Gene Copy-Number Polymorphism Caused by Retrotransposition in Humans

English version České info

The era of whole-genome sequencing has revealed that gene copy-number changes caused by duplication and deletion events have important evolutionary, functional, and phenotypic consequences. Recent studies have therefore focused on revealing the extent of variation in copy-number within natural populations of humans and other species. These studies have found a large number of copy-number variants (CNVs) in humans, many of which have been shown to have clinical or evolutionary importance. For the most part, these studies have failed to detect an important class of gene copy-number polymorphism: gene duplications caused by retrotransposition, which result in a new intron-less copy of the parental gene being inserted into a random location in the genome. Here we describe a computational approach leveraging next-generation sequence data to detect gene copy-number variants caused by retrotransposition (retroCNVs), and we report the first genome-wide analysis of these variants in humans. We find that retroCNVs account for a substantial fraction of gene copy-number differences between any two individuals. Moreover, we show that these variants may often result in expressed chimeric transcripts, underscoring their potential for the evolution of novel gene functions. By locating the insertion sites of these duplicates, we are able to show that retroCNVs have had an important role in recent human adaptation, and we also uncover evidence that positive selection may currently be driving multiple retroCNVs toward fixation. Together these findings imply that retroCNVs are an especially important class of polymorphism, and that future studies of copy-number variation should search for these variants in order to illuminate their potential evolutionary and functional relevance.

Vyšlo v časopise: Gene Copy-Number Polymorphism Caused by Retrotransposition in Humans. PLoS Genet 9(1): e32767. doi:10.1371/journal.pgen.1003242
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003242

Souhrn

Zdroje

1. DemuthJP, De BieT, StajichJE, CristianiniN, HahnMW (2006) The evolution of mammalian gene families. PLoS ONE 1: e85 doi:10.1371/journal.pone.0000085.

2. ConradDF, PintoD, RedonR, FeukL, GokcumenO, et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature 464: 704–712.

3. DennisMY, NuttleX, SudmantPH, AntonacciF, GravesTA, et al. (2012) Evolution of human-specific neural SRGAP2 genes by incomplete segmental duplication. Cell 149: 912–922.

4. IskowRC, GokcumenO, LeeC (2012) Exploring the role of copy number variants in human adaptation. Trends Genet 28: 245–257.

5. GreenbergAJ, MoranJR, FangS, WuCI (2006) Adaptive loss of an old duplicated gene during incipient speciation. Mol Biol Evol 23: 401–410.

6. LongMY, LangleyCH (1993) Natural selection and the origin of jingwei, a chimeric processed functional gene in Drosophila. Science 260: 91–95.

7. ConantGC, WolfeKH (2008) Turning a hobby into a job: How duplicated genes find new functions. Nat Rev Genet 9: 938–950.

8. HahnMW (2009) Distinguishing among evolutionary models for the maintenance of gene duplicates. J Hered 100: 605–617.

9. GirirajanS, CampbellCD, EichlerEE (2011) Human copy number variation and complex genetic disease. Annu Rev Genet 45: 203–226.

10. McCarrollSA, AltshulerDM (2007) Copy-number variation and association studies of human disease. Nat Genet 39: S37–S42.

11. StankiewiczP, LupskiJR (2010) Structural variation in the human genome and its role in disease. Annu Rev Med 437–455.

12. KiddJM, CooperGM, DonahueWF, HaydenHS, SampasN, et al. (2008) Mapping and sequencing of structural variation from eight human genomes. Nature 453: 56–64.

13. McCarrollSA, KuruvillaFG, KornJM, CawleyS, NemeshJ, et al. (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40: 1166–1174.

14. RedonR, IshikawaS, FitchKR, FeukL, PerryGH, et al. (2006) Global variation in copy number in the human genome. Nature 444: 444–454.

15. SebatJ, LakshmiB, TrogeJ, AlexanderJ, YoungJ, et al. (2004) Large-scale copy number polymorphism in the human genome. Science 305: 525–528.

16. CarretoL, EirizMF, GomesAC, PereiraPM, SchullerD, et al. (2008) Comparative genomics of wild type yeast strains unveils important genome diversity. BMC Genomics 9: 524.

17. EmersonJJ, Cardoso-MoreiraM, BorevitzJO, LongM (2008) Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster. Science 320: 1629–1631.

