Global Properties and Functional Complexity of Human Gene Regulatory Variation

English version České info

Identification and functional interpretation of gene regulatory variants is a major focus of modern genomics. The application of genetic mapping to molecular and cellular traits has enabled the detection of regulatory variation on genome-wide scales and revealed an enormous diversity of regulatory architecture in humans and other species. In this review I summarise the insights gained and questions raised by a decade of genetic mapping of gene expression variation. I discuss recent extensions of this approach using alternative molecular phenotypes that have revealed some of the biological mechanisms that drive gene expression variation between individuals. Finally, I highlight outstanding problems and future directions for development.

Vyšlo v časopise: Global Properties and Functional Complexity of Human Gene Regulatory Variation. PLoS Genet 9(5): e32767. doi:10.1371/journal.pgen.1003501
Kategorie: Review
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003501

Souhrn

Zdroje

1. ENCODE Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.

2. HindorffL, SethupathyP, JunkinsH, RamosE, MehtaJ, et al. (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of the United States of America 106: 9362–9367.

3. JansenR, NapJ (2001) Genetical genomics: the added value from segregation. Trends in Genetics 17: 388–391.

4. DermitzakisE (2012) Cellular genomics for complex traits. Nature Reviews Genetics 13: 215–220.

5. GiladY, RifkinS, PritchardJ (2008) Revealing the architecture of gene regulation: the promise of eQTL studies. Trends in Genetics 24: 408–415.

6. NicaA, MontgomeryS, DimasA, StrangerB, BeazleyC, et al. (2010) Candidate causal regulatory effects by integration of expression QTLs with complex trait genetic associations. PLoS Genet 6(4): e1000895 doi:10.1371/journal.pgen.1000895.

7. NicolaeD, GamazonE, ZhangW, DuanS, DolanM, et al. (2010) Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6(4): e1000888 doi:10.1371/journal.pgen.1000888.

8. BremR, YvertGl, ClintonR, KruglyakL (2002) Genetic dissection of transcriptional regulation in budding yeast. Science (New York, NY) 296: 752–755.

9. SchadtE, MonksS, DrakeT, LusisA, CheN, et al. (2003) Genetics of gene expression surveyed in maize, mouse and man. Nature 422: 297–302.

10. CheungV, ConlinL, WeberT, ArcaroM, JenK-Y, et al. (2003) Natural variation in human gene expression assessed in lymphoblastoid cells. Nature Genetics 33: 422–425.

11. MonksSA, LeonardsonA, ZhuH, CundiffP, PietrusiakP (2004) Genetic inheritance of gene expression in human cell lines. Am J Hum Genet 75: 1095–105.

12. MorleyM, MolonyC, WeberT, DevlinJ, EwensK, et al. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430: 743–747.

13. PriceA, HelgasonA, ThorleifssonG, McCarrollS, KongA, et al. (2011) Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals. PLoS Genet 7(2): e1001317 doi:10.1371/journal.pgen.1001317.

14. PowellJ, HendersA, McRaeA, WrightM, MartinN, et al. (2012) Genetic control of gene expression in whole blood and lymphoblastoid cell lines is largely independent. Genome Research 22: 456–466.

15. GoringHH, CurranJ, JohnsonM, DyerT, CharlesworthJ, et al. (2007) Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nature Genetics 39: 1208–1216.

16. DixonA, LiangL, MoffattM, ChenW, HeathS, et al. (2007) A genome-wide association study of global gene expression. Nature Genetics 39: 1202–1207.

17. EmilssonV, ThorleifssonG, ZhangB, LeonardsonA, ZinkF, et al. (2008) Genetics of gene expression and its effect on disease. Nature 452: 423–428.

18. GrundbergE, SmallK, HedmanA, NicaA, BuilA, et al. (2012) Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat Genet 44: 1084–1089.

