Abstract
Copy number variants (CNVs), deletions and duplications of segments of DNA, account for at least five times more variable base pairs in humans than single-nucleotide variants. Several common CNVs were shown to change coding and regulatory sequences and thus dramatically affect adaptive phenotypes involving immunity, perception, metabolism, skin structure, among others. Some of these CNVs were also associated with susceptibility to cancer, infection, and metabolic disorders. These observations raise the possibility that CNVs are a primary contributor to human phenotypic variation and consequently evolve under selective pressures. Indeed, locus-specific haplotype-level analyses revealed signatures of natural selection on several CNVs. However, more traditional tests of selection which are often applied to single-nucleotide variation often have diminished statistical power when applied to CNVs because they often do not show strong linkage disequilibrium with nearby variants. Recombination-based formation mechanisms of CNVs lead to frequent recurrence and gene conversion events, breaking the linkage disequilibrium involving CNVs. Similar methodological challenges also prevent routine genome-wide association studies to adequately investigate the impact of CNVs on heritable human disease. Thus, we argue that the full relevance of CNVs to human health and evolution is yet to be elucidated. We further argue that a holistic investigation of formation mechanisms within an evolutionary framework would provide a powerful framework to understand the functional and biomedical impact of CNVs. In this paper, we review several cases where studies reveal diverse evolutionary histories and unexpected functional consequences of CNVs. We hope that this review will encourage further work on CNVs by both evolutionary and medical geneticists.
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References
Abyzov A et al (2013) Analysis of variable retroduplications in human populations suggests coupling of retrotransposition to cell division. Genome Res 23:2042–2052
Alkan C, Coe BP, Eichler EE (2011) Genome structural variation discovery and genotyping. Nat Rev Genet 12:363–376
Ambatipudi KS et al (2010) Human common salivary protein 1 (CSP-1) promotes binding of Streptococcus mutans to experimental salivary pellicle and glucans formed on hydroxyapatite surface. J Proteome Res 9:6605–6614
An P et al (2009) APOBEC3B deletion and risk of HIV-1 acquisition. J Infect Dis 200:1054–1058
Arakawa N et al (2019) Expression changes of structural protein genes may be related to adaptive skin characteristics specific to humans. Genome Biol Evol 11:613–628. https://doi.org/10.1093/gbe/evz007
Atkinson FS, Hancock D, Petocz P, Brand-Miller JC (2018) The physiologic and phenotypic significance of variation in human amylase gene copy number. Am J Clin Nutr 108:737–748. https://doi.org/10.1093/ajcn/nqy164
Bailey JA, Yavor AM, Massa HF, Trask BJ, Eichler EE (2001) Segmental duplications: organization and impact within the current human genome project assembly. Genome Res 11:1005–1017
Bailey JA et al (2002) Recent segmental duplications in the human genome. Science 297:1003–1007
Bamshad MJ et al (2002) A strong signature of balancing selection in the 5′ cis-regulatory region of CCR9. Proc Natl Acad Sci U S A 99:10539–10544
Bank RA et al (1992) Variation in gene copy number and polymorphism of the human salivary amylase isoenzyme system in Caucasians. Hum Genet 89:213–222
Behera SK, Praharaj AB, Dehury B, Negi S (2015) Exploring the role and diversity of mucins in health and disease with special insight into non-communicable diseases. Glycoconj J 32:575–613
Bickhart DM, Liu GE (2014) The challenges and importance of structural variation detection in livestock. Front Genet 5:37
Boehlke C, Zierau O, Hannig C (2015) Salivary amylase—the enzyme of unspecialized euryphagous animals. Arch Oral Biol 60:1162–1176. https://doi.org/10.1016/j.archoralbio.2015.05.008
Boettger LM et al (2016) Recurring exon deletions in the HP (haptoglobin) gene contribute to lower blood cholesterol levels. Nat Genet 48:359–366
Bournazos S, Woof JM, Hart SP, Dransfield I (2009) Functional and clinical consequences of Fc receptor polymorphic and copy number variants. Clin Exp Immunol 157:244–254
Bragulla HH, Homberger DG (2009) Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia. J Anat 214:516–559
Burchell B, Brierley CH, Monaghan G, Clarke DJ (1997) The structure and function of the UDP-glucuronosyltransferase gene family. In: Goldstein DS, Eisenhofer G, McCarty R (eds) Advances in pharmacology, vol 42. Academic Press, Cambridge, pp 335–338
Byars SG, Voskarides K (2019) Genes that improved fitness also cost modern humans: evidence for genes with antagonistic effects on longevity and disease. Evol Med Public Health 2019:4–6
Chaisson MJP et al (2019) Multi-platform discovery of haplotype-resolved structural variation in human genomes. Nat Commun 10:1784
Chang HHY, Pannunzio NR, Adachi N, Lieber MR (2017) Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol 18:495–506
Chuong EB, Elde NC, Feschotte C (2017) Regulatory activities of transposable elements: from conflicts to benefits. Nat Rev Genet 18:71–86
Ciomborowska J, Rosikiewicz W, Szklarczyk D, Makałowski W, Makałowska I (2013) ‘Orphan’ retrogenes in the human genome. Mol Biol Evol 30:384–396
Conrad DF et al (2010) Origins and functional impact of copy number variation in the human genome. Nature 464:704–712
Cordaux R, Batzer MA (2009) The impact of retrotransposons on human genome evolution. Nat Rev Genet 10:691–703
Cullen BR (2006) Role and mechanism of action of the APOBEC3 family of antiretroviral resistance factors. J Virol 80:1067–1076
Currall BB, Chiang C, Talkowski ME, Morton CC (2013) Mechanisms for structural variation in the human genome. Curr Genet Med Rep 1:81–90
Daugherty MD, Malik HS (2012) Rules of engagement: molecular insights from host-virus arms races. Annu Rev Genet 46:677–700
de Silva E, Stumpf MPH (2004) HIV and the CCR29-Δ32 resistance allele. FEMS Microbiol Lett 241:1–12
de Cid R et al (2009) Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet 41:211–215
Deininger PL, Moran JV, Batzer MA, Kazazian HH Jr (2003) Mobile elements and mammalian genome evolution. Curr Opin Genet Dev 13:651–658
Dekker J, Rossen JWA, Büller HA, Einerhand AWC (2002) The MUC family: an obituary. Trends Biochem Sci 27:126–131
Derti A, Roth FP, Church GM, Wu C-T (2006) Mammalian ultraconserved elements are strongly depleted among segmental duplications and copy number variants. Nat Genet 38:1216–1220
Duane WC, Frerichs R, Levitt MD (1972) Simultaneous study of the metabolic turnover and renal excretion of salivary amylase-125I and pancreatic amylase-131I in the baboon. J Clin Invest 51:1504–1513
Eaaswarkhanth M et al (2016) Atopic dermatitis susceptibility variants in filaggrin hitchhike hornerin selective sweep. Genome Biol Evol 8:3240–3255
Eichler EE (2019) Genetic variation, comparative genomics, and the diagnosis of disease. N Engl J Med 381:64–74
Enard D, Depaulis F, Roest Crollius H (2010) Human and non-human primate genomes share hotspots of positive selection. PLoS Genet 6:e1000840
Fábián TK, Hermann P, Beck A, Fejérdy P, Fábián G (2012) Salivary defense proteins: their network and role in innate and acquired oral immunity. Int J Mol Sci 13:4295–4320
Fablet M, Bueno M, Potrzebowski L, Kaessmann H (2009) Evolutionary origin and functions of retrogene introns. Mol Biol Evol 26:2147–2156
Falchi M et al (2014) Low copy number of the salivary amylase gene predisposes to obesity. Nat Genet 46:492–497
Fan H, Chu J-Y (2007) A brief review of short tandem repeat mutation. Genom Proteom Bioinform 5:7–14
Feschotte C (2008) Transposable elements and the evolution of regulatory networks. Nat Rev Genet 9:397–405
Fu W, Zhang F, Wang Y, Gu X, Jin L (2010) Identification of copy number variation hotspots in human populations. Am J Hum Genet 87:494–504
Galvani AP, Novembre J (2005) The evolutionary history of the CCR43-Δ32 HIV-resistance mutation. Microbes Infect 7:302–309
Gilad Y, Przeworski M, Lancet D (2004) Loss of olfactory receptor genes coincides with the acquisition of full trichromatic vision in primates. PLoS Biol 2:E5