18. OssowskiS, SchneebergerK, ClarkRM, LanzC, WarthmannN, et al. (2008) Sequencing of natural strains of Arabidopsis thaliana with short reads. Genome Res 18: 2024–2033.

19. SchriderDR, HahnMW (2010) Gene copy-number polymorphism in nature. Proceedings of the Royal Society B 277: 3213–3221.

20. BaileyJA, GuZP, ClarkRA, ReinertK, SamonteRV, et al. (2002) Recent segmental duplications in the human genome. Science 297: 1003–1007.

21. SchriderDR, HahnMW (2010) Lower linkage disequilibrium at CNVs is due to both recurrent mutation and transposing duplications. Mol Biol Evol 27: 103–111.

22. BrosiusJ (1991) Retroposons - seeds of evolution. Science 251: 753–753.

23. MarquesAC, DupanloupI, VinckenboschN, ReymondA, KaessmannH (2005) Emergence of young human genes after a burst of retroposition in primates. PLoS Biol 3: e357 doi:10.1371/journal.pbio.0030357.

24. OkamuraK, NakaiK (2008) Retrotransposition as a source of new promoters. Mol Biol Evol 25: 1231–1238.

25. BaertschR, DiekhansM, KentWJ, HausslerD, BrosiusJ (2008) Retrocopy contributions to the evolution of the human genome. BMC Genomics 9.

26. VinckenboschN, DupanloupI, KaessmannH (2006) Evolutionary fate of retroposed gene copies in the human genome. Proc Natl Acad Sci U S A 103: 3220–3225.

27. BaiYS, CasolaC, FeschotteC, BetranE (2007) Comparative genomics reveals a constant rate of origination and convergent acquisition of functional retrogenes in Drosophila. Genome Biol 8: R11.

28. BetránE, ThorntonK, LongM (2002) Retroposed new genes out of the X in Drosophila. Genome Res 12: 1854–1859.

29. EmersonJJ, KaessmannH, BetranE, LongMY (2004) Extensive gene traffic on the mammalian X chromosome. Science 303: 537–540.

30. SchriderDR, StevensK, CardenoCM, LangleyCH, HahnMW (2011) Genome-wide analysis of retrogene polymorphisms in Drosophila melanogaster. Genome Res 21: 2087–2095.

31. ChiefariE, IiritanoS, PaonessaF, Le PeraI, ArcidiaconoB, et al. (2010) Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes. Nat Commun 1: 40.

32. PolisenoL, SalmenaL, ZhangJ, CarverB, HavemanWJ, et al. (2010) A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465: 1033–1038.

33. KarakocE, AlkanC, O'RoakBJ, DennisMY, VivesL, et al. (2011) Detection of structural variants and indels within exome data. Nat Methods 9: 176–178.

34. AltshulerDL, DurbinRM, AbecasisGR, BentleyDR, ChakravartiA, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.

35. PotrzebowskiL, VinckenboschN, MarquesAC, ChalmelF, JegouB, et al. (2008) Chromosomal gene movements reflect the recent origin and biology of therian sex chromosomes. PLoS Biol 6: e80 doi:10.1371/journal.pbio.0060080.

36. Diaz-CastilloC, RanzJM (2012) Nuclear chromosome dynamics in the Drosophila male germ line contribute to the nonrandom genomic distribution of retrogenes. Mol Biol Evol 29: 2105–2108.

37. GalantePAF, VidalDO, de SouzaJE, CamargoAA, de SouzaSJ (2007) Sense-antisense pairs in mammals: functional and evolutionary considerations. Genome Biol 8: R40.

38. KojimaKK, OkadaN (2009) mRNA retrotransposition coupled with 5′ inversion as a possible source of new genes. Mol Biol Evol 26: 1405–1420.

39. RogersRL, HartlDL (2011) Chimeric genes as a source of rapid evolution in Drosophila melanogaster. Mol Biol Evol 29: 517–529.

40. CourseauxA, NahonJL (2001) Birth of two chimeric genes in the Hominidae lineage. Science 291: 1293–1297.

41. RogallaP, KazmierczakB, FlohrAM, HaukeS, BullerdiekJ (2000) Back to the roots of a new exon - The molecular archaeology of a SP100 splice variant. Genomics 63: 117–122.

