title: Validating discovered Cis-acting regulatory genetic variants: application of an allele specific expression approach to HapMap populations.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. sc11@sanger.ac.uk
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Julian
authors.initials: J
authors.lastname: Forton
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Raj
authors.forename: Bert
authors.initials: B
authors.lastname: Mohr
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.forename: Andrew
authors.initials: A
authors.lastname: Fry
authors.forename: Valentina D
authors.initials: VD
authors.lastname: Mangano
authors.forename: Claire
authors.initials: C
authors.lastname: Vandiedonck
authors.forename: Anna
authors.initials: A
authors.lastname: Richardson
authors.forename: Kirk
authors.initials: K
authors.lastname: Rockett
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping / Q000379:methods*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D015894:Genome, Human; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid