Transcriptome Sequencing from Diverse Human Populations Reveals Differentiated Regulatory Architecture

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Previous gene expression studies have identified factors influencing population-level variation in gene regulation. However, these efforts have been limited to a small set of well-studied populations. By leveraging the high resolution of RNA sequencing and broad population sampling, we survey the landscape of transcriptome variation across a globally distributed set of seven populations that span a breadth of human genetic variation and major dispersal events. We assess differences in gene expression, transcript structure, and regulatory variation. We find only 44 transcripts that show significant differences in expression, likely as a result of the small sample size, but we find that 25% of the variance in gene expression is due to population differences. This is a larger fraction than previously observed, and it is likely due to the greater breadth of human diversity assayed in this study. We also find that population-specific variance is mostly due to transcription variability rather than the configuration of expressed gene products. Additionally, known common regulatory variants have similar effects across populations including those we study here. These data and results serve as a resource cataloging the wide array of gene expression regulation affecting population variation among diverse groups, improving our understanding of transcriptional diversity.

Vyšlo v časopise: Transcriptome Sequencing from Diverse Human Populations Reveals Differentiated Regulatory Architecture. PLoS Genet 10(8): e32767. doi:10.1371/journal.pgen.1004549
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004549

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Zdroje

1. LappalainenT, SammethM, FriedländerMR, 't HoenPAC, MonlongJ, et al. (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501: 506–11 doi:10.1038/nature12531

2. MontgomerySB, LappalainenT, Gutierrez-ArcelusM, DermitzakisET (2011) Rare and common regulatory variation in population-scale sequenced human genomes. PLoS Genet 7: e1002144 doi:10.1371/journal.pgen.1002144

3. StrangerBE, MontgomerySB, DimasAS, PartsL, StegleO, et al. (2012) Patterns of cis regulatory variation in diverse human populations. PLoS Genet 8: e1002639 doi:10.1371/journal.pgen.1002639

4. Gonzàlez-PortaM, CalvoM, SammethM, GuigóR (2012) Estimation of alternative splicing variability in human populations. Genome Res 22: 528–538 doi:10.1101/gr.121947.111

5. RamachandranS, DeshpandeO, RosemanCC, RosenbergNA, FeldmanMW, et al. (2005) Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa. Proc Natl Acad Sci U S A 102: 15942–15947 doi:10.1073/pnas.0507611102

6. RosenbergNA, MahajanS, RamachandranS, ZhaoC, PritchardJK, et al. (2005) Clines, clusters, and the effect of study design on the inference of human population structure. PLoS Genet 1: e70 doi:10.1371/journal.pgen.0010070

7. HennBM, GignouxCR, JobinM, GrankaJM, MacphersonJM, et al. (2011) Hunter-gatherer genomic diversity suggests a southern African origin for modern humans. Proc Natl Acad Sci U S A 108: 5154–5162 doi:10.1073/pnas.1017511108

8. LohmuellerKE, IndapAR, SchmidtS, BoykoAR, HernandezRD, et al. (2008) Proportionally more deleterious genetic variation in European than in African populations. Nature 451: 994–997 doi:10.1038/nature06611

9. MacArthurDG, BalasubramanianS, FrankishA, HuangN, MorrisJ, et al. (2012) A systematic survey of loss-of-function variants in human protein-coding genes. Science 335: 823–828 doi:10.1126/science.1215040

10. IdaghdourY, StoreyJD, JadallahSJ, GibsonG (2008) A genome-wide gene expression signature of environmental geography in leukocytes of Moroccan Amazighs. PLoS Genet 4: e1000052 doi:10.1371/journal.pgen.1000052

11. StrangerBE, NicaAC, ForrestMS, DimasA, BirdCP, et al. (2007) Population genomics of human gene expression. Nat Genet 39: 1217–1224 doi:10.1038/ng2142

12. MontgomerySB, SammethM, Gutierrez-ArcelusM, LachRP, IngleC, et al. (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464: 773–777 doi:10.1038/nature08903

13. PickrellJK, MarioniJC, PaiAA, DegnerJF, EngelhardtBE, et al. (2010) Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464: 768–772 doi:10.1038/nature08872

