Validating discovered Cis-acting regulatory genetic variants: application of an allele specific expression approach to HapMap populations.


Campino, S; Forton, J; Raj, S; Mohr, B; Auburn, S; Fry, A; Mangano, VD; Vandiedonck, C; Richardson, A; Rockett, K; Clark, TG; Kwiatkowski, DP; (2008) Validating discovered Cis-acting regulatory genetic variants: application of an allele specific expression approach to HapMap populations. PLoS One, 3 (12). e4105. ISSN 1932-6203 DOI: https://doi.org/10.1371/journal.pone.0004105

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Abstract

BACKGROUND: Localising regulatory variants that control gene expression is a challenge for genome research. Several studies have recently identified non-coding polymorphisms associated with inter-individual differences in gene expression. These approaches rely on the identification of signals of association against a background of variation due to other genetic and environmental factors. A complementary approach is to use an Allele-Specific Expression (ASE) assay, which is more robust to the effects of environmental variation and trans-acting genetic factors. METHODOLOGY/PRINCIPAL FINDINGS: Here we apply an ASE method which utilises heterozygosity within an individual to compare expression of the two alleles of a gene in a single cell. We used individuals from three HapMap population groups and analysed the allelic expression of genes with cis-regulatory regions previously identified using total gene expression studies. We were able to replicate the results in five of the six genes tested, and refined the cis- associated regions to a small number of variants. We also showed that by using multi-populations it is possible to refine the associated cis-effect DNA regions. CONCLUSIONS/SIGNIFICANCE: We discuss the efficacy and drawbacks of both total gene expression and ASE approaches in the discovery of cis-acting variants. We show that the ASE approach has significant advantages as it is a cleaner representation of cis-acting effects. We also discuss the implication of using different populations to map cis-acting regions and the importance of finding regulatory variants which contribute to human phenotypic variation.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
PubMed ID: 19116668
Web of Science ID: 265466600022
URI: http://researchonline.lshtm.ac.uk/id/eprint/4461

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