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Evidence for Hitchhiking of Deleterious Mutations within the Human Genome


Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles.


Vyšlo v časopise: Evidence for Hitchhiking of Deleterious Mutations within the Human Genome. PLoS Genet 7(8): e32767. doi:10.1371/journal.pgen.1002240
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002240

Souhrn

Deleterious mutations present a significant obstacle to adaptive evolution. Deleterious mutations can inhibit the spread of linked adaptive mutations through a population; conversely, adaptive substitutions can increase the frequency of linked deleterious mutations and even result in their fixation. To assess the impact of adaptive mutations on linked deleterious mutations, we examined the distribution of deleterious and neutral amino acid polymorphism in the human genome. Within genomic regions that show evidence of recent hitchhiking, we find fewer neutral but a similar number of deleterious SNPs compared to other genomic regions. The higher ratio of deleterious to neutral SNPs is consistent with simulated hitchhiking events and implies that positive selection eliminates some deleterious alleles and increases the frequency of others. The distribution of disease-associated alleles is also altered in hitchhiking regions. Disease alleles within hitchhiking regions have been associated with auto-immune disorders, metabolic diseases, cancers, and mental disorders. Our results suggest that positive selection has had a significant impact on deleterious polymorphism and may be partly responsible for the high frequency of certain human disease alleles.


Zdroje

1. MortonNECrowJFMullerHJ 1956 An estimate of the mutational damage in man from data on consanguineous marriages. Proc Natl Acad Sci U S A 42 855 863

2. LynchMGabrielW 1990 Mutational load and the survival of small populations. Evolution 44 1725 1737

3. LandeR 1994 Risk of population extinction from fixation of new deleterious mutations. Evolution 48 1460 1469

4. GabrielWLynchMBurgerR 1993 Muller's ratchet and mutational meltdowns. Evolution 47 1744 1757

5. FelsensteinJ 1974 The evolutionary advantage of recombination. Genetics 78 737 756

6. CharlesworthB 1990 Mutation-selection balance and the evolutionary advantage of sex and recombination. Genet Res 55 199 221

7. FayJCWyckoffGJWuCI 2001 Positive and negative selection on the human genome. Genetics 158 1227 1234

8. SunyaevSRamenskyVKochILatheWKondrashovA 2001 Prediction of deleterious human alleles. Hum Mol Genet 10 591 597

9. ChunSFayJC 2009 Identification of deleterious mutations within three human genomes. Genome Res 19 1553 1561

10. NgPCHenikoffS 2006 Predicting the effects of amino acid substitutions on protein function. Annu Rev Genomics Hum Genet 7 61 80

11. JordanDMRamenskyVESunyaevSR 2010 Human allelic variation: perspective from protein function, structure, and evolution. Curr Opin Struct Biol 20 342 350

12. FayJWuC 2003 Sequence divergence, functional constraint, and selection in protein evolution. Annu Rev Genomics Hum Genet 4 213 235

13. FayJWuC 2001 The neutral theory in the genomic era. Curr Opin Genet Dev 11 642 646

14. BoykoARWilliamsonSHIndapARDegenhardtJDHernandezRD 2008 Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet 4 e1000083 doi:10.1371/journal.pgen.1000083

15. LohmuellerKEIndapARSchmidtSBoykoARHernandezRD 2008 Proportionally more deleterious genetic variation in European than in African populations. Nature 451 994 997

16. NeelJV 1962 Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet 14 353 362

17. KondrashovASunyaevSKondrashovF 2002 Dobzhansky-Muller incompatibilities in protein evolution. Proc Natl Acad Sci U S A 99 14878 14883

18. BartonNH 1995 Linkage and the limits to natural selection. Genetics 140 821 841

19. BirkyCWJWalshJB 1988 Effects of linkage on rates of molecular evolution. Proc Natl Acad Sci U S A 85 6414 6418

20. BachtrogDGordoI 2004 Adaptive evolution of asexual populations under Muller's ratchet. Evolution 58 1403 1413

21. JohnsonTBartonNH 2002 The effect of deleterious alleles on adaptation in asexual populations. Genetics 162 395 411

22. HartfieldMOttoSP 2011 Recombination and hitchhiking of deleterious alleles. Evolution In press

23. RiceWR 1987 Genetic hitchhiking and the evolution of reduced genetic activity of the Y sex chromosome. Genetics 116 161 167