19. BremR, StoreyJ, WhittleJ, KruglyakL (2005) Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436: 701–703.

20. PetrettoE, MangionJ, DickensN, CookS, KumaranM, et al. (2006) Heritability and tissue specificity of expression quantitative trait loci. PLoS Genet 2(10): e172 doi:10.1371/journal.pgen.0020172.

21. ZellerT, WildP, SzymczakS, RotivalM, SchillertA, et al. (2010) Genetics and beyond—the transcriptome of human monocytes and disease susceptibility. PloS ONE 5(5): e10693 doi:10.1371/journal.pone.0010693.

22. StrangerB, ForrestM, DunningM, IngleC, BeazleyC, et al. (2007) Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science (New York, NY) 315: 848–853.

23. SkellyD, RonaldJ, AkeyJ (2009) Inherited variation in gene expression. Annual Review of Genomics and Human Genetics 10: 313–332.

24. StrangerB, MontgomeryS, DimasA, PartsL, StegleO, et al. (2012) Patterns of cis regulatory variation in diverse human populations. PLoS Genet 8: e1002639 doi:10.1371/journal.pgen.1002639.

25. CheungV, SpielmanR, EwensK, WeberT, MorleyM, et al. (2005) Mapping determinants of human gene expression by regional and genome-wide association. Nature 437: 1365–1369.

26. PickrellJ, MarioniJ, PaiA, DegnerJ, EngelhardtB, et al. (2010) Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464: 768–772.

27. VeyrierasJ-B, KudaravalliS, KimS, DermitzakisE, GiladY, et al. (2008) High-resolution mapping of expression-QTLs yields insight into human gene regulation. PLoS Genet 4(10): e1000214 doi:10.1371/journal.pgen.1000214.

28. DimasA, DeutschS, StrangerB, MontgomeryS, BorelC, et al. (2009) Common regulatory variation impacts gene expression in a cell type-dependent manner. Science (New York, NY) 325: 1246–1250.

29. GaffneyD, VeyrierasJ-B, DegnerJ, Pique-RegiR, PaiA, et al. (2012) Dissecting the regulatory architecture of gene expression QTLs. Genome Biology 13: R7.

30. VeyrierasJ-B, GaffneyD, PickrellJ, GiladY, StephensM, et al. (2012) Exon-specific QTLs skew the inferred distribution of expression QTLs detected using gene expression array data. PloS ONE 7: e30629 doi:10.1371/journal.pone.0030629.

31. LalondeE, HaK, WangZ, BemmoA, KleinmanC, et al. (2011) RNA sequencing reveals the role of splicing polymorphisms in regulating human gene expression. Genome Research 21: 545–554.

32. PriceA, PattersonN, HancksD, MyersS, ReichD, et al. (2008) Effects of cis and trans genetic ancestry on gene expression in African Americans. PLoS Genet 4: e1000294 doi:10.1371/journal.pgen.1000294.

33. CheungV, NayakR, WangI, ElwynS, CousinsS, et al. (2010) Polymorphic cis- and trans-regulation of human gene expression. PLoS Biol 8: e1000480 doi:10.1371/journal.pbio.1000480.

34. BreitlingR, LiY, TessonB, FuJ, WuC, et al. (2008) Genetical genomics: spotlight on QTL hotspots. PLoS Genet 4: e1000232 doi:10.1371/journal.pgen.1000232.

35. StegleO, PartsL, DurbinR, WinnJ (2010) A Bayesian framework to account for complex non-genetic factors in gene expression levels greatly increases power in eQTL studies. PLoS Comp Biol 6: e1000770 doi:10.1371/journal.pcbi.1000770.

36. PowellJ, HendersA, McRaeA, CaracellaA, SmithS, et al. (2012) The Brisbane Systems Genetics Study: genetical genomics meets complex trait genetics. PloS ONE 7: e35430 doi:10.1371/journal.pone.0035430.

