Statistical Analysis Reveals Co-Expression Patterns of Many Pairs of Genes in Yeast Are Jointly Regulated by Interacting Loci

English version České info

Expression quantitative trait loci (eQTL) studies have generated large amounts of data in different organisms. The analyses of these data have led to many novel findings and biological insights on expression regulations. However, the role of epistasis in the joint regulation of multiple genes has not been explored. This is largely due to the computational complexity involved when multiple traits are simultaneously considered against multiple markers if an exhaustive search strategy is adopted. In this article, we propose a computationally feasible approach to identify pairs of chromosomal regions that interact to regulate co-expression patterns of pairs of genes. Our approach is built on a bivariate model whose covariance matrix depends on the joint genotypes at the candidate loci. We also propose a filtering process to reduce the computational burden. When we applied our method to a yeast eQTL dataset profiled under both the glucose and ethanol conditions, we identified a total of 225 and 224 modules, with each module consisting of two genes and two eQTLs where the two eQTLs epistatically regulate the co-expression patterns of the two genes. We found that many of these modules have biological interpretations. Under the glucose condition, ribosome biogenesis was co-regulated with the signaling and carbohydrate catabolic processes, whereas silencing and aging related genes were co-regulated under the ethanol condition with the eQTLs containing genes involved in oxidative stress response process.

Vyšlo v časopise: Statistical Analysis Reveals Co-Expression Patterns of Many Pairs of Genes in Yeast Are Jointly Regulated by Interacting Loci. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003414
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003414

Souhrn

Zdroje

1. BremRB, YvertG, ClintonR, KruglyakL (2002) Genetic dissection of transcriptional regulation in budding yeast. Science 296 : 752–755.

2. BremRB, StoreyJD, WhittleJ, KruglyakL (2005) Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436 : 701–3.

3. SmithEN, KruglyakL (2008) Genecenvironment interaction in yeast gene expression. PLoS Biol 6: e83 doi:10.1371/journal.pbio.0060083.

4. SchadtEE, MonksSA, DrakeTA, LusisAJ, CheN, et al. (2003) Genetics of gene expression surveyed in maize, mouse and man. Nature 422 : 297–302.

5. MorleyM, MolonyCM, WeberTM, DevlinJL, EwensKG, et al. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430 : 743–747.

6. van WageningenS, KemmerenP, LijnzaadP, MargaritisT, BenschopJJ, et al. (2010) Functional overlap and regulatory links shape genetic interactions between signaling pathways. Cell 143 : 991–1004.

7. ZhengJ, BenschopJJ, ShalesM, KemmerenP, GreenblattJ, et al. (2010) Epistatic relationships reveal the functional organization of yeast transcription factors. Mol Syst Biol 6 : 420–.

8. StoreyJD, AkeyJM, KruglyakL (2005) Multiple locus linkage analysis of genomewide expression in yeast. PLoS Biol 3: e267 doi:10.1371/journal.pbio.0030267.

9. ZhangW, ZhuJ, SchadtEE, LiuJS (2010) A bayesian partition method for detecting pleiotropic and epistatic eqtl modules. PLoS Comput Biol 6: e1000642 doi:10.1371/journal.pcbi.1000642.

10. YangC, HeZ, WanX, YangQ, XueH, et al. (2009) Snpharvester: a filtering-based approach for detecting epistatic interactions in genome-wide association studies. Bioinformatics 25 : 504–511.

11. LeeS, XingEP (2012) Leveraging input and output structures for joint mapping of epistatic and marginal eqtls. Bioinformatics 28: i137–i146.

12. LiKC (2002) Genome-wide coexpression dynamics: Theory and application. Proceedings of the National Academy of Sciences 99 : 16875–16880.

13. SunW, YuanS, LiKC (2008) Trait-trait dynamic interaction: 2d-trait eqtl mapping for genetic variation study. BMC Genomics 9 : 242.

