A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes

English version České info

GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available.

Vyšlo v časopise: A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes. PLoS Genet 9(8): e32767. doi:10.1371/journal.pgen.1003684
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003684

Souhrn

Zdroje

1. ChenJM, CooperDN, ChuzhanovaN, FerecC, PatrinosGP (2007) Gene conversion: mechanisms, evolution and human disease. Nat Rev Genet 8: 762–775.

2. MaraisG (2003) Biased gene conversion: implications for genome and sex evolution. Trends Genet 19: 330–338.

3. DuretL, GaltierN (2009) Biased gene conversion and the evolution of mammalian genomic landscapes. Annu Rev Genom Hum G 10: 285–311.

4. LambBC (1984) The properties of meiotic gene conversion important in its effects on evolution. Heredity (Edinb) 53(Pt 1): 113–138.

5. BrownTC, JiricnyJ (1988) Different base/base mispairs are corrected with different efficiencies and specificities in monkey kidney cells. Cell 54: 705–711.

6. GaltierN, DuretL (2007) Adaptation or biased gene conversion? Extending the null hypothesis of molecular evolution. Trends Genet 23: 273–277.

7. BerglundJ, PollardKS, WebsterMT (2009) Hotspots of biased nucleotide substitutions in human genes. PLoS Biol 27: e26.

8. GaltierN, DuretL, GléminS, RanwezV (2009) GC-biased gene conversion promotes the fixation of deleterious amino acid changes in primates. Trends Genet 25: 1–5.

9. RatnakumarA, MoussetS, GleminS, BerglundJ, GaltierN, et al. (2010) Detecting positive selection within genomes: the problem of biased gene conversion. Philos Trans R Soc Lond B Biol Sci 365: 2571–2580.

10. GléminS (July 2010) Surprising fitness consequences of GC-biased gene conversion: I. mutation load and inbreeding depression. Genetics 185: 939–959.

11. NecşuleaA, PopaA, CooperDN, StensonPD, MouchiroudD, et al. (2011) Meiotic recombination favors the spreading of deleterious mutations in human populations. Hum Mutat 32: 198–206.

12. CapraJA, PollardKS (2011) Substitution patterns are GC-biased in divergent sequences across the metazoans. Genome Biology and Evolution 3: 516–527.

13. KostkaD, HubiszMJ, SiepelA, PollardKS (2012) The role of GC-biased gene conversion in shaping the fastest evolving regions of the human genome. Mol Biol Evol 29: 1047–1057.

14. ManceraE, BourgonR, BrozziA, HuberW, SteinmetzLM (2008) High-resolution mapping of meiotic crossovers and non-crossovers in yeast. Nature 454: 479–485.

15. DreszerTR, WallGD, HausslerD, PollardKS (2007) Biased clustered substitutions in the human genome: the footprints of male-driven biased gene conversion. Genome Res 17: 1420–1430.

16. DuretL, ArndtPF (2008) The impact of recombination on nucleotide substitutions in the human genome. PLoS Genet 4: e1000071.

17. KatzmanS, CapraJA, HausslerD, PollardKS (2011) Ongoing GC-biased evolution is widespread in the human genome and enriched near recombination hot spots. Genome Biology and Evolution 3: 614–626.

18. NagylakiT (1983) Evolution of a finite population under gene conversion. Proc Natl Acad Sci USA 80: 6278–6281.

19. LartillotN (2013) Phylogenetic patterns of GC-biased gene conversion in placental mammals and the evolutionary dynamics of recombination landscapes. Molecular Biology and Evolution 30: 489–502.

20. JeffreysAJ, MurrayJ, NeumannR (1998) High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. Mol Cell 2: 267–273.

21. KongA, ThorleifssonG, GudbjartssonDF, MassonG, SigurdssonA, et al. (2010) Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467: 1099–1103.

22. MyersS, BottoloL, FreemanC, McVeanG, DonnellyP (2005) A fine-scale map of recombination rates and hotspots across the human genome. Science 310: 321–324.

23. PtakSE, HindsDA, KoehlerK, NickelB, PatilN, et al. (2005) Fine-scale recombination patterns differ between chimpanzees and humans. Nat Genet 37: 429–434.

24. WincklerW, MyersSR, RichterDJ, OnofrioRC, McDonaldGJ, et al. (2005) Comparison of fine-scale recombination rates in humans and chimpanzees. Science 308: 107–111.

25. AutonA, Fledel-AlonA, PfeiferS, VennO, SegurelL, et al. (2012) A fine-scale chimpanzee genetic map from population sequencing. Science 336: 193–198.

26. HubiszMJ, PollardKS, SiepelA (2011) PHAST and RPHAST: phylogenetic analysis with space/time models. Briefings in Bioinformatics 12: 41–51.

