Detection, validation, and downstream analysis of allelic variation in gene expression

Daniel C. Ciobanu, Lu Lu, Khyobeni Mozhui, Xusheng Wang, Manjunatha Jagalur, John A. Morris, William L. Taylor, Klaus Dietz, Perikles Simon, Robert W. Williams

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Common sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control-or cis modulation-rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40-50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to ∼80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higherorder phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility.

Original languageEnglish (US)
Pages (from-to)119-128
Number of pages10
JournalGenetics
Volume184
Issue number1
DOIs
StatePublished - Jan 1 2010

ASJC Scopus subject areas

  • Genetics

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    Ciobanu, D. C., Lu, L., Mozhui, K., Wang, X., Jagalur, M., Morris, J. A., Taylor, W. L., Dietz, K., Simon, P., & Williams, R. W. (2010). Detection, validation, and downstream analysis of allelic variation in gene expression. Genetics, 184(1), 119-128. https://doi.org/10.1534/genetics.109.107474