Balancing Selection in the Human Genome

Abstract

Balancing selection maintains advantageous diversity in populations by a variety of mechanisms. As a source for functional polymorphism, it contributes to the genetic and phenotypic diversity of present‐day human populations. Classically, most of our understanding of the influence of balancing selection in humans was based on few well‐known examples, but recent advances at the genome scale (made possible by newly available genomic databases and analytical methods) provide further insights on the influence and targets of balancing selection in humans. Such studies have pointed out the uniqueness of the MHC locus, but suggest that more typical cases of balancing selection exist. Our growing understanding of the targets of balancing selection in humans suggests that although this is not a pervasive force in the human genome, it has played a role in the maintenance of functionally relevant polymorphism in humans.

Key Concepts:

  • Balancing selection maintains genetic and phenotypic diversity in populations.

  • Different mechanisms constitute balancing selection, all of which maintain advantageous polymorphism in populations.

  • Balancing selection is not pervasive in humans, but it has shaped the evolution of critical genes for individual survival.

  • The MHC complex in chromosome 6 shows striking, and unique, genetic signatures of balancing selection.

  • Advantageous diversity for MHC‐dependent antigen presentation has shaped the patterns of diversity of diverse genomic loci.

  • The genetic signatures of balancing selection can be identified both by studying individual genes and by analysing genome‐wide patterns of diversity.

  • Genome‐wide analyses are key to identify previously unknown (and unsuspected) targets of natural selection.

  • Targets of balancing selection remain undiscovered in the human genome.

Keywords: balancing selection; population genomics; evolution; human evolution; genome; overdominance; heterosis; frequency‐dependent selection; diversity; polymorphism

Figure 1.

Expected distribution of allele frequencies (site frequency spectrum, SFS) under (a) neutrality; (b) balancing selection with a frequency equilibrium of 0.5; and (c) balancing selection with a frequency equilibrium of 0.2. The x‐axis represents the number of derived alleles observed in the sample, and the y‐axis the frequency of that allele‐frequency bin in the locus. Note the excess of alleles close to the frequency equilibrium.

Figure 2.

Graphical representation of the haploid coalescent process, with sampled present‐day haplotypes on the bottom and generations growing upwards back in time. Downwards and forward in time, lines connect every haplotype with its offspring. In each generation, every haplotype either does not reproduce (its line goes extinct), it has one offspring (it has one line going downwards) or it has more than one offspring (it has more than one line going downwards). The most recent common ancestor (MRCA) of all individuals in the present‐day sample is shown as the transition between the grey lines (which represents extinct lineages) to solid colour. Neutral mutations, which are depicted as circles, appear randomly at a constant rate. Mutations present in lineages observed in the present‐day sample are SNPs and are depicted as open green circles; those that appeared in extinct lineages are not observed and are depicted as grey circles. Upwards and backwards in time, lines connect every haplotype with its parent haplotype (the haplotype present in its parent). Each pair of present‐day haplotypes finds a common ancestor (they coalesce) at some point in the past, until the MRCA where all present‐day haplotypes first coalesce. (a) Coalescent under neutrality: 21 SNPs and (b) coalescent under balancing selection that maintains two forms (blue and red) that differ in one functional SNP (blue and red circle): 38 SNPs.

Figure 3.

Typical haplotype network of a loci under long‐term balancing selection with a frequency equilibrium of 0.5 and limited recombination between the selected forms. This represents the haplotype network of ERAP2. In this case, haplotype A encodes for a functional form of the protein, whereas haplotype B encodes for a nonfunctional form of ERAP2. Reproduced from Andrés et al. ().

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References

Alonso S, Lopez S, Izagirre N and de la Rua C (2008) Overdominance in the human genome and olfactory receptor activity. Molecular Biological Evolution 25: 997–1001.

Andrés AM, Dennis MY, Kretzschmar WW et al. (2010) Balancing selection maintains a form of ERAP2 that undergoes nonsense‐mediated decay and affects antigen presentation. PLoS Genetics 6: e1001157.