Girirajan S, Campbell CD, Eichler EE (2011) Human copy number variation and complex genetic disease. Annu Rev Genet 45:203–226
Go Y, Niimura Y (2008) Similar numbers but different repertoires of olfactory receptor genes in humans and chimpanzees. Mol Biol Evol 25:1897–1907
Gokcumen O et al (2011) Refinement of primate copy number variation hotspots identifies candidate genomic regions evolving under positive selection. Genome Biol 12:R52
Gokcumen O et al (2013) Primate genome architecture influences structural variation mechanisms and functional consequences. Proc Natl Acad Sci U S A 110:15764–15769
Gu S et al (2015) Alu-mediated diverse and complex pathogenic copy-number variants within human chromosome 17 at p13.3. Hum Mol Genet 24:4061–4077
Gumucio DL, Wiebauer K, Caldwell RM, Samuelson LC, Meisler MH (1988) Concerted evolution of human amylase genes. Mol Cell Biol 8:1197–1205
Gurdasani D, Barroso I, Zeggini E, Sandhu MS (2019) Genomics of disease risk in globally diverse populations. Nat Rev Genet 20:520–535. https://doi.org/10.1038/s41576-019-0144-0
Hagenbüchle O, Bovey R, Young RA (1980) Tissue-specific expression of mouse α-amylase genes: nucleotide sequence of isoenzyme mRNAs from pancreas and salivary gland. Cell 21:179–187. https://doi.org/10.1016/0092-8674(80)90125-7
Hahn MW, Demuth JP, Han S-G (2007) Accelerated rate of gene gain and loss in primates. Genetics 177:1941–1949
Hastings PJ, Lupski JR, Rosenberg SM, Ira G (2009) Mechanisms of change in gene copy number. Nat Rev Genet 10:551–564
Hayden S et al (2014) A cluster of olfactory receptor genes linked to frugivory in bats. Mol Biol Evol 31:917–927
Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88
Hedges DJ, Batzer MA (2005) From the margins of the genome: mobile elements shape primate evolution. BioEssays 27:785–794
Hirata H et al (2010) Function of UDP-glucuronosyltransferase 2B17 (UGT2B17) is involved in endometrial cancer. Carcinogenesis 31:1620–1626
Hollox EJ, Armour JAL (2008) Directional and balancing selection in human beta-defensins. BMC Evol Biol 8:113
Hoover KC et al (2015) Global survey of variation in a human olfactory receptor gene reveals signatures of non-neutral evolution. Chem Senses 40:481–488
Hrdy D, Baden HP (1973) Biochemical variation of hair keratins in man and non-human primates. Am J Phys Anthropol 39:19–24
Huddleston J et al (2017) Discovery and genotyping of structural variation from long-read haploid genome sequence data. Genome Res 27:677–685
Hurles M (2004) Gene duplication: the genomic trade in spare parts. PLoS Biol 2:E206
Imahashi M et al (2014) Lack of association between intact/deletion polymorphisms of the APOBEC3B gene and HIV-1 risk. PLoS ONE 9:e92861
Iskow RC, Gokcumen O, Lee C (2012) Exploring the role of copy number variants in human adaptation. Trends Genet 28:245–257
Itaya S et al (2010) No evidence of an association between the APOBEC3B deletion polymorphism and susceptibility to HIV infection and AIDS in Japanese and Indian populations. J Infect Dis 202:815–816 (author reply 816–817)
Jablonski NG (2008) Skin: a natural history. University of California Press, Berkeley
Jablonski NG, Chaplin G (2000) The evolution of human skin coloration. J Hum Evol 39:57–106
Jackson B et al (2005) Late cornified envelope family in differentiating epithelia—response to calcium and ultraviolet irradiation. J Invest Dermatol 124:1062–1070
Jancova P, Anzenbacher P, Anzenbacherova E (2010) Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154:103–116
Jha P et al (2012) Deletion of the APOBEC3B gene strongly impacts susceptibility to falciparum malaria. Infect Genet Evol 12:142–148
Jiang W et al (2012) Copy number variation leads to considerable diversity for B but not A haplotypes of the human KIR genes encoding NK cell receptors. Genome Res 22:1845–1854
Karypidis A-H, Olsson M, Andersson S-O, Rane A, Ekström L (2008) Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate. Pharmacogenom J 8:147–151
Kawamura S, Melin AD (2017) Evolution of genes for color vision and the chemical senses in primates. In: Saitou N (ed) Evolution of the human genome I: the genome and genes. Springer, Tokyo, pp 181–216
