Aberrant Gene Expression in Humans

English version České info

The uniqueness of individuals is due to differences in the combination of genetic, epigenetic and environmental determinants. Understanding the genetic basis of phenotypic variation is a key objective in genetics. Gene expression has been considered as an intermediate phenotype, and the association between gene expression and commonly-occurring genetic variants in the general population has been convincingly established. However, there are few methods to assess the impact of rare genetic variants, such as private SNPs, on gene expression. Here we describe a systematic approach, based on the theory of multivariate outlier detection, to identify individuals that show unusual or aberrant gene expression, relative the rest of the study cohort. Through characterizing detected outliers and corresponding gene sets, we are able to identify which gene sets tend to be aberrantly expressed and which individuals show deviant gene expression within a population. One of our major findings is that private SNPs may contribute to aberrant expression in outlier individuals. These private SNPs are more frequently located in the enhancer and promoter regions of genes that are aberrantly expressed, suggesting a possible regulatory function of these SNPs. Overall, our results provide new insight into the determinants of inter-individual variation, which have not been evaluated by large population-level cohort studies.

Vyšlo v časopise: Aberrant Gene Expression in Humans. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004942
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004942

Souhrn

Zdroje

1. Kilpinen H, Barrett JC (2013) How next-generation sequencing is transforming complex disease genetics. Trends Genet 29 : 23–30. doi: 10.1016/j.tig.2012.10.001 23103023

2. Cirulli ET, Goldstein DB (2010) Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet 11 : 415–425. doi: 10.1038/nrg2779 20479773

3. Lappalainen T, Sammeth M, Friedlander MR, t Hoen PA, Monlong J, et al. (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature 501 : 506–511. doi: 10.1038/nature12531 24037378

4. Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, et al. (2012) Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat Genet 44 : 502–510. doi: 10.1038/ng.2205 22446964

5. Stranger BE, Nica AC, Forrest MS, Dimas A, Bird CP, et al. (2007) Population genomics of human gene expression. Nat Genet 39 : 1217–1224. doi: 10.1038/ng2142 17873874

6. Montgomery SB, Sammeth M, Gutierrez-Arcelus M, Lach RP, Ingle C, et al. (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464 : 773–777. doi: 10.1038/nature08903 20220756

7. Brown AA, Buil A, Vinuela A, Lappalainen T, Zheng HF, et al. (2014) Genetic interactions affecting human gene expression identified by variance association mapping. Elife 3: e01381. doi: 10.7554/eLife.01381 24771767

8. Hulse AM, Cai JJ (2013) Genetic variants contribute to gene expression variability in humans. Genetics 193 : 95–108. doi: 10.1534/genetics.112.146779 23150607

9. Wang G, Yang E, Brinkmeyer-Langford CL, Cai JJ (2014) Additive, epistatic, and environmental effects through the lens of expression variability QTL in a twin cohort. Genetics 196 : 413–425. doi: 10.1534/genetics.113.157503 24298061

10. Li X, Battle A, Karczewski KJ, Zappala Z, Knowles DA, et al. (2014) Transcriptome sequencing of a large human family identifies the impact of rare noncoding variants. Am J Hum Genet 95 : 245–256. doi: 10.1016/j.ajhg.2014.08.004 25192044

11. Zani S, Riani M, Corbellini A (1998) Robust bivariate boxplots and multiple outlier detection. Computational Statistics & Data Analysis 28 : 257–270. doi: 10.1016/S0167-9473(98)00040-1

12. Mahalanobis PC (1936) On the generalised distance in statistics. Proc Nat Inst Sci India (Calcutta) 2 : 49–55.

13. Garrett RG (1989) The Chi-Square Plot -⁠ a Tool for Multivariate Outlier Recognition. Journal of Geochemical Exploration 32 : 319–341. doi: 10.1016/0375-6742(89)90071-X

14. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, 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 16199517

15. Welter D, MacArthur J, Morales J, Burdett T, Hall P, et al. (2014) The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 42: D1001–1006. doi: 10.1093/nar/gkt1229 24316577

16. Stranger BE, Montgomery SB, Dimas AS, Parts L, Stegle O, et al. (2012) Patterns of cis regulatory variation in diverse human populations. PLoS Genet 8: e1002639. doi: 10.1371/journal.pgen.1002639 22532805

17. Leek JT, Storey JD (2007) Capturing heterogeneity in gene expression studies by surrogate variable analysis. PLoS Genet 3 : 1724–1735. doi: 10.1371/journal.pgen.0030161 17907809

18. GTEx_Consortium (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45 : 580–585. doi: 10.1038/ng.2653 23715323

19. Wallace TA, Prueitt RL, Yi M, Howe TM, Gillespie JW, et al. (2008) Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res 68 : 927–936. doi: 10.1158/0008-5472.CAN-07-2608 18245496

20. Wright FA, Sullivan PF, Brooks AI, Zou F, Sun W, et al. (2014) Heritability and genomics of gene expression in peripheral blood. Nat Genet.

21. Marinov GK, Williams BA, McCue K, Schroth GP, Gertz J, et al. (2014) From single-cell to cell-pool transcriptomes: stochasticity in gene expression and RNA splicing. Genome Res 24 : 496–510. doi: 10.1101/gr.161034.113 24299736

22. Grundberg E, Small KS, Hedman AK, Nica AC, Buil A, et al. (2012) Mapping cis -⁠ and trans-regulatory effects across multiple tissues in twins. Nat Genet 44 : 1084–1089. doi: 10.1038/ng.2394 22941192

23. Yang S, Liu Y, Jiang N, Chen J, Leach L, et al. (2014) Genome-wide eQTLs and heritability for gene expression traits in unrelated individuals. BMC Genomics 15 : 13. doi: 10.1186/1471-2164-15-13 24405759

24. Hoffman MM, Ernst J, Wilder SP, Kundaje A, Harris RS, et al. (2013) Integrative annotation of chromatin elements from ENCODE data. Nucleic Acids Research 41 : 827–841. doi: 10.1093/nar/gks1284 23221638

25. Montgomery SB, Lappalainen T, Gutierrez-Arcelus M, Dermitzakis ET (2011) Rare and common regulatory variation in population-scale sequenced human genomes. PLoS Genet 7: e1002144. doi: 10.1371/journal.pgen.1002144 21811411

26. Jayasinghe BS, Volz DC (2012) Aberrant ligand-induced activation of G protein-coupled estrogen receptor 1 (GPER) results in developmental malformations during vertebrate embryogenesis. Toxicol Sci 125 : 262–273. doi: 10.1093/toxsci/kfr269 21984484

27. Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J, et al. (2010) Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol (Oxf) 73 : 1–15.19719763

28. Spiegel AM, Weinstein LS (2004) Inherited diseases involving g proteins and g protein-coupled receptors. Annu Rev Med 55 : 27–39. doi: 10.1146/annurev.med.55.091902.103843 14746508

29. Keinan A, Clark AG (2012) Recent explosive human population growth has resulted in an excess of rare genetic variants. Science 336 : 740–743. doi: 10.1126/science.1217283 22582263

30. Visscher PM, Hill WG, Wray NR (2008) Heritability in the genomics era -⁠ concepts and misconceptions. Nature Reviews Genetics 9 : 255–266. doi: 10.1038/nrg2322 18319743

31. Price AL, Helgason A, Thorleifsson G, McCarroll SA, Kong A, et al. (2011) Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals. PLoS Genet 7: e1001317. doi: 10.1371/journal.pgen.1001317 21383966

32. Zaitlen N, Kraft P (2012) Heritability in the genome-wide association era. Hum Genet 131 : 1655–1664. doi: 10.1007/s00439-012-1199-6 22821350

33. Stegle O, Parts L, Piipari M, Winn J, Durbin R (2012) Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses. Nature Protocols 7 : 500–507. doi: 10.1038/nprot.2011.457 22343431

34. Rousseeuw PJ (1984) Least Median of Squares Regression. Journal of the American Statistical Association 79 : 871–880. doi: 10.1080/01621459.1984.10477105

35. Verboven S, Hubert M (2005) LIBRA: a MATLAB library for robust analysis. Chemometrics and Intelligent Laboratory Systems 75 : 127–136. doi: 10.1016/j.chemolab.2004.06.003

36. Rousseeuw PJ, Vanzomeren BC (1990) Unmasking Multivariate Outliers and Leverage Points. Journal of the American Statistical Association 85 : 633–639. doi: 10.2307/2289999

37. Filzmoser P, Maronna R, Werner M (2008) Outlier identification in high dimensions. Computational Statistics & Data Analysis 52 : 1694–1711. doi: 10.1016/j.csda.2007.05.018