Andrés AM, Hubisz MJ, Indap A et al. (2009) Targets of balancing selection in the human genome. Molecular Biological Evolution 26: 2755–2764.

Asthana S, Schmidt S and Sunyaev S (2005) A limited role for balancing selection. Trends in Genetics 21: 30–32.

Bamshad MJ, Mummidi S, Gonzalez E et al. (2002) A strong signature of balancing selection in the 5’ cis‐regulatory region of CCR5. Proceedings of the National Academy of Sciences of the USA 99: 10539–10544.

Barton NH and Etheridge AM (2004) The effect of selection on genealogies. Genetics 166: 1115–1131.

Bubb KL, Bovee D, Buckley D et al. (2006) Scan of human genome reveals no new loci under ancient balancing selection. Genetics 173: 2165–2177.

Cagliani R, Fumagalli M, Biasin M et al. (2010a) Long‐term balancing selection maintains trans‐specific polymorphisms in the human TRIM5 gene. Human Genetics 128: 577–588.

Cagliani R, Fumagalli M, Riva S et al. (2008) The signature of long‐standing balancing selection at the human defensin beta‐1 promoter. Genome Biology 9: R143.

Cagliani R, Fumagalli M, Riva S et al. (2010b) Polymorphisms in the CPB2 gene are maintained by balancing selection and result in haplotype‐preferential splicing of exon 7. Molecular Biological Evolution 27: 1945–1954.

Cagliani R, Riva S, Biasin M et al. (2010c) Genetic diversity at endoplasmic reticulum aminopeptidases is maintained by balancing selection and is associated with natural resistance to HIV‐1 infection. Human Molecular Genetics 19: 4705–4714.

Charlesworth B, Nordborg M and Charlesworth D (1997) The effects of local selection, balanced polymorphism and background selection on equilibrium patterns of genetic diversity in subdivided populations. Genetic Research 70: 155–174.

Ferrer‐Admetlla A, Bosch E, Sikora M et al. (2008) Balancing selection is the main force shaping the evolution of innate immunity genes. Journal of Immunology 181: 1315–1322.

Ferrer‐Admetlla A, Sikora M, Laayouni H et al. (2009) A natural history of FUT2 polymorphism in humans. Molecular Biological Evolution 26: 1993–2003.

Fumagalli M, Cagliani R, Pozzoli U et al. (2009b) Widespread balancing selection and pathogen‐driven selection at blood group antigen genes. Genome Research 19: 199–212.

Fumagalli M, Pozzoli U, Cagliani R et al. (2009a) Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions. Journal of Experimental Medicine 206: 1395–1408.

Fumagalli M, Pozzoli U, Cagliani R et al. (2010) Genome‐wide identification of susceptibility alleles for viral infections through a population genetics approach. PLoS Genetics 6: e1000849.

Gabriel SE, Brigman KN, Koller BH, Boucher RC and Stutts MJ (1994) Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 266: 107–109.

Garrigan D, Mobasher Z, Kingan SB, Wilder JA and Hammer MF (2005) Deep haplotype divergence and long‐range linkage disequilibrium at xp21.1 provide evidence that humans descend from a structured ancestral population. Genetics 170: 1849–1856.

Gendzekhadze K, Norman PJ, Abi‐Rached L et al. (2009) Co‐evolution of KIR2DL3 with HLA‐C in a human population retaining minimal essential diversity of KIR and HLA class I ligands. Proceedings of the National Academy of Sciences of the USA 106: 18692–18697.

Hartl DL and Clark AG (2007) Principles of Population Genetics. Sunderland, MA: Sinauer Associates.

Hirayasu K, Ohashi J, Kashiwase K et al. (2006) Long‐term persistence of both functional and non‐functional alleles at the leukocyte immunoglobulin‐like receptor A3 (LILRA3) locus suggests balancing selection. Human Genetics 119: 436–443.

Hodgkinson A and Eyre‐Walker A (2010) The genomic distribution and local context of coincident SNPs in human and chimpanzee. Genome Biolecular Evolution 2: 547–557.

Hodgkinson A, Ladoukakis E and Eyre‐Walker A (2009) Cryptic variation in the human mutation rate. PLoS Biology 7: e1000027.