27. Siepel A, Haussler D (2005) Phylogenetic hidden Markov models. In: Nielsen R, editor, Statistical Methods in Molecular Evolution, New York: Springer. pp. 325–351.

28. SiepelA, BejeranoG, PedersenJS, HinrichsAS, HouM, et al. (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15: 1034–1050.

29. WebbAJ, BergIL, JeffreysA (2008) Sperm cross-over activity in regions of the human genome showing extreme breakdown of marker association. Proc Natl Acad Sci USA 105: 10471–10476.

30. RomiguierJ, RanwezV, DouzeryEJ, GaltierN (2010) Contrasting GC-content dynamics across 33 mammalian genomes: Relationship with life-history traits and chromosome sizes. Genome Research 20: 1001–1009.

31. IJdoJW, BaldiniA, WardDC, ReedersST, WellsRA (1991) Origin of human chromosome 2: an ancestral telomere-telomere fusion. Proceedings of the National Academy of Sciences 88: 9051–9055.

32. International Hapmap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 339: 851–861.

33. The 1000 Genomes Project Consortium (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.

34. SherryST, WardMH, KholodovM, BakerJ, PhanL, et al. (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Research 29: 308–311.

35. StensonP, MortM, BallE, HowellsK, PhillipsA, et al. (2009) The Human Gene Mutation Database: 2008 update. Genome Med 1: 13.

36. ZhangY, DeS, GarnerJ, SmithK, WangSA, et al. (2010) Systematic analysis, comparison, and integration of disease based human genetic association data and mouse genetic phenotypic information. BMC Medical Genomics 3: 1.

37. BoyleAP, HongEL, HariharanM, ChengY, SchaubMA, et al. (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 22: 1790–1797.

38. PollardK, SalamaS, KingB, KernA, DreszerT, et al. (2006) Forces shaping the fastest evolving regions in the human genome. PLoS Genet 2: e168.

39. KatzmanS, KernAD, PollardKS, SalamaSR, HausslerD (2010) GC-biased evolution near human accelerated regions. PLoS Genet 6: e1000960.

40. Lindblad-TohK, GarberM, ZukO, LinMF, ParkerBJ, et al. (2011) A high-resolution map of human evolutionary constraint using 29 mammals. Nature 478: 476–482.

41. KosiolC, VinarT, da FonsecaR, HubiszM, BustamanteC, et al. (2008) Patterns of positive selection in six mammalian genomes. PLoS Genet 4: e1000144.

42. GeorgeRD, McVickerG, DiederichR, NgSB, MacKenzieAP, et al. (2011) Trans genomic capture and sequencing of primate exomes reveals new targets of positive selection. Genome Research 21: 1686–1694.

43. MugalCF, ArndtPF, EllegrenH (2013) Twisted Signatures of GC-Biased Gene Conversion Embedded in an Evolutionary Stable Karyotype. Molecular Biology and Evolution [epub ahead of print] doi:10.1093/molbev/mst067

44. NavarroA, BartonNH (2003) Chromosomal speciation and molecular divergence–accelerated evolution in rearranged chromosomes. Science 300: 321–324.

45. MyersS, FreemanC, AutonA, DonnellyP, McVeanG (2008) A common sequence motif associated with recombination hot spots and genome instability in humans. Nat Genet 40: 1124–1129.

46. SpencerCC, DeloukasP, HuntS, MullikinJ, MyersS, et al. (2006) The influence of recombination on human genetic diversity. PLoS Genet 2: e148.

47. Siepel A, Pollard K, Haussler D (2006) New methods for detecting lineage-specific selection. In: Proc. 10th Int'l Conf. on Research in Computational Molecular Biology. Berlin: Springer-Verlag, pp. 190–205.

48. HasegawaM, KishinoH, YanoT (1985) Dating the human-ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol 22: 160–174.

49. MeyerLR, ZweigAS, HinrichsAS, KarolchikD, KuhnRM, et al. (2013) The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res 41: D64–69.

50. BlanchetteM, KentWJ, RiemerC, ElnitskiL, SmitAFA, et al. (2004) Aligning multiple genomic sequences with the threaded blockset aligner. Genome Res 14: 708–715.

51. FlicekP, AmodeMR, BarrellD, BealK, BrentS, et al. (2011) Ensembl 2011. Nucleic Acids Research 39: D800–D806.

52. HarrowJ, FrankishA, GonzalezJM, TapanariE, DiekhansM, et al. (2012) Gencode: The reference human genome annotation for the encode project. Genome Research 22: 1760–1774.

53. KarolchikD, HinrichsAS, FureyTS, RoskinKM, SugnetCW, et al. (2004) The UCSC table browser data retrieval tool. Nucleic Acids Research 32: D493–D496.

54. ArbizaL, GronauI, AksoyBA, HubiszMJ, GulkoB, et al. (2013) Genome-wide inference of natural selection on human transcription factor binding sites. Nat Genet 45: 723–729.