14. HoYY, ParmigianiG, LouisTA, CopeLM (2011) Modeling liquid association. Biometrics 67 : 133–141.

15. ChenJ, XieJ, LiH (2011) A penalized likelihood approach for bivariate conditional normal models for dynamic co-expression analysis. Biometrics 67 : 299–308.

16. DayeZJ, ChenJ, LiH (2012) High-dimensional heteroscedastic regression with an application to eqtl data analysis. Biometrics 68 : 316–326.

17. GibsonG (2008) The environmental contribution to gene expression profiles. Nat Rev Genet 9 : 575–81.

18. TiroshI, ReikhavS, LevyAA, BarkaiN (2009) A yeast hybrid provides insight into the evolution of gene expression regulation. Science 324 : 659–62.

19. HeidtmanM, ChenCZ, CollinsRN, BarloweC (2003) A role for yip1p in copii vesicle biogenesis. J Cell Biol 163 : 57–69.

20. SandmannT, HerrmannJM, DengjelJ, SchwarzH, SpangA (2003) Suppression of coatomer mutants by a new protein family with copi and copii binding motifs in saccharomyces cerevisiae. Mol Biol Cell 14 : 3097–113.

21. Lorente-RodriguezA, HeidtmanM, BarloweC (2009) Multicopy suppressor analysis of thermosensitive yip1 alleles implicates got1 in transport from the er. J Cell Sci 122 : 1540–50.

22. PowersJ, BarloweC (1998) Transport of axl2p depends on erv14p, an er-vesicle protein related to the drosophila cornichon gene product. J Cell Biol 142 : 1209–22.

23. SchuldinerM, CollinsSR, ThompsonNJ, DenicV, BhamidipatiA, et al. (2005) Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell 123 : 507–19.

24. CostanzoM, BaryshnikovaA, BellayJ, KimY, SpearED, et al. (2010) The genetic landscape of a cell. Science 327 : 425–31.

25. PowersJ, BarloweC (2002) Erv14p directs a transmembrane secretory protein into copii-coated transport vesicles. Mol Biol Cell 13 : 880–91.

26. HahnJS, ThieleDJ (2002) Regulation of the saccharomyces cerevisiae slt2 kinase pathway by the stress-inducible sdp1 dual specificity phosphatase. J Biol Chem 277 : 21278–84.

27. MonteiroPT, MendesND, TeixeiraMC, d'OreyS, TenreiroS, et al. (2008) Yeastract-discoverer: new tools to improve the analysis of transcriptional regulatory associations in saccharomyces cerevisiae. Nucleic Acids Res 36: D132–6.

28. TeixeiraMC, MonteiroP, JainP, TenreiroS, FernandesAR, et al. (2006) The yeastract database: a tool for the analysis of transcription regulatory associations in saccharomyces cerevisiae. Nucleic Acids Res 34: D446–51.

29. IknerA, ShiozakiK (2005) Yeast signaling pathways in the oxidative stress response. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 569 : 13–27.

30. GruschkeS, KehreinK, RomplerK, GroneK, IsraelL, et al. (2011) Cbp3-cbp6 interacts with the yeast mitochondrial ribosomal tunnel exit and promotes cytochrome b synthesis and assembly. J Cell Biol 193 : 1101–14.

31. YinZ, WilsonS, HauserNC, TournuH, HoheiselJD, et al. (2003) Glucose triggers different global responses in yeast, depending on the strength of the signal, and transiently stabilizes ribosomal protein mrnas. Mol Microbiol 48 : 713–24.

32. GeladeR, Van de VeldeS, Van DijckP, TheveleinJM (2003) Multi-level response of the yeast genome to glucose. Genome Biol 4 : 233.

33. HarashimaT, HeitmanJ (2002) The galpha protein gpa2 controls yeast differentiation by interacting with kelch repeat proteins that mimic gbeta subunits. Mol Cell 10 : 163–73.

34. ChambersA, PackhamEA, GrahamIR (1995) Control of glycolytic gene expression in the budding yeast (saccharomyces cerevisiae). Curr Genet 29 : 1–9.

