Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci

• Published in: Human molecular genetics Vol. 16; no. 11; pp. 1367 - 1380
• Main Authors: Wang, Zihua, Wang, Jingbo, Tantoso, Erwin, Wang, Baoshuang, Tai, Amy Y.P., Ooi, London L.P.J., Chong, Samuel S., Lee, Caroline G.L.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.06.2007; Oxford Publishing Limited (England)
• Subjects: ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetic Markers; Genetics of eukaryotes. Biological and molecular evolution; Humans; Molecular and cellular biology; Multigene Family; Selection, Genetic; Drug; Cassette; Gene; Positive selection; Genetics; Locus; ATP
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddm087

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.