14. MontgomerySB, GoodeD, KvikstadE, AlbersCA, ZhangZ, et al. (2013) The origin, evolution and functional impact of short insertion-deletion variants identified in 179 human genomes. Genome Res 749–761 doi:10.1101/gr.148718.112

15. NicaAC, MontgomerySB, DimasAS, StrangerBE, BeazleyC, et al. (2010) Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet 6: e1000895 doi:10.1371/journal.pgen.1000895

16. NicolaeDL, GamazonE, ZhangW, DuanS, DolanME, et al. (2010) Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6: e1000888 doi:10.1371/journal.pgen.1000888

17. ZhangW, DuanS, BleibelWK, WiselSA, HuangRS, et al. (2009) Identification of common genetic variants that account for transcript isoform variation between human populations. Hum Genet 125: 81–93 doi:10.1007/s00439-008-0601-x

18. JuYS, KimJ-I, KimS, HongD, ParkH, et al. (2011) Extensive genomic and transcriptional diversity identified through massively parallel DNA and RNA sequencing of eighteen Korean individuals. Nat Genet 43: 745–752 doi:10.1038/ng.872

19. DunhamI, KundajeA, AldredSF, CollinsPJ, DavisCA, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74 doi:10.1038/nature11247

20. PickrellJK, PaiAA, GiladY, PritchardJK (2010) Noisy splicing drives mRNA isoform diversity in human cells. PLoS Genet 6: e1001236 doi:10.1371/journal.pgen.1001236

21. CannHM (2002) A Human Genome Diversity Cell Line Panel. Science 296: 261b–262 doi:10.1126/science.296.5566.261b

22. PriceAL, TandonA, PattersonN, BarnesKC, RafaelsN, et al. (2009) Sensitive detection of chromosomal segments of distinct ancestry in admixed populations. PLoS Genet 5: e1000519 doi:10.1371/journal.pgen.1000519

23. TrapnellC, WilliamsBA, PerteaG, MortazaviA, KwanG, et al. (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 28: 511–515 doi:10.1038/nbt.1621

24. 't HoenPaC, FriedländerMR, AlmlöfJ, SammethM, PulyakhinaI, et al. (2013) Reproducibility of high-throughput mRNA and small RNA sequencing across laboratories. Nat Biotechnol 31: 1015–1022 doi:10.1038/nbt.2702

25. HansenKD, BrennerSE, DudoitS (2010) Biases in Illumina transcriptome sequencing caused by random hexamer priming. Nucleic Acids Res 38: e131 doi:10.1093/nar/gkq224

26. LiJ, JiangH, WongWH (2010) Modeling non-uniformity in short-read rates in RNA-Seq data. Genome Biol 11: R50 doi:10.1186/gb-2010-11-5-r50

27. HansenKD, IrizarryRA, WuZ (2012) Removing technical variability in RNA-seq data using conditional quantile normalization. Biostatistics 13: 204–216 doi:10.1093/biostatistics/kxr054

28. JakobssonM, ScholzSW, ScheetP, GibbsJR, VanLiereJM, et al. (2008) Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451: 998–1003 doi:10.1038/nature06742

29. LiJZ, AbsherDM, TangH, SouthwickAM, CastoAM, et al. (2008) Worldwide human relationships inferred from genome-wide patterns of variation. Science 319: 1100–1104 doi:10.1126/science.1153717

30. McCarthyDJ, ChenY, SmythGK (2012) Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res 40: 4288–4297 doi:10.1093/nar/gks042

31. FerrisMT, AylorDL, BottomlyD, WhitmoreAC, AicherLD, et al. (2013) Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathog 9: e1003196 doi:10.1371/journal.ppat.1003196

32. FejermanL, ChenGK, EngC, HuntsmanS, HuD, et al. (2012) Admixture mapping identifies a locus on 6q25 associated with breast cancer risk in US Latinas. Hum Mol Genet 21: 1907–1917 doi:10.1093/hmg/ddr617