35. MizunoT, KishimotoT, ShinzatoT, HawR, ChambersA, et al. (2004) Role of the n-terminal region of rap1p in the transcriptional activation of glycolytic genes in saccharomyces cerevisiae. Yeast 21 : 851–66.

36. BalciunasD, RonneH (1995) Three subunits of the rna polymerase ii mediator complex are involved in glucose repression. Nucleic Acids Res 23 : 4421–5.

37. CollinsSR, MillerKM, MaasNL, RoguevA, FillinghamJ, et al. (2007) Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map. Nature 446 : 806–10.

38. KaeberleinM (2010) Lessons on longevity from budding yeast. Nature 464 : 513–9.

39. KenyonCJ (2010) The genetics of ageing. Nature 464 : 504–12.

40. CherryJM, HongEL, AmundsenC, BalakrishnanR, BinkleyG, et al. (2012) Saccharomyces genome database: the genomics resource of budding yeast. Nucleic Acids Res 40: D700–5.

41. OrlandiI, BettigaM, AlberghinaL, VaiM (2004) Transcriptional profiling of ubp10 null mutant reveals altered subtelomeric gene expression and insurgence of oxidative stress response. J Biol Chem 279 : 6414–25.

42. MoazedD, KistlerA, AxelrodA, RineJ, JohnsonAD (1997) Silent information regulator protein complexes in saccharomyces cerevisiae: a sir2/sir4 complex and evidence for a regulatory domain in sir4 that inhibits its interaction with sir3. Proc Natl Acad Sci U S A 94 : 2186–91.

43. KennedyBK, GottaM, SinclairDA, MillsK, McNabbDS, et al. (1997) Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in s. cerevisiae. Cell 89 : 381–91.

44. GuarenteL (2000) Sir2 links chromatin silencing, metabolism, and aging. Genes Dev 14 : 1021–6.

45. RepM, ProftM, RemizeF, TamasM, SerranoR, et al. (2001) The saccharomyces cerevisiae sko1p transcription factor mediates hog pathway-dependent osmotic regulation of a set of genes encoding enzymes implicated in protection from oxidative damage. Mol Microbiol 40 : 1067–83.

46. VendrellA, Martinez-PastorM, Gonzalez-NovoA, Pascual-AhuirA, SinclairDA, et al. (2011) Sir2 histone deacetylase prevents programmed cell death caused by sustained activation of the hog1 stress-activated protein kinase. EMBO Rep 12 : 1062–8.

47. ZhouJ, ZhouBO, LenzmeierBA, ZhouJQ (2009) Histone deacetylase rpd3 antagonizes sir2 -⁠ dependent silent chromatin propagation. Nucleic Acids Res 37 : 3699–713.

48. KimS, BenguriaA, LaiCY, JazwinskiSM (1999) Modulation of life-span by histone deacetylase genes in saccharomyces cerevisiae. Mol Biol Cell 10 : 3125–36.

49. DulaML, HolmesSG (2000) Mga2 and spt23 are modifiers of transcriptional silencing in yeast. Genetics 156 : 933–41.

50. NevittT, PereiraJ, AzevedoD, GuerreiroP, Rodrigues-PousadaC (2004) Expression of yap4 in saccharomyces cerevisiae under osmotic stress. Biochem J 379 : 367–74.

51. HeoJM, Livnat-LevanonN, TaylorEB, JonesKT, DephoureN, et al. (2010) A stress-responsive system for mitochondrial protein degradation. Mol Cell 40 : 465–80.

52. TranJR, TomsicLR, BrodskyJL (2011) A cdc48p-associated factor modulates endoplasmic reticulum-associated degradation, cell stress, and ubiquitinated protein homeostasis. J Biol Chem 286 : 5744–55.

53. ShcherbikN, HainesDS (2007) Cdc48p(npl4p/ufd1p) binds and segregates membrane -⁠ anchored/tethered complexes via a polyubiquitin signal present on the anchors. Mol Cell 25 : 385–97.