24. LuJTangTTangHHuangJShiS 2006 The accumulation of deleterious mutations in rice genomes: a hypothesis on the cost of domestication. Trends Genet 22 126 131

25. CruzFVilàCWebsterMT 2008 The legacy of domestication: accumulation of deleterious mutations in the dog genome. Mol Biol Evol 25 2331 2336

26. Maynard-SmithJHaighJ 1974 The hitch-hiking effect of a favourable gene. Genet Res 23 23 35

27. FayJCWuCI 2000 Hitchhiking under positive Darwinian selection. Genetics 155 1405 1413

28. DurbinRMAbecasisGRAltshulerDLAutonABrooksLD 2010 A map of human genome variation from population-scale sequencing. Nature 467 1061 1073

29. CharlesworthBMorganMCharlesworthD 1993 The effect of deleterious mutations on neutral molecular variation. Genetics 134 1289 1303

30. StephanWCharlesworthBMcVeanG 1999 The effect of background selection at a single locus on weakly selected, partially linked variants. Genetical Research 73 133 146

31. NordborgMCharlesworthBCharlesworthD 1996 The effect of recombination on background selection. Genet Res 67 159 174

32. ReedFAAkeyJMAquadroCF 2005 Fitting background-selection predictions to levels of nucleotide variation and divergence along the human autosomes. Genome Res 15 1211 1221

33. AkeyJM 2009 Constructing genomic maps of positive selection in humans: where do we go from here? Genome Res 19 711 722

34. KimYStephanW 2002 Detecting a local signature of genetic hitchhiking along a recombining chromosome. Genetics 160 765 777

35. VoightBFKudaravalliSWenXPritchardJK 2006 A map of recent positive selection in the human genome. PLoS Biol 4 e72 doi:10.1371/journal.pbio.0040072

36. TangKThorntonKRStonekingM 2007 A new approach for using genome scans to detect recent positive selection in the human genome. PLoS Biol 5 e171 doi:10.1371/journal.pbio.0050171

37. PickrellJKCoopGNovembreJKudaravalliSLiJZ 2009 Signals of recent positive selection in a worldwide sample of human populations. Genome Res 19 826 837

38. BierneN 2010 The distinctive footprints of local hitchhiking in a varied environment and global hitchhiking in a subdivided population. Evolution 64 3254 3272

39. BersaglieriTSabetiPCPattersonNVanderploegTSchaffnerSF 2004 Genetic signatures of strong recent positive selection at the lactase gene. Am J Hum Genet 74 1111 1120

40. LewinskyRHJensenTGKMøllerJStensballeAOlsenJ 2005 T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro. Hum Mol Genet 14 3945 3953

41. SabetiPCVarillyPFryBLohmuellerJHostetterE 2007 Genome-wide detection and characterization of positive selection in human populations. Nature 449 913 918

42. GrossmanSRShylakhterIKarlssonEKByrneEHMoralesS 2010 A composite of multiple signals distinguishes causal variants in regions of positive selection. Science 327 883 886

43. LamasonRLMohideenMPKMestJRWongACNortonHL 2005 SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science 310 1782 1786

44. SulemPGudbjartssonDFStaceySNHelgasonARafnarT 2007 Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 39 1443 1452

45. HuttonSMSpritzRA 2008 A comprehensive genetic study of autosomal recessive ocular albinism in Caucasian patients. Invest Ophthalmol Vis Sci 49 868 872

46. GudbjartssonDFSulemPStaceySNGoldsteinAMRafnarT 2008 ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma. Nat Genet 40 886 891

47. NijbroekGSoodSMcIntoshIFrancomanoCABullE 1995 Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons. Am J Hum Genet 57 8 21

48. SchrijverILiuWBrennTFurthmayrHFranckeU 1999 Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet 65 1007 1020

49. LiuWOOefnerPJQianCOdomRSFranckeU 1997–1998 Denaturing HPLC-identified novel FBN1 mutations, polymorphisms, and sequence variants in Marfan syndrome and related connective tissue disorders. Genet Test 1 237 242

