common diseases. Curr. Opin. Genet. Dev. 16, 630–636 (2006).
Smirnova, I., Hamblin, M. T., McBride, C., Beutler, B. & Di Rienzo, A. Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans. Genetics 158, 1657–1664 (2001).
Schroder, N. W. & Schumann, R. R. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect. Dis. 5, 156–164 (2005).
Ma, X. et al. Full-exon resequencing reveals Toll-like receptor variants contribute to human susceptibility to tuberculosis disease. PLoS ONE 2, e1318 (2007).
Misch, E. A. et al. Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction. PLoS Negl. Trop. Dis. 2, e231 (2008).
Pickrell, J. K. et al. Signals of recent positive selection in a worldwide sample of human populations. Genome Res. 19, 826–837 (2009).
Gilad, Y., Rifkin, S. A. & Pritchard, J. K. Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet. 24, 408–415 (2008).
Dimas, A. S. et al. Modifier effects between regulatory and protein-coding variation. PLoS Genet. 4, e1000244 (2008).
Stranger, B. E. et al. Population genomics of human gene expression. Nature Genet. 39, 1217–1224 (2007).
Kudaravalli, S., Veyrieras, J. B., Stranger, B. E., Dermitzakis, E. T. & Pritchard, J. K. Gene expression levels are a target of recent natural selection in the human genome. Mol. Biol. Evol. 26, 649–658 (2009).
Dimas, A. S. et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246–1250 (2009).
Ko, D. C. et al. A genome-wide in vitro bacterial-infection screen reveals human variation in the host response associated with inflammatory disease. Am. J. Hum. Genet. 85, 214–227 (2009).
Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).
Beutler, B. et al. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24, 353–389 (2006).
Medzhitov, R. Toll-like receptors and innate immunity. Nature Rev. Immunol. 1, 135–145 (2001).
Leulier, F. & Lemaitre, B. Toll-like receptors — taking an evolutionary approach. Nature Rev. Genet. 9, 165–178 (2008). An outstanding overview of the origins, evolution and different functions of TLRs across the animal kingdom.
Kawai, T. & Akira, S. Innate immune recognition of viral infection. Nature Immunol. 7, 131–137 (2006).
Geijtenbeek, T. B., van Vliet, S. J., Engering, A., ' t Hart, B. A. & van Kooyk, Y. Self- and nonself-recognition by C-type lectins on dendritic cells. Annu. Rev. Immunol. 22, 33–54 (2004).
Fritz, J. H., Ferrero, R. L., Philpott, D. J. & Girardin, S. E. Nod-like proteins in immunity, inflammation and disease. Nature Immunol. 7, 1250–1257 (2006).
Takeuchi, O. & Akira, S. Recognition of viruses by innate immunity. Immunol. Rev. 220, 214–224 (2007).
Schatz, D. G., Oettinger, M. A. & Schlissel, M. S. V(D)J recombination: molecular biology and regulation. Annu. Rev. Immunol. 10, 359–383 (1992).
Bendelac, A., Bonneville, M. & Kearney, J. F. Autoreactivity by design: innate B and T lymphocytes. Nature Rev. Immunol. 1, 177–186 (2001).
Klein, J. Natural History of the Major Histocompatibility Complex (Wiley, New York, 1986).
McDevitt, H. O. Discovering the role of the major histocompatibility complex in the immune response. Annu. Rev. Immunol. 18, 1–17 (2000).
Hurst, L. D. Genetics and the understanding of selection. Nature Rev. Genet. 10, 83–93 (2009).
Nielsen, R. Molecular signatures of natural selection. Annu. Rev. Genet. 39, 197–218 (2005).
Kreitman, M. Methods to detect selection in populations with applications to the human. Annu. Rev. Genomics Hum. Genet. 1, 539–559 (2000). References 152–154 are thorough reviews on how natural selection acts, its signatures and implications, and the different methods used for detecting selection based on population genetic data.
Eyre-Walker, A. & Keightley, P. D. High genomic deleterious mutation rates in hominids. Nature 397, 344–347 (1999).
Kryukov, G. V., Pennacchio, L. A. & Sunyaev, S. R. Most rare missense alleles are deleterious in humans: implications for complex disease and association studies. Am. J. Hum. Genet. 80, 727–739 (2007).
Przeworski, M., Coop, G. & Wall, J. D. The signature of positive selection on standing genetic variation. Evolution 59, 2312–2323 (2005).
Charlesworth, D. Balancing selection and its effects on sequences in nearby genome regions. PLoS Genet. 2, e64 (2006).
McDonald, J. H. & Kreitman, M. Adaptive protein evolution at the Adh locus in Drosophila. Nature 351, 652–654 (1991).
Nielsen, R. & Yang, Z. Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene. Genetics 148, 929–936 (1998).
Yang, Z. & Bielawski, J. P. Statistical methods for detecting molecular adaptation. Trends Ecol. Evol. 15, 496–503 (2000).
Guindon, S., Black, M. & Rodrigo, A. Proceedings of the SMBE Tri-National Young Investigators' Workshop 2005. Control of the false discovery rate applied to the detection of positively selected amino acid sites. Mol. Biol. Evol. 23, 919–926 (2006).
Thornton, K. R., Jensen, J. D., Becquet, C. & Andolfatto, P. Progress and prospects in mapping recent selection in the genome. Heredity 98, 340–348 (2007).
Weir, C. L. & Cockerham, C. C. Estimating F-statistics for the analysis of population structure. Evolution 38, 1358–1370 (1984).
Hartl, D. L. & Clark, A. G. Principles of Population Genetics (Sinauer Associates Inc., Sunderland, 2007).