54. BeltraoP, TrinidadJC, FiedlerD, RoguevA, LimWA, et al. (2009) Evolution of phosphoregulation: comparison of phosphorylation patterns across yeast species. PLoS Biol 7: e1000134 doi:10.1371/journal.pbio.1000134.

55. ChanTF, CarvalhoJ, RilesL, ZhengXF (2000) A chemical genomics approach toward understanding the global functions of the target of rapamycin protein (tor). Proc Natl Acad Sci U S A 97 : 13227–32.

56. HuangX, LiuJ, DicksonRC (2012) Down-regulating sphingolipid synthesis increases yeast lifespan. PLoS Genet 8: e1002493 doi:10.1371/journal.pgen.1002493.

57. Pascual-AhuirA (2007) ProftM (2007) The sch9 kinase is a chromatin-associated transcriptional activator of osmostress-responsive genes. EMBO J 26 : 3098–108.

58. WeiM, FabrizioP, HuJ, GeH, ChengC, et al. (2008) Life span extension by calorie restriction depends on rim15 and transcription factors downstream of ras/pka, tor, and sch9. PLoS Genet 4: e13 doi:10.1371/journal.pgen.0040013.

59. HuberA, FrenchSL, TekotteH, YerlikayaS, StahlM, et al. (2011) Sch9 regulates ribosome biogenesis via stb3, dot6 and tod6 and the histone deacetylase complex rpd3l. EMBO J 30 : 3052–64.

60. KangHM, YeC, EskinE (2008) Accurate discovery of expression quantitative trait loci under confounding from spurious and genuine regulatory hotspots. Genetics 180 : 1909–25.

61. ZhengW, ZhaoH, ManceraE, SteinmetzLM, SnyderM (2010) Genetic analysis of variation in transcription factor binding in yeast. Nature 464 : 1187–91.

62. DegnerJF, PaiAA, Pique-RegiR, VeyrierasJB, GaffneyDJ, et al. (2012) Dnase i sensitivity qtls are a major determinant of human expression variation. Nature 482 : 390–4.

63. WuZ, ZhaoH (2009) Statistical power of model selection strategies for genome-wide association studies. PLoS Genet 5: e1000582 doi:10.1371/journal.pgen.1000582.

64. TuZ, WangL, ArbeitmanMN, ChenT, SunF (2006) An integrative approach for causal gene identification and gene regulatory pathway inference. Bioinformatics 22: e489–96.

65. LeeSI, DudleyAM, DrubinD, SilverPA, KroganNJ, et al. (2009) Learning a prior on regulatory potential from eqtl data. PLoS Genet 5: e1000358 doi:10.1371/journal.pgen.1000358.

66. Yeger-LotemE, RivaL, SuLJ, GitlerAD, CashikarAG, et al. (2009) Bridging high-throughput genetic and transcriptional data reveals cellular responses to alpha-synuclein toxicity. Nat Genet 41 : 316–23.

67. Gat-ViksI, MellerR, KupiecM, ShamirR (2010) Understanding gene sequence variation in the context of transcription regulation in yeast. PLoS Genet 6: e1000800 doi:10.1371/journal.pgen.1000800.

68. BallardDH, ChoJ, ZhaoH (2010) Comparisons of multi-marker association methods to detect association between a candidate region and disease. Genet Epidemiol 34 : 201–12.

69. BeckerJ, WendlandJR, HaenischB, NothenMM, SchumacherJ (2012) A systematic eqtl study of cis-trans epistasis in 210 hapmap individuals. Eur J Hum Genet 20 : 97–101.

70. HannumG, SrivasR, GuenoleA, van AttikumH, KroganNJ, et al. (2009) Genome-wide association data reveal a global map of genetic interactions among protein complexes. PLoS Genet 5: e1000782 doi:10.1371/journal.pgen.1000782.

71. Huang daW, ShermanBT, LempickiRA (2009) Systematic and integrative analysis of large gene lists using david bioinformatics resources. Nat Protoc 4 : 44–57.

72. Huang daW, ShermanBT, LempickiRA (2009) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 37 : 1–13.