Variance of Gene Expression Identifies Altered Network Constraints in Neurological Disease

English version České info

Gene expression analysis has become a ubiquitous tool for studying a wide range of human diseases. In a typical analysis we compare distinct phenotypic groups and attempt to identify genes that are, on average, significantly different between them. Here we describe an innovative approach to the analysis of gene expression data, one that identifies differences in expression variance between groups as an informative metric of the group phenotype. We find that genes with different expression variance profiles are not randomly distributed across cell signaling networks. Genes with low-expression variance, or higher constraint, are significantly more connected to other network members and tend to function as core members of signal transduction pathways. Genes with higher expression variance have fewer network connections and also tend to sit on the periphery of the cell. Using neural stem cells derived from patients suffering from Schizophrenia (SZ), Parkinson's disease (PD), and a healthy control group, we find marked differences in expression variance in cell signaling pathways that shed new light on potential mechanisms associated with these diverse neurological disorders. In particular, we find that expression variance of core networks in the SZ patient group was considerably constrained, while in contrast the PD patient group demonstrated much greater variance than expected. One hypothesis is that diminished variance in SZ patients corresponds to an increased degree of constraint in these pathways and a corresponding reduction in robustness of the stem cell networks. These results underscore the role that variation plays in biological systems and suggest that analysis of expression variance is far more important in disease than previously recognized. Furthermore, modeling patterns of variability in gene expression could fundamentally alter the way in which we think about how cellular networks are affected by disease processes.

Vyšlo v časopise: Variance of Gene Expression Identifies Altered Network Constraints in Neurological Disease. PLoS Genet 7(8): e32767. doi:10.1371/journal.pgen.1002207
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002207

Souhrn

Zdroje

1. 2006 The MicroArray Quality Control (MAQC) project shows inter -⁠ and intraplatform reproducibility of gene expression measurements. Nat Biotech 24 1151 1161

2. LevskyJMShenoySMPezoRCSingerRH 2002 Single-cell gene expression profiling. Science 297 836 840

3. OzbudakEMThattaiMKurtserIGrossmanADvan OudenaardenA 2002 Regulation of noise in the expression of a single gene. Nat Genet 31 69 73

4. CaiLFriedmanNXieXS 2006 Stochastic protein expression in individual cells at the single molecule level. Nature 440 358 362

5. MarJCRubioRQuackenbushJ 2006 Inferring steady state single-cell gene expression distributions from analysis of mesoscopic samples. Genome Biol 7 R119

6. RajARifkinSAndersenEOudenaardenAv 2010 Variability in gene expression underlies incomplete penetrance. Nature 463 913 919

7. RavasiTWellsCForestAUnderhillDMWainwrightBJ 2002 Generation of diversity in the innate immune system: macrophage heterogeneity arises from gene-autonomous transcriptional probability of individual inducible genes. J Immunol 168 44 50

8. Colman-LernerAGordonASerraEChinTResnekovO 2005 Regulated cell-to-cell variation in a cell-fate decision system. Nature 437 699 706

9. EichlerEEFlintJGibsonGKongALealSM 2010 Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11 446 450

10. ManolioTACollinsFSCoxNJGoldsteinDBHindorffLA 2009 Finding the missing heritability of complex diseases. Nature 461 747 753

11. FeinbergAPIrizarryRA 2010 Evolution in health and medicine Sackler colloquium: Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc Natl Acad Sci U S A 107 Suppl 1 1757 1764

12. RaserJO'SheaE 2005 Noise in gene expression: origins, consequences, and control. Science 309 2010 2013

13. MurrellWFeronFWetzigACameronNSplattK 2005 Multipotent stem cells from adult olfactory mucosa. Dev Dyn 233 496 515

14. MurrellWWetzigADonnellanMFéronFBurneTH 2008 Olfactory mucosa is potential source for autologous stem cell therapy for Parkinson's disease. . Stem Cells 26 2183 2192

15. LuJFéronFHoSMMackay-SimAWaitePME 2001 Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats. . Brain Research 889 344 357

16. MatigianNAbrahamsenGSutharsanRCookAVitaleA 2010 Disease-specific, neurosphere-derived cells as models for brain disorders

17. MatigianNAMcCurdyRDFéronFPerryCSmithH 2008 Fibroblast and lymphoblast gene expression profiles in schizophrenia: are non-neural cells informative? PLoS ONE 3 e2412 doi:10.1371/journal.pone.0002412

18. MarJWellsCQuackenbushJ 2010 Identifying Pathway Modules that Drive Kauffman's Gene Expression Attractor Landscape

19. LiaoBJinY 2010 Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner. Cell Res 20 332 344

20. RybakAFuchsHHadianKSmirnovaLWulczynEA 2009 The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2. Nat Cell Biol 11 1411 1420

21. ZhangZLiaoBXuMJinY 2007 Post-translational modification of POU domain transcription factor Oct-4 by SUMO-1. FASEB J 21 3042 3051

22. AshburnerMBallCABlakeJABotsteinDButlerH 2000 Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25 25 29

23. EichlerEENickersonDAAltshulerDBowcockAMBrooksLD 2007 Completing the map of human genetic variation. Nature 447 161 165

24. PurcellSMWrayNRStoneJLVisscherPM International Schizophrenia Consortium 2009 Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460 748 752

25. GibsonG 2009 Decanalization and the origin of complex disease. Nat Rev Genet 10 134 140

26. KalmarTLimCHaywardPMuñoz-DescalzoSNicholsJ 2009 Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biol 7 e1000149 doi:10.1371/journal.pbio.1000149

27. HoughSRLaslettALGrimmondSBKolleGPMF 2009 A continuum of cell states spans pluripotency and lineage commitment in human embryonic stem cells. PLoS ONE 4 e7708 doi:10.1371/journal.pone.0007708

28. AnselJBottinHRodriguez-BeltranCDamonCNagarajanM 2008 Cell-to-cell stochastic variation in gene expression is a complex genetic trait. PLoS Genet 4 e1000049 doi:10.1371/journal.pgen.1000049

29. HarrisonPJ 1997 Schizophrenia: a disorder of neurodevelopment? Curr Opin Neurobiol 7 285 289

30. McGrathJJFeronFPBurneTHMackay-SimAEylesDW 2003 The neurodevelopmental hypothesis of schizophrenia: a review of recent developments. Ann Med 35 86 93

31. MarencoSWeinbergerDR 2000 The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave. Dev Psychopathol 12 501 527

32. MeyerUFeldonJ 2009 Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol

33. de LeonJDadvandMCanusoCWhiteAOStanillaJK 1995 Schizophrenia and smoking: an epidemiological survey in a state hospital. Am J Psychiatry 152 453 455

34. ZammitSAllebeckPDalmanCLundbergIHemmingssonT 2003 Investigating the association between cigarette smoking and schizophrenia in a cohort study. Am J Psychiatry 160 2216 2221

35. FowlerILCarrVJCarterNTLewinTJ 1998 Patterns of current and lifetime substance use in schizophrenia. Schizophr Bull 24 443 455

36. AsadaMEbiharaSNumachiYOkazakiTYamandaS 2008 Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter. Int J Cancer 123 511 518

37. WaddingtonC 1959 Canalization of development and genetic assimilation of acquired characters. Nature 183 1654 1655

38. KauffmanS 2004 A proposal for using the ensemble approach to understand genetic regulatory networks. J Theor Biol 230 581 590

39. SaeedAIBhagabatiNKBraistedJCLiangWSharovV 2006 TM4 microarray software suite. Methods Enzymol 411 134 193