33. SongM-S, ChoY-H, ParkS-J, PascuaPNQ, BaekYH, et al. (2013) Early regulation of viral infection reduces inflammation and rescues mx-positive mice from lethal avian influenza infection. Am J Pathol 182: 1308–1321 doi:10.1016/j.ajpath.2012.12.022

34. BighamAW, BuckinghamKJ, HusainS, EmondMJ, BofferdingKM, et al. (2011) Host genetic risk factors for West Nile virus infection and disease progression. PLoS One 6: e24745 doi:10.1371/journal.pone.0024745

35. SubramanianA, TamayoP, MoothaVK, MukherjeeS, EbertBL, et al. (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 102: 15545–15550 doi:10.1073/pnas.0506580102

36. Barbosa-MoraisNL, IrimiaM, PanQ, XiongHY, GueroussovS, et al. (2012) The evolutionary landscape of alternative splicing in vertebrate species. Science 338: 1587–1593 doi:10.1126/science.1230612

37. MerkinJ, RussellC, ChenP, BurgeCB (2012) Evolutionary dynamics of gene and isoform regulation in Mammalian tissues. Science 338: 1593–1599 doi:10.1126/science.1228186

38. StoreyJD, MadeoyJ, StroutJL, WurfelM, RonaldJ, et al. (2007) Gene-Expression Variation Within and Among Human Populations. 80: 502–509 doi:10.1086/512017

39. PodderS, GhoshTC (2012) Evolutionary dynamics of human autoimmune disease genes and malfunctioned immunological genes. BMC Evol Biol 12: 10 doi:10.1186/1471-2148-12-10

40. PickrellJK, CoopG, NovembreJ, KudaravalliS, LiJZ, et al. (2009) Signals of recent positive selection in a worldwide sample of human populations. Genome Res 19: 826–837 doi:10.1101/gr.087577.108

41. ParkhomchukD, BorodinaT, AmstislavskiyV, BanaruM, HallenL, et al. (2009) Transcriptome analysis by strand-specific sequencing of complementary DNA. Nucleic Acids Res 37: e123 doi:10.1093/nar/gkp596

42. DePristoMa, BanksE, PoplinR, GarimellaKV, MaguireJR, et al. (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43: 491–498 doi:10.1038/ng.806

43. LiH, DurbinR (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760 doi:10.1093/bioinformatics/btp324

44. McKennaA, HannaM, BanksE, SivachenkoA, CibulskisK, et al. (2010) The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20: 1297–1303 doi:10.1101/gr.107524.110

45. WeirBS, CockerhamCC (1984) Estimating F-Statistics for the Analysis of Population Structure. Evolution (N Y) 38: 1358–1370.

46. TrapnellC, PachterL, SalzbergSL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25: 1105–1111 doi:10.1093/bioinformatics/btp120

47. DavydovEV, GoodeDL, SirotaM, CooperGM, SidowA, et al. (2010) Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol 6: e1001025 doi:10.1371/journal.pcbi.1001025

48. MassinghamT, GoldmanN (2005) Detecting amino acid sites under positive selection and purifying selection. Genetics 169: 1753–1762 doi:10.1534/genetics.104.032144

49. FlicekP, AhmedI, AmodeMR, BarrellD, BealK, et al. (2013) Ensembl 2013. Nucleic Acids Res 41: D48–55 doi:10.1093/nar/gks1236

50. MeyerLR, ZweigAS, HinrichsAS, KarolchikD, KuhnRM, et al. (2013) The UCSC Genome Browser database: extensions and updates 2013. Nucleic Acids Res 41: D64–9 doi:10.1093/nar/gks1048

51. GarberM, GuttmanM, ClampM, ZodyMC, FriedmanN, et al. (2009) Identifying novel constrained elements by exploiting biased substitution patterns. Bioinformatics 25: i54–62 doi:10.1093/bioinformatics/btp190

52. LiuX, JianX, BoerwinkleE (2011) dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Hum Mutat 32: 894–899 doi:10.1002/humu.21517

53. HennBM, Cavalli-SforzaLL, FeldmanMW (2012) The great human expansion. Proc Natl Acad Sci U S A 109: 17758–17764 doi:10.1073/pnas.1212380109