Comparative and evolutionary pharmacogenetics of ABCB1: Complex signatures of positive selection on coding and regulatory regions

BACKGROUND: As a major mediator in the complex interplay between humans and the xenobiotic environment, the ABCBI transporter gene is an obvious candidate for comparative and evolutionary pharmacogenetic studies. It has been recently reported that common variants in its coding region, which are variously associated with drug response and disease susceptibility, may have conferred differential selective sweep in various populations. Fully profiling the alletic architecture and explicitly interrogating the natural selection at ABCBI are needed to understand its evolutionary population genetics. METHODS AND RESULTS: Using a comprehensive single nucleotide polymorphism variants in coding and regulatory regions, as well as comparable genotype data from the Environmental Genome Project, we systematically characterized the extent and length of linkage disequilibrium throughout the ABCBI locus in three major ethnic populations (African, European, and Chinese). We observed pronounced signals of recent positive selection on the derived alleles of three common single nucleotide polymorphisms coding regions: e12/1236T, e21/2677T, and e26/3435T in the Chinese, as well as on extended haplotype homozygosity were also observed for two potentially functional common variants in the 5′f/-4489G (rs17149810) in the Chinese and 5′f/-693T (rs3213619) in the Africans, respectively, which may have shaped the phylogenetically inferred star-like haplotype structure of the 5′flanking region. CONCLUSION: Our finding reveal complex signatures of natural selection on both coding and regulatory regions of the human ABCBI gene, point to potential functional relevance of its regulatory variants, and suggest that evolutionary dynamics and transcriptional regulation may underline the phenotypic variation in xenobiotic disposition and varying predisposition to complex in which xenobiotics play a role.