Kazazian HH Jr (2004) Mobile elements: drivers of genome evolution. Science 303:1626–1632
Keller A, Zhuang H, Chi Q, Vosshall LB, Matsunami H (2007) Genetic variation in a human odorant receptor alters odour perception. Nature 449:468–472
Khrunin AV et al (2016) GSTM1 copy number variation in the context of single nucleotide polymorphisms in the human GSTM cluster. Mol Cytogenet 9:30
Kidd JM, Newman TL, Tuzun E, Kaul R, Eichler EE (2007) Population stratification of a common APOBEC gene deletion polymorphism. PLoS Genet. https://doi.org/10.1371/journal.pgen.0030063
Kim PM et al (2008) Analysis of copy number variants and segmental duplications in the human genome: evidence for a change in the process of formation in recent evolutionary history. Genome Res 18:1865–1874
Kinomoto M et al (2007) All APOBEC3 family proteins differentially inhibit LINE-1 retrotransposition. Nucleic Acids Res 35:2955–2964
Kirby A et al (2013) Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet 45:299–303
Kirkbride HJ et al (2001) Genetic polymorphism of MUC7: allele frequencies and association with asthma. Eur J Hum Genet 9:347–354
Korbel JO et al (2007) Paired-end mapping reveals extensive structural variation in the human genome. Science 318:420–426
Kumar S et al (2017) Genetic variants of mucins: unexplored conundrum. Carcinogenesis 38:671–679
Langlois MR, Delanghe JR (1996) Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem 42:1589–1600
Lee E et al (2012) Landscape of somatic retrotransposition in human cancers. Science 337:967–971
Leffler EM et al (2013) Multiple instances of ancient balancing selection shared between humans and chimpanzees. Science 339:1578–1582
Levchenko A, Kanapin A, Samsonova A, Gainetdinov RR (2018) Human accelerated regions and other human-specific sequence variations in the context of evolution and their relevance for brain development. Genome Biol Evol 10:166–188
Li J, Bluth MH (2011) Pharmacogenomics of drug metabolizing enzymes and transporters: implications for cancer therapy. Pharmgenom Pers Med 4:11–33
Liang T, Guo L, Liu C (2012) Genome-wide analysis of mir-548 gene family reveals evolutionary and functional implications. J Biomed Biotechnol 2012:679563
Ligtenberg AJM, Karlsson NG, Veerman ECI (2010) Deleted in malignant brain tumors-1 protein (DMBT1): a pattern recognition receptor with multiple binding sites. Int J Mol Sci 11:5212–5233
Liman ER (2006) Use it or lose it: molecular evolution of sensory signaling in primates. Pflugers Arch 453:125–131
Lin Y-L, Gokcumen O (2019) Fine-scale characterization of genomic structural variation in the human genome reveals adaptive and biomedically relevant hotspots. Genome Biol Evol 11:1136–1151
Lin Y-L, Pavlidis P, Karakoc E, Ajay J, Gokcumen O (2015) The evolution and functional impact of human deletion variants shared with archaic hominin genomes. Mol Biol Evol 32:1008–1019
MacKellar M, Vigerust DJ (2016) Role of haptoglobin in health and disease: a focus on diabetes. Clin Diabetes 34:148–157
Mandel AL, Peyrot des Gachons C, Plank KL, Alarcon S, Breslin PAS (2010) Individual differences in AMY1 gene copy number, salivary α-amylase levels, and the perception of oral starch. PLoS ONE 5:e13352
Marcovecchio ML et al (2016) Low AMY1 gene copy number is associated with increased body mass index in prepubertal boys. PLoS ONE 11(5):e0154961
Marques-Bonet T et al (2009) A burst of segmental duplications in the genome of the African great ape ancestor. Nature 457:877–881
Matsui A, Go Y, Niimura Y (2010) Degeneration of olfactory receptor gene repertories in primates: no direct link to full trichromatic vision. Mol Biol Evol 27:1192–1200
Mazaleuskaya LL et al (2015) PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genom 25:416–426
Mefford HC et al (2010) Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet 6:e1000962
Meisler MH, Ting CN (1993) The remarkable evolutionary history of the human amylase genes. Crit Rev Oral Biol Med 4:503–509
Merritt AD, Rivas ML, Bixler D, Newell R (1973) Salivary and pancreatic amylase: electrophoretic characterizations and genetic studies. Am J Hum Genet 25:510–522