37. FehrmannR, JansenR, VeldinkJ, WestraH-J, ArendsD, et al. (2011) Trans-eQTLs reveal that independent genetic variants associated with a complex phenotype converge on intermediate genes, with a major role for the HLA. PLoS Genet 7(8): e1002197 doi:10.1371/journal.pgen.1002197.

38. RotivalM, ZellerT, WildP, MaoucheS, SzymczakS, et al. (2011) Integrating genome-wide genetic variations and monocyte expression data reveals trans-regulated gene modules in humans. PLoS Genet 7: e1002367 doi:10.1371/journal.pgen.1002367.

39. SmirnovD, MorleyM, ShinE, SpielmanR, CheungV (2009) Genetic analysis of radiation-induced changes in human gene expression. Nature 459: 587–591.

40. NieZ, HuG, WeiG, CuiK, YamaneA, et al. (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151: 68–79.

41. LovenJ, OrlandoD, SigovaA, LinC, RahlP, et al. (2012) Revisiting global gene expression analysis. Cell 151: 476–482.

42. BullaugheyK, ChavarriaC, CoopG, GiladY (2009) Expression quantitative trait loci detected in cell lines are often present in primary tissues. Human Molecular Genetics 18: 4296–4303.

43. ChoyE, YelenskyR, BonakdarS, PlengeR, SaxenaR, et al. (2008) Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet 4: e1000287 doi:10.1371/journal.pgen.1000287.

44. PlagnolV, UzE, WallaceC, StevensH, ClaytonD, et al. (2008) Extreme clonality in lymphoblastoid cell lines with implications for allele specific expression analyses. PloS ONE 3: e2966 doi:10.1371/journal.pone.0002966.

45. HeinzenE, GeD, CroninK, MaiaJ, ShiannaK, et al. (2008) Tissue-specific genetic control of splicing: implications for the study of complex traits. PLoS Biol 6: e1 doi:10.1371/journal.pbio.1000001.

46. SchadtE, MolonyC, ChudinE, HaoK, YangX (2008) Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6: e107 doi:10.1371/journal.pbio.0060107.

47. GrundbergE, KwanT, GeB, LamK, KokaV, et al. (2009) Population genomics in a disease targeted primary cell model. Genome Research 19: 1942–1952.

48. GibbsJ, van der BrugM, HernandezD, TraynorB, NallsM, et al. (2010) Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 6(5): e1000952 doi:10.1371/journal.pgen.1000952.

49. FairfaxB, MakinoS, RadhakrishnanJ, PlantK, LeslieS, et al. (2012) Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nature Genetics 44: 502–510.

50. FuJ, WolfsM, DeelenP, WestraH-J, FehrmannR, et al. (2012) Unraveling the regulatory mechanisms underlying tissue-dependent genetic variation of gene expression. PLoS Genet 8(1): e1002431 doi:10.1371/journal.pgen.1002431.

51. DingJ, GudjonssonJ, LiangL, StuartP, LiY, et al. (2010) Gene expression in skin and lymphoblastoid cells: Refined statistical method reveals extensive overlap in cis-eQTL signals. American Journal of Human Genetics 87: 779–789.

52. NicaA, PartsL, GlassD, NisbetJ, BarrettA, et al. (2011) The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet 7(2): e1002003 doi:10.1371/journal.pgen.1002003.

53. GreenawaltD, DobrinR, ChudinE, HatoumI, SuverC, et al. (2011) A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome research 21: 1008–1016.

54. MoffattM, KabeschM, LiangL, DixonA, StrachanD, et al. (2007) Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448: 470–473.

55. Cantero-RecasensG, FandosCs, Rubio-MoscardoF, ValverdeM, VicenteRn (2010) The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Human Molecular Genetics 19: 111–121.

56. BluettJ, BowesJ, HoP, McHughN, BartonA (2013) Use of ENCODE and eQTL data to identify potential functional genetic variants at the 5q31 psoriatic arthritis susceptibility locus. The Lancet

57. MusunuruK, StrongA, Frank-KamenetskyM, LeeN, AhfeldtT, et al. (2010) From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature 466: 714–719.