Phillips, P. C. Epistasis — the essential role of gene interactions in the structure and evolution of genetic systems. Nature Rev. Genet. 9, 855–867 (2008).
Vilches, C. & Parham, P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu. Rev. Immunol. 20, 217–251 (2002).
Rajagopalan, S. & Long, E. O. Understanding how combinations of HLA and KIR genes influence disease. J. Exp. Med. 201, 1025–1029 (2005).
Norman, P. J. et al. Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans. Nature Genet. 39, 1092–1099 (2007).
Acknowledgements
We would like to thank L. Abel, M. Ben-Ali, J. L. Casanova, Y. Gilad, B. Jabri, O. Neyrolles, E. Patin, G. Perry, M. Przeworski, H. Quach and P. Sansonetti for helpful comments and discussions, and J. Akey, M. Carrington and R. Single for sharing data that helped the writing of this Review. L.B.B. is supported by a Human Frontier Science Program postdoctoral fellowship. This work was supported by the Institut Pasteur, the Centre National de la Recherche Scientifique, the Fondation pour la Recherche Médicale, and an Agence Nationale de la Recherche research grant (ANR-08-MIEN-009-01) to L.Q.-M.
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Supplementary information
Supplementary Table 1
List of immunity-related genes reported to be rapidly evolving in the human-lineage, in the chimpanzee-lineage, or in both. (XLS 58 kb)
Supplementary Table 2
List of immunity-related genes presenting signatures of recent positive selection as revealed by at least one genome-wide scan for selection. (XLS 118 kb)
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Supplementary Note (PDF 266 kb)
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FURTHER INFORMATION
Lluís Quintana-Murci's laboratory
Human Genome Diversity Project selection browser
Innate Immunity Program in Genomics Applications
National Human Genome Research Institute catalogue of published GWA studies
National Institute of Environmental Health Sciences Environmental Genome Project
Glossary
- Innate immunity
-
Non-specific and evolutionarily ancient mechanisms that form the first line of host defence against infection. Innate immunity, which is inborn and does not involve memory, provides immediate defence and is found in all classes of plants and animals.
- Adaptive immunity
-
A highly adaptable and specific immune response that can adjust to new pathogens (structures) and that retains a memory of prior exposure to them. Thought to have arisen in jawed vertebrates, the adaptive immune system is stimulated by the innate immune system.
- McDonald–Kreitman test
-
The McDonald–Kreitman test compares the ratio of polymorphism (within-species variation) to divergence (between-species variation) at non-synonymous and synonymous sites.
- Gene Ontology
-
A widely used classification system of gene functions and other gene attributes that uses a controlled vocabulary. The ontology covers three domains; cellular components, molecular functions and biological processes.
- Simian immunodeficiency virus
-
A type of retrovirus found in African non-human primates. Unlike HIV infections in humans, simian immunodeficiency virus infections in their natural hosts are usually non-pathogenic.
- Copy-number variation
-
A class of DNA sequence variant (including deletions and duplications) in which the result is a departure from the expected diploid representation of DNA sequence.
- Erythrocyte
-
A cell that contains haemoglobin and that can carry oxygen to the body. They are also known as red blood cells.
- Antigen
-
Any substance that the immune system can respond to by producing antibodies.
- Linkage disequilibrium
-
The non-random association of alleles at two or more loci. The pattern of linkage disequilibrium in a genomic region is affected by mutation, recombination, genetic drift, natural selection and demographic history.
- Genetic hitchhiking
-
The process by which a neutral, or in some cases deleterious, mutation may increase in population frequency owing to linkage with a positively selected mutation.
- Outlier approaches
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Popular approaches for detecting selection that identify loci that present extreme values for a given statistic from empirical genome-wide genetic data. It is assumed that these 'outlier loci' are enriched for loci targeted by selection.
- Interleukins
-
A group of secreted proteins that are produced by immune cells and that can modulate immune and inflammatory responses.
- Fixation
-
The increase in the frequency of a genetic variant in a population to 100%.
- Haplotype
-
The allelic composition over a contiguous chromosome stretch.
- Complement pathway
-
The complement system is a complex protein cascade that is involved in both innate and adaptive immunity. Three pathways activate the complement system: the classical pathway, the alternative pathway and the lectin pathway.
- Ficolins
-
A group of humoral proteins that contain a collagen-like domain and a fibrinogen-like domain. They can bind carbohydrate molecules on pathogens, apoptotic and necrotic cells to activate the lectin complement pathway.
- Caspases
-
Enzymes that play an important part in the immune system by activating numerous cellular proteins that are involved in apoptosis, necrosis, immunity and inflammation. They are synthesized as inactive procaspases that are later activated by proteolytic cleavage into active caspases.
- Fitness
-
A measure of the capacity of an organism to survive and reproduce.
- Leprosy reversal reaction
-
A syndrome that is characterized by the rapid activation of a T helper 1 inflammatory response to Mycobacterium leprae. This reaction can cause substantial morbidity.
- Genome-wide association studies
-
Studies in which associations between genetic variation and a phenotype or trait of interest are identified by genotyping cases (for example, diseased individuals) and controls (for example, healthy individuals) for a set of genetic variants that capture variation across the entire genome.
- Expression quantitative trait loci
-
Regions of the genome at which genetic allelic variation is associated with variation in gene expression.
- Quantitative trait loci
-
Regions of the genome at which genetic variation is associated with a particular phenotypic characteristic or trait (for example, height, weight or skin colour).
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Barreiro, L., Quintana-Murci, L. From evolutionary genetics to human immunology: how selection shapes host defence genes. Nat Rev Genet 11, 17–30 (2010). https://doi.org/10.1038/nrg2698
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DOI: https://doi.org/10.1038/nrg2698
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