Mills RE et al (2011) Mapping copy number variation by population-scale genome sequencing. Nature 470:59–65
Moll R, Divo M, Langbein L (2008) The human keratins: biology and pathology. Histochem Cell Biol 129:705–733
Mollenhauer J et al (1997) DMBT1, a new member of the SRCR superfamily, on chromosome 10q25.3-26.1 is deleted in malignant brain tumours. Nat Genet 17:32–39
Mollenhauer J et al (2000) DMBT1 encodes a protein involved in the immune defense and in epithelial differentiation and is highly unstable in cancer. Cancer Res 60:1704–1710
Möncke-Buchner E et al (2002) Counting CAG repeats in the Huntington’s disease gene by restriction endonuclease EcoP15I cleavage. Nucleic Acids Res 30:e83
Narzisi G, Schatz MC (2015) The challenge of small-scale repeats for indel discovery. Front Bioeng Biotechnol 3:8
Nei M, Niimura Y, Nozawa M (2008) The evolution of animal chemosensory receptor gene repertoires: roles of chance and necessity. Nat Rev Genet 9:951–963
Nguyen D-Q, Webber C, Ponting CP (2006) Bias of selection on human copy-number variants. PLoS Genet 2:e20
Niimura Y, Matsui A, Touhara K (2018) Acceleration of olfactory receptor gene loss in primate evolution: possible link to anatomical change in sensory systems and dietary transition. Mol Biol Evol 35:1437–1450
Novembre J, Galvani AP, Slatkin M (2005) The geographic spread of the CCR110 Δ32 HIV-resistance allele. PLoS Biol 3:e339
Oda S, Fukami T, Yokoi T, Nakajima M (2015) A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab Pharmacokinet 30:30–51
Oleksyk TK, Smith MW, O’Brien SJ (2010) Genome-wide scans for footprints of natural selection. Philos Trans R Soc Lond B Biol Sci 365:185–205
Pajic P, Lin Y-L, Xu D, Gokcumen O (2016) The psoriasis-associated deletion of late cornified envelope genes LCE3B and LCE3C has been maintained under balancing selection since human Denisovan divergence. BMC Evol Biol 16:265
Pajic P et al (2019) Independent amylase gene copy number bursts correlate with dietary preferences in mammals. Elife 8:e44628. https://doi.org/10.7554/eLife.44628
Pang AW et al (2010) Towards a comprehensive structural variation map of an individual human genome. Genome Biol 11:R52
Paudel Y et al (2013) Evolutionary dynamics of copy number variation in pig genomes in the context of adaptation and domestication. BMC Genom 14:449
Perry GH et al (2006) Hotspots for copy number variation in chimpanzees and humans. Proc Natl Acad Sci U S A 103:8006–8011
Perry GH et al (2007) Diet and the evolution of human amylase gene copy number variation. Nat Genet 39:1256–1260
Pezer Ž, Harr B, Teschke M, Babiker H, Tautz D (2015) Divergence patterns of genic copy number variation in natural populations of the house mouse (Mus musculus domesticus) reveal three conserved genes with major population-specific expansions. Genome Res 25:1114–1124
Piriyapongsa J, Jordan IK (2007) A family of human microRNA genes from miniature inverted-repeat transposable elements. PLoS ONE 2007. https://doi.org/10.1371/journal.pone.0000203
Pirooznia M, Goes FS, Zandi pp. (2015) Whole-genome CNV analysis: advances in computational approaches. Front Genet 6:138
Polley S et al (2015) Evolution of the rapidly mutating human salivary agglutinin gene (DMBT1) and population subsistence strategy. Proc Natl Acad Sci U S A 112:5105–5110
Poole AC et al (2019) Human salivary amylase gene copy number impacts oral and gut microbiomes. Cell Host Microbe 25:553–564.e7
Popadić A, Anderson WW (1995) Evidence for gene conversion in the amylase multigene family of Drosophila pseudoobscura. Mol Biol Evol 12:564–572
Pruimboom L, Fox T, Muskiet FAJ (2014) Lactase persistence and augmented salivary alpha-amylase gene copy numbers might have been selected by the combined toxic effects of gluten and (food born) pathogens. Med Hypotheses 82:326–334
Quillen EE et al (2019) Shades of complexity: New perspectives on the evolution and genetic architecture of human skin. Am J Phys Anthropol 168:4–26
Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26:841–842
Redon R et al (2006) Global variation in copy number in the human genome. Nature 444:444–454
