Human Molecular Genetics Advance Access originally published online on April 5, 2007
Human Molecular Genetics 2007 16(11):1367-1380; doi:10.1093/hmg/ddm087
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Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci
1 Department of Biochemistry, 2 Department of Pediatrics, 3 Graduate Programme in Bioengineering, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 4 Bioinformatics Institute, Singapore, 5 Division of Medical Sciences, 6 Department of Surgical Oncology, National Cancer Center, Singapore, 7 Department of Surgery, Singapore General Hospital, Singapore and 8 Children's Medical Institute and Department of Laboratory Medicine, National University Hospital, Singapore
* To whom correspondence should be addressed at: Division of Medical Sciences, National Cancer Center, Level 6, Lab 5, 11 Hospital Drive, Singapore 169610, Singapore. Tel: +65 64368353; Fax: +65 62241778; Email: bchleec{at}nus.edu.sg (C.G.L.L.) or Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore. Tel: +65 67724152; Fax: +65 67797486; Email: paecs{at}nus.edu.sg (S.S.C.)
Received January 10, 2007; Revised March 19, 2007; Accepted March 31, 2007
Members of the ATP-binding cassette (ABC) superfamily of transporters have been implicated as major players in drug response. Single nucleotide polymorphisms (SNPs) in the ABC transporter genes may account for variation in drug response between individuals. Given the abundance of SNPs within the human genome, identification of functionally important SNPs is difficult. Here, we utilized signatures of recent positive selection (RPS) to identify SNPs in ABC genes that have potential functional significance by using the long-range-haplotype test to search for signatures of RPS at 18 ABC genes involved in drug transport. From the genotype data of these 18 ABC genes in four populations extracted from the HapMap database, at least one SNP in each of these genes displayed genomic signatures of RPS in at least one population. However, only 13 SNPs in 10 ABC genes from three populations retained statistical significance after Type I error reduction. The functional significance of six of these RPS SNPs, including those that failed multiple testing correction (MTC), has been reported previously. We experimentally confirmed a functional effect for two SNPs, including one that failed to show evidence of RPS after MTC. These observations suggest that Type I error reduction may inadvertently increase Type II error. Although the remaining positively selected SNPs have yet to be functionally validated, our study illustrates the feasibility of using this strategy to identify SNPs within ‘adaptive’ genes that may confer functional effect, prior to testing their roles in individual/population drug response variation or in complex disease susceptibility.
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