50. HindorffLASethupathyPJunkinsHARamosEMMehtaJP 2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106 9362 9367

51. BeckerKGBarnesKCBrightTJWangSA 2004 The genetic association database. Nat Genet 36 431 432

52. HermissonJPenningsPS 2005 Soft sweeps: molecular population genetics of adaptation from standing genetic variation. Genetics 169 2335 2352

53. TournamilleCColinYCartronJPLe Van KimC 1995 Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat Genet 10 224 228

54. Di RienzoAHudsonRR 2005 An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet 21 596 601

55. Chimpanzee Sequencing and Analysis Consortium 2005 Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437 69 87

56. OlsonMVVarkiA 2003 Sequencing the chimpanzee genome: insights into human evolution and disease. Nat Rev Genet 4 20 28

57. ReichDELanderES 2001 On the allelic spectrum of human disease. Trends Genet 17 502 510

58. GabrielSEBrigmanKNKollerBHBoucherRCStuttsMJ 1994 Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science 266 107 109

59. WiufC 2001 Do delta F508 heterozygotes have a selective advantage? Genet Res 78 41 47

60. OlsonM 1999 When less is more: gene loss as an engine of evolutionary change. Am J Hum Genet 64 18 23

61. ThomsonG 1995 HLA disease associations: models for the study of complex human genetic disorders. Crit Rev Clin Lab Sci 32 183 219

62. HughesALYeagerM 1998 Natural selection and the evolutionary history of major histocompatibility complex loci. Front Biosci 3 d509 16

63. WilliamsonSHHubiszMJClarkAGPayseurBABustamanteCD 2007 Localizing recent adaptive evolution in the human genome. PLoS Genet 3 e90 doi:10.1371/journal.pgen.0030090

64. ToomajianCKreitmanM 2002 Sequence variation and haplotype structure at the human HFE locus. Genetics 161 1609 1623

65. DistanteSRobsonKJHGraham-CampbellJArnaiz-VillenaABrissotP 2004 The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet 115 269 279

66. SoranzoNSpectorTDManginoMKühnelBRendonA 2009 A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nat Genet 41 1182 1190

67. HuffCDWitherspoonDZhangYGatenbeeCDensonLA 2011 Crohn's disease and genetic hitchhiking at IBD5. Mol Biol Evol In press

68. MorralNBertranpetitJEstivillXNunesVCasalsT 1994 The origin of the major cystic fibrosis mutation (delta F508) in European populations. Nat Genet 7 169 175

69. AnguianoAOatesRDAmosJADeanMGerrardB 1992 Congenital bilateral absence of the vas deferens. A primarily genital form of cystic fibrosis. JAMA 267 1794 1797

70. CooperDNStensonPDChuzhanovaNA 2006 The Human Gene Mutation Database (HGMD) and its exploitation in the study of mutational mechanisms. Curr Protoc Bioinformatics 1.13.1 1.13.20

71. EwensW 2004 Mathematical population genetics New York Springer 417

72. CaiJJMacphersonJMSellaGPetrovDA 2009 Pervasive hitchhiking at coding and regulatory sites in humans. PLoS Genet 5 e1000336 doi:10.1371/journal.pgen.1000336

73. McVeanGAwadallaPFearnheadP 2002 A coalescent-based method for detecting and estimating recombination from gene sequences. Genetics 160 1231 1241

74. NecşuleaAPopaACooperDNStensonPDMouchiroudD 2011 Meiotic recombination favors the spreading of deleterious mutations in human populations. Hum Mutat 32 198 206

75. AltshulerDMGibbsRAPeltonenLAltshulerDMGibbsRA 2010 Integrating common and rare genetic variation in diverse human populations. Nature 467 52 58

76. CarlsonCSThomasDJEberleMASwansonJELivingstonRJ 2005 Genomic regions exhibiting positive selection identified from dense genotype data. Genome Res 15 1553 1565

77. KelleyJLMadeoyJCalhounJCSwansonWAkeyJM 2006 Genomic signatures of positive selection in humans and the limits of outlier approaches. Genome Res 16 980 989

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Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


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