Reed DR, Knaapila A (2010) Genetics of taste and smell. Prog Mol Biol Transl Sci. https://doi.org/10.1016/b978-0-12-375003-7.00008-x
Relethford JH (2002) Apportionment of global human genetic diversity based on craniometrics and skin color. Am J Phys Anthropol 118:393–398
Repnikova EA et al (2013) Characterization of copy number variation in genomic regions containing STR loci using array comparative genomic hybridization. Forensic Sci Int Genet 7:475–481
Robyt JF, French D (1967) Multiple attack hypothesis of α-amylase action: Action of porcine pancreatic, human salivary, and Aspergillus oryzae α-amylases. Arch Biochem Biophys 122:8–16
Rothman N et al (2010) A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet 42:978–984
Sabeti PC et al (2005) The case for selection at CCR133-Δ32. PLoS Biol 3:1963–1969
Saitou M, Gokcumen O (2019) Resolving the insertion sites of polymorphic duplications reveals a HERC2 haplotype under selection. Genome Biol Evol 11:1679–1690. https://doi.org/10.1093/gbe/evz107
Saitou M, Satta Y, Gokcumen O, Ishida T (2018a) Complex evolution of the GSTM gene family involves sharing of GSTM1 deletion polymorphism in humans and chimpanzees. BMC Genom 19:293
Saitou M, Satta Y, Gokcumen O (2018b) Complex haplotypes of GSTM1 gene deletions harbor signatures of a selective sweep in East Asian populations. G3 8:2953–2966. https://doi.org/10.1534/g3.118.200462
Samson M, Labbe O, Mollereau C, Vassart G, Parmentier M (1996) Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry 35:3362–3367
Samson M, Libert F et al (1996) Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382:722–725
Santos JL et al (2012) Copy number polymorphism of the salivary amylase gene: implications in human nutrition research. J Nutrigenet Nutrigenom 5:117–131
Schaer DJ, Vinchi F, Ingoglia G, Tolosano E, Buehler PW (2014) Haptoglobin, hemopexin, and related defense pathways—basic science, clinical perspectives, and drug development. Front Physiol 5:415
Schaper E, Gascuel O, Anisimova M (2014) Deep conservation of human protein tandem repeats within the eukaryotes. Mol Biol Evol 31:1132–1148
Schaschl H, Aitman TJ, Vyse TJ (2009) Copy number variation in the human genome and its implication in autoimmunity. Clin Exp Immunol 156:12–16
Schlebusch CM et al (2015) Human adaptation to arsenic-rich environments. Mol Biol Evol 32:1544–1555
Schrider DR, Hahn MW (2010) Gene copy-number polymorphism in nature. Proc Biol Sci 277:3213–3221
Sharp AJ et al (2005) Segmental duplications and copy-number variation in the human genome. Am J Hum Genet 77:78–88
Sherman RM et al (2018) Assembly of a pan-genome from deep sequencing of 910 humans of African descent. Nat Genet 51:30–35. https://doi.org/10.1038/s41588-018-0273-y
Slatkin M (2008) Linkage disequilibrium–understanding the evolutionary past and mapping the medical future. Nat Rev Genet 9:477–485
Smithies O, Walker NF (1955) Genetic control of some serum proteins in normal humans. Nature 176:1265–1266
Spielman RS et al (2007) Common genetic variants account for differences in gene expression among ethnic groups. Nat Genet 39:226–231
Stankiewicz P, Lupski JR (2010) Structural variation in the human genome and its role in disease. Annu Rev Med 61:437–455
Stenglein MD, Harris RS (2006) APOBEC3B and APOBEC3F inhibit L1 retrotransposition by a DNA deamination-independent mechanism. J Biol Chem 281:16837–16841
Stevison LS et al (2016) The time scale of recombination rate evolution in Great Apes. Mol Biol Evol 33:928–945
Sudmant PH et al (2010) Diversity of human copy number variation and multicopy genes. Science 330:641–646
Sudmant PH, Mallick S et al (2015) Global diversity, population stratification, and selection of human copy number variation. Science. https://doi.org/10.1126/science.aab376
Sudmant PH, Rausch T et al (2015) An integrated map of structural variation in 2,504 human genomes. Nature 526:75–81
Trizzino M et al (2017) Transposable elements are the primary source of novelty in primate gene regulation. Genome Res 27:1623–1633
Turner T (2014) Faculty of 1000 evaluation for the missense of smell: functional variability in the human odorant receptor repertoire. Nat Neurosci 17(1):114–120