58. de JongS, van EijkK, ZeegersD, StrengmanE, JansonE, et al. (2012) Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes. European Journal of Human Genetics 20: 1004–1008.

59. ZhongH, YangX, KaplanL, MolonyC, SchadtE (2010) Integrating pathway analysis and genetics of gene expression for genome-wide association studies. American Journal of Human Genetics 86: 581–591.

60. CooksonW, LiangL, AbecasisGa, MoffattM, LathropM (2009) Mapping complex disease traits with global gene expression. Nature Reviews Genetics 10: 184–194.

61. FudaN, ArdehaliM, LisJ (2009) Defining mechanisms that regulate RNA polymerase II transcription in vivo. Nature 461: 186–192.

62. DegnerJ, PaiA, Pique-RegiR, VeyrierasJ-B, GaffneyD, et al. (2012) DNaseI sensitivity QTLs are a major determinant of human expression variation. Nature 482: 390–394.

63. HeintzmanN, HonG, HawkinsR, KheradpourP, StarkA, et al. (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459: 108–112.

64. ErnstJ, KheradpourP, MikkelsenT, ShoreshN, WardL, et al. (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473: 43–49.

65. ZhengW, ZhaoH, ManceraE, SteinmetzL, SnyderM (2010) Genetic analysis of variation in transcription factor binding in yeast. Nature 464: 1187–1191.

66. KasowskiM, GrubertF, HeffelfingerC, HariharanM, AsabereA, et al. (2010) Variation in transcription factor binding among humans. Science (New York, NY) 328: 232–235.

67. McDaniellR, LeeB-K, SongL, LiuZ, BoyleA, et al. (2010) Heritable individual-specific and allele-specific chromatin signatures in humans. Science (New York, NY) 328: 235–239.

68. ReddyT, GertzJ, PauliF, KuceraK, VarleyK, et al. (2012) Effects of sequence variation on differential allelic transcription factor occupancy and gene expression. Genome Research 22: 860–869.

69. KadotaM, YangH, HuN, WangC, HuY, et al. (2007) Allele-specific chromatin immunoprecipitation studies show genetic influence on chromatin state in human genome. PLoS Genet 3(5): e81 doi:10.1371/journal.pgen.0030081.

70. MauranoM, WangH, KutyavinT, StamatoyannopoulosJ (2012) Widespread site-dependent buffering of human regulatory polymorphism. PLoS Genet 8(3): e1002599 doi:10.1371/journal.pgen.1002599.

71. KerkelK, SpadolaA, YuanE, KosekJ, JiangL, et al. (2008) Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nature Genetics 40: 904–908.

72. ZhangY, RohdeC, ReinhardtR, Voelcker-RehageC, JeltschA (2009) Non-imprinted allele-specific DNA methylation on human autosomes. Genome Biology 10(12): R138.

73. SchalkwykL, MeaburnE, SmithR, DempsterE, JeffriesA, et al. (2010) Allelic skewing of DNA methylation is widespread across the genome. American Journal of Human Genetics 86: 196–212.

74. ShoemakerR, DengJ, WangW, ZhangK (2010) Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Research 20: 883–889.

75. SchillingE, El ChartouniC, RehliM (2009) Allele-specific DNA methylation in mouse strains is mainly determined by cis-acting sequences. Genome Research 19: 2028–2035.

76. XieW, BarrC, KimA, YueF, LeeA, et al. (2012) Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome. Cell 148: 816–831.

77. BellJ, PaiA, PickrellJ, GaffneyD, Pique-RegiR, et al. (2011) DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biology 12: R10.

78. ZhangD, ChengL, BadnerJ, ChenC, ChenQ, et al. (2010) Genetic control of individual differences in gene-specific methylation in human brain. American Journal of Human Genetics 86: 411–419.

79. ThurmanR, RynesE, HumbertR, VierstraJ, MauranoM, et al. (2012) The accessible chromatin landscape of the human genome. Nature 489: 75–82.