Hudson RR and Kaplan NL (1988) The coalescent process in models with selection and recombination. Genetics 120: 831–840.

Hughes AL, Packer B, Welch R, Chanock SJ and Yeager M (2005) High level of functional polymorphism indicates a unique role of natural selection at human immune system loci. Immunogenetics 57: 821–827.

Muehlenbachs A, Fried M, Lachowitzer J, Mutabingwa TK and Duffy PE (2008) Natural selection of FLT1 alleles and their association with malaria resistance in utero. Proceedings of the National Academy of Sciences of the USA 105: 14488–14491.

Mukherjee S, Sarkar‐Roy N, Wagener DK and Majumder PP (2009) Signatures of natural selection are not uniform across genes of innate immune system, but purifying selection is the dominant signature. Proceedings of the National Academy of Sciences of the USA 106: 7073–7078.

Newbigin E and Uyenoyama MK (2005) The evolutionary dynamics of self‐incompatibility systems. Trends in Genetics 21: 500–505.

Newman RM, Hall L, Connole M et al. (2006) Balancing selection and the evolution of functional polymorphism in Old World monkey TRIM5alpha. Proceedings of the National Academy of Sciences of the USA 103: 19134–19139.

Nielsen R, Hubisz MJ, Hellmann I et al. (2009) Darwinian and demographic forces affecting human protein coding genes. Genome Research 19: 838–849.

Nordborg M (1997) Structured coalescent processes on different time scales. Genetics 146: 1501–1514.

Norman PJ, Abi‐Rached L, Gendzekhadze K et al. (2007) Unusual selection on the KIR3DL1/S1 natural killer cell receptor in Africans. Nature Genetics 39: 1092–1099.

Olendorf R, Rodd FH, Punzalan D et al. (2006) Frequency‐dependent survival in natural guppy populations. Nature 441: 633–636.

Pasvol G, Weatherall DJ and Wilson RJ (1978) Cellular mechanism for the protective effect of haemoglobin S against P. falciparum malaria. Nature 274: 701–703.

Plagnol V and Wall JD (2006) Possible ancestral structure in human populations. PLoS Genetics 2: e105.

Prugnolle F, Manica A, Charpentier M et al. (2005) Pathogen‐driven selection and worldwide HLA class I diversity. Current Biology 15: 1022–1027.

Quinton PM (1994) Human genetics. What is good about cystic fibrosis? Current Biology 4: 742–743.

Single RM, Martin MP, Gao X et al. (2007) Global diversity and evidence for coevolution of KIR and HLA. Nature Genetics 39: 1114–1119.

Smith MJ (1998) Evolutionary Genetics. Oxford, NY: Oxford University Press.

Takahata N and Nei M (1990) Allelic genealogy under overdominant and frequency‐dependent selection and polymorphism of major histocompatibility complex loci. Genetics 124: 967–978.

Wall JD (2000) Detecting ancient admixture in humans using sequence polymorphism data. Genetics 154: 1271–1279.

Wang K, Baldassano R, Zhang H et al. (2010) Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects. Human Molecular Genetics 19: 2059–2067.

Williamson S, Fledel‐Alon A and Bustamante CD (2004) Population genetics of polymorphism and divergence for diploid selection models with arbitrary dominance. Genetics 168: 463–475.

Further Reading

Bamshad M and Wooding SP (2003) Signatures of natural selection in the human genome. Nature Review. Genetics 4: 99–111.

Barreiro LB and Quintana‐Murci L (2010) From evolutionary genetics to human immunology: how selection shapes host defence genes. Nature Review. Genetics 11: 17–30.

Hein J, Schierup MH and Wiuf C (2005) Gene Genealogies, Variation and Evolution. Oxford: Oxford University Press.

Mitchell‐Olds T, Willis JH and Goldstein DB (2007) Which evolutionary processes influence natural genetic variation for phenotypic traits? Nature Review. Genetics 8: 845–856.

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How to Cite close
Andrés, Aida M(Mar 2011) Balancing Selection in the Human Genome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022863]