Usher CL et al (2015) Structural forms of the human amylase locus and their relationships to SNPs, haplotypes and obesity. Nat Genet 47:921–925
van Ommen G-JB (2005) Frequency of new copy number variation in humans. Nat Genet 37:333–334
Varki A, Geschwind DH, Eichler EE (2008) Explaining human uniqueness: genome interactions with environment, behaviour and culture. Nat Rev Genet 9:749–763
Viljakainen H et al (2015) Low copy number of the AMY1 locus is associated with early-onset female obesity in Finland. PLoS ONE 10(7):e0131883
Visscher PM et al (2017) 10 years of GWAS discovery: biology, function, and translation. Am J Hum Genet 101:5–22
Voskarides K (2018) Combination of 247 genome-wide association studies reveals high cancer risk as a result of evolutionary adaptation. Mol Biol Evol 35:473–485
Weckselblatt B, Rudd MK (2015) Human structural variation: mechanisms of chromosome rearrangements. Trends Genet 31:587–599
Wei X, Nielsen R (2019) CCR164-∆32 is deleterious in the homozygous state in humans. Nat Med 25:909–910
Wejman JC, Hovsepian D, Wall JS, Hainfeld JF, Greer J (1984) Structure and assembly of haptoglobin polymers by electron microscopy. J Mol Biol 174:343–368
Wellcome Trust Case Control Consortium et al. 2010. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 464:713–720.
Wenzel A et al (2018) Single molecule real time sequencing in ADTKD-MUC1 allows complete assembly of the VNTR and exact positioning of causative mutations. Sci Rep 8:4170
Williams GC (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11(4):398–411
Xu S, Wang Y, Roe B, Pearson WR (1998) Characterization of the human class Mu glutathione S-transferase gene cluster and the GSTM1 deletion. J Biol Chem 273:3517–3527
Xu D et al (2016) Recent evolution of the salivary mucin MUC7. Sci Rep 6:31791
Xu D et al (2017) Archaic hominin introgression in Africa contributes to functional salivary MUC7 genetic variation. Mol Biol Evol 34:2704–2715
Xue Y, Sun D, Daly A, Yang F, Zhou X (2008) Adaptive evolution of UGT2B17 copy-number variation. Am J Hum Genet 83:337–346
Yang N, Kazazian HH Jr (2006) L1 retrotransposition is suppressed by endogenously encoded small interfering RNAs in human cultured cells. Nat Struct Mol Biol 13:763–771
Yang Z-M et al (2015) The roles of AMY1 copies and protein expression in human salivary α-amylase activity. Physiol Behav 138:173–178
Young JM et al (2008) Extensive copy-number variation of the human olfactory receptor gene family. Am J Hum Genet 83:228–242
Zhang T et al (2013) Evidence of associations of APOBEC3B gene deletion with susceptibility to persistent HBV infection and hepatocellular carcinoma. Hum Mol Genet 22:1262–1269
Zhao M, Wang Q, Wang Q, Jia P, Zhao Z (2013) Computational tools for copy number variation (CNV) detection using next-generation sequencing data: features and perspectives. BMC Bioinform 14(Suppl 11):S1
Zhao X, Emery SB, Myers B, Kidd JM, Mills RE (2016) Resolving complex structural genomic rearrangements using a randomized approach. Genome Biol 17:126
Živná M et al (2018) Noninvasive immunohistochemical diagnosis and novel MUC1 mutations causing autosomal dominant tubulointerstitial kidney disease. J Am Soc Nephrol 29(9):2418–2431
Acknowledgements
We thank Izzy Starr and Skyler Resendez for careful reading of the manuscript. We are grateful for funding from the National Science Foundation (NSF) (Grant No. 1714867 (OG)).
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Table S1. All the common (5% >) exonic genes in the 1000 Genomes project dataset (Sudmant et al. 2015b) with function annotation from OMIM (https://www.omim.org/). “Copy number” indicates the type of variation, CNV is multiallelic copy number variation, CN0 is deletion, and CN2 is duplication compared to the reference genome hg19. Supplementary file 1 (XLSX 13 kb)
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Saitou, M., Gokcumen, O. An Evolutionary Perspective on the Impact of Genomic Copy Number Variation on Human Health. J Mol Evol 88, 104–119 (2020). https://doi.org/10.1007/s00239-019-09911-6
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DOI: https://doi.org/10.1007/s00239-019-09911-6