TY - JOUR
T1 - Validating discovered Cis-acting regulatory genetic variants
T2 - Application of an allele specific expression approach to HapMap populations
AU - Campino, Susana
AU - Forton, Julian
AU - Raj, Srilakshmi
AU - Mohr, Bert
AU - Auburn, Sarah
AU - Fry, Andrew
AU - Mangano, Valentina D.
AU - Vandiedonck, Claire
AU - Richardson, Anna
AU - Rockett, Kirk
AU - Clark, Taane G.
AU - Kwiatkowski, Dominic P.
PY - 2008/12/31
Y1 - 2008/12/31
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0004105
DO - 10.1371/journal.pone.0004105
M3 - Article
C2 - 19116668
AN - SCOPUS:58149357315
SN - 1932-6203
VL - 3
JO - PloS one
JF - PloS one
IS - 12
M1 - e4105
ER -