42. JonesCD, CusterAW, BegunDJ (2005) Origin and evolution of a chimeric fusion gene in Drosophila subobscura, D. madeirensis and D. guanche. Genetics 170: 207–219.

43. WangW, BrunetFG, NevoE, LongM (2002) Origin of sphinx, a young chimeric RNA gene in Drosophila melanogaster. Proc Natl Acad Sci U S A 99: 4448–4453.

44. JonesCD, BegunDJ (2005) Parallel evolution of chimeric fusion genes. Proc Natl Acad Sci U S A 102: 11373–11378.

45. MontgomerySB, SammethM, Gutierrez-ArcelusM, LachRP, IngleC, et al. (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464: 773–U151.

46. GalantePAF, ParmigianiRB, ZhaoQ, CaballeroOL, de SouzaJE, et al. (2011) Distinct patterns of somatic alterations in a lymphoblastoid and a tumor genome derived from the same individual. Nucleic Acids Res 39: 6056–6068.

47. SabetiPC, VarillyP, FryB, LohmuellerJ, HostetterE, et al. (2007) Genome-wide detection and characterization of positive selection in human populations. Nature 449: 913–918.

48. VoightBF, KudaravalliS, WenXQ, PritchardJK (2006) A map of recent positive selection in the human genome. PLoS Biol 4: e72 doi:10.1371/journal.pbio.0040072.

49. HudsonRR, KaplanNL (1986) On the divergence of alleles in nested subsamples from finite populations. Genetics 113: 1057–1076.

50. HudsonRR (2002) Generating samples under a Wright-Fisher neutral model of genetic variation. Bioinformatics 18: 337–338.

51. HudsonRR, BaileyK, SkareckyD, KwiatowskiJ, AyalaFJ (1994) Evidence for positive selection in the superoxide dismutase (Sod) region of Drosophila melanogaster. Genetics 136: 1329–1340.

52. AnagnouNP, AntonarakisSE, ObrienSJ, ModiWS, NienhuisAW (1988) Chromosomal localization and racial distribution of the polymorphic human dihydrofolate-reductase pseudogene (DHFRPI). Am J Hum Genet 42: 345–352.

53. McEnteeG, MinguzziS, O'BrienK, Ben LarbiN, LoscherC, et al. (2011) The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional. Proc Natl Acad Sci U S A 108: 15157–15162.

54. CarioH, SmithDEC, BlomH, BlauN, BodeH, et al. (2011) Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet 88: 226–231.

55. UrlaubG, ChasinLA (1980) Isolation of Chinese hamster cell mutants deficient in dihydrofolate reductase activity. Proc Natl Acad Sci U S A 77: 4216–4220.

56. HawserS, LociuroS, IslamK (2006) Dihydrofolate reductase inhibitors as antibacterial agents. Biochem Pharmacol 71: 941–948.

57. Huennekens FM (1994) The methotrexate story: A paradigm for development of cancer chemotherapeutic agents. In: Weber G, editor. Advances in Enzyme Regulation, Vol 34. pp. 397–419.

58. Cardenas-NaviaLI, CruzP, LinJC, RosenbergSA, SamuelsY, et al. (2010) Novel somatic mutations in heterotrimeric G proteins in melanoma. Cancer Biol Ther 10: 33–37.

59. SenderekJ, BergmannC, WeberS, KetelsenUP, SchorleH, et al. (2003) Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. Hum Mol Genet 12: 349–356.

60. FlicekP, AmodeMR, BarrellD, BealK, BrentS, et al. (2012) Ensembl 2012. Nucleic Acids Res 40: D84–D90.

61. KentWJ (2002) BLAT - The BLAST-like alignment tool. Genome Res 12: 656–664.

62. HinrichsAS, KarolchikD, BaertschR, BarberGP, BejeranoG, et al. (2006) The UCSC Genome Browser Database: update 2006. Nucleic Acids Res 34: D590–D598.

63. Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. In: S KSaM, editor. Methods and Protocols: Methods in Molecular Biology. Totowa, NJ: Humana Press. pp. 365–386.

64. ScheetP, StephensM (2006) A fast and flexible statistical model for large-scale population genotype data: Applications to inferring missing genotypes and haplotypic phase. Am J Hum Genet 78: 629–644.

65. FrazerKA, BallingerDG, CoxDR, HindsDA, StuveLL, et al. (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449: 851–861.