80. FraserH, LamL, NeumannS, KoborM (2012) Population-specificity of human DNA methylation. Genome Biology 13: R8.

81. MajewskiJ, PastinenT (2011) The study of eQTL variations by RNA-seq: from SNPs to phenotypes. Trends in Genetics 27: 72–79.

82. KwanT, BenovoyD, DiasC, GurdS, SerreD, et al. (2007) Heritability of alternative splicing in the human genome. Genome Research 17: 1210–1218.

83. KwanT, BenovoyD, DiasC, GurdS, ProvencherC, et al. (2008) Genome-wide analysis of transcript isoform variation in humans. Nature Genetics 40: 225–231.

84. ZhangW, DuanS, BleibelW, WiselS, HuangR, et al. (2009) Identification of common genetic variants that account for transcript isoform variation between human populations. Human Genetics 125: 81–93.

85. FraserH, XieX (2009) Common polymorphic transcript variation in human disease. Genome Research 19: 567–575.

86. MontgomeryS, SammethM, Gutierrez-ArcelusM, LachR, IngleC, et al. (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464: 773–777.

87. PaiA, CainC, Mizrahi-ManO, De LeonS, LewellenN, et al. (2012) The contribution of RNA decay quantitative trait Loci to inter-individual variation in steady-state gene expression levels. PLoS Genet 8(10): e1003000 doi:10.1371/journal.pgen.1003000.

88. BorelC, DeutschS, LetourneauA, MigliavaccaE, MontgomeryS, et al. (2011) Identification of cis- and trans-regulatory variation modulating microRNA expression levels in human fibroblasts. Genome Research 21: 68–73.

89. PartsL, HedmanÖK, KeildsonS, KnightsA, Abreu-GoodgerC, et al. (2012) Extent, causes, and consequences of small RNA expression variation in human adipose tissue. PLoS Genet 8(5): e1002704 doi:10.1371/journal.pgen.1002704.

90. RantalainenM, HerreraB, NicholsonG, BowdenR, WillsQ, et al. (2011) MicroRNA expression in abdominal and gluteal adipose tissue is associated with mRNA expression levels and partly genetically driven. PloS ONE 6(11): e27338 doi:10.1371/journal.pone.002733.

91. YoonO, HsuT, ImJ, BremR (2012) Genetics and regulatory impact of alternative polyadenylation in human B-lymphoblastoid cells. PLoS Genet 8(8): e1002882 doi:10.1371/journal.pgen.1002882.

92. LeeS-I, DudleyA, DrubinD, SilverP, KroganN, et al. (2009) Learning a prior on regulatory potential from eQTL data. PLoS Genet 5(1): e1000358 doi: 10.1371/journal.pgen.1000358.

93. KhanZ, BloomJ, AminiS, SinghM, PerlmanD, et al. (2012) Quantitative measurement of allele-specific protein expression in a diploid yeast hybrid by LC-MS. Molecular Systems Biology 8: 602.

94. BarreiroL, TailleuxL, PaiA, GicquelB, MarioniJ, et al. (2012) Deciphering the genetic architecture of variation in the immune response to Mycobacterium tuberculosis infection. Proceedings of the National Academy of Sciences of the United States of America 109: 1204–1209.

95. MaranvilleJ, LucaF, RichardsA, WenX, WitonskyD, et al. (2011) Interactions between glucocorticoid treatment and cis-regulatory polymorphisms contribute to cellular response phenotypes. PLoS Genet 7(7): e1002162 doi:10.1371/journal.pgen.1002162.

96. XiaK, ShabalinA, HuangS, MadarV, ZhouY-H, et al. (2012) seeQTL: A searchable database for human eQTLs. Bioinformatics (Oxford, England) 28: 451–452.

97. LeekJ, StoreyJ (2007) Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 3(9): e161 doi:10.1371/journal.pgen.0030161.