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Human Molecular Genetics Advance Access published online on June 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi212
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received March 28, 2005
Revised May 4, 2005
Accepted June 5, 2005

Article

A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection

Zihua Wang 1, Baoshuang Wang 2, Kun Tang 3, Edmund JD Lee 4, Samuel S Chong 5, and Caroline GL Lee 6*

1 Departments of Biochemistry, National University of Singapore, SINGAPORE; Graduate Programme in Bioengineering, National University of Singapore, SINGAPORE
2 Division of Medical Sciences, National Cancer Center, SINGAPORE
3 Departments of Biochemistry, National University of Singapore, SINGAPORE
4 Departments of Pharmacology, National University of Singapore, SINGAPORE
5 Departments of Pediatrics & Obstetrics/Gynecology, National University of Singapore, SINGAPORE; Departments of Pediatrics and Gynecology & Obstetrics, and McKusick-Nathans Institute of Genetic Medicine, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
6 Departments of Biochemistry, National University of Singapore, SINGAPORE; Division of Medical Sciences, National Cancer Center, Level 6, Lab 5, 11 Hospital Drive, Singapore 169610, SINGAPORE

* To whom correspondence should be addressed.
Caroline GL Lee, E-mail: bchleec{at}nus.edu.sg


  Abstract

Searching for genomic evidence of positive selection has been hailed as an attractive strategy for identifying functional polymorphisms. Here, we demonstrate the feasibility of identifying functional polymorphism at the MRP1 gene locus using this strategy. The 190-kDa MRP1 protein is an efflux pump that regulates the accumulation of xenobiotics and drugs in cells. Functional sequence variations within this gene might account, in part, for inter-individual and population differences in drug response. To identify single nucleotide polymorphisms (SNPs) within the MRP1 gene with potentially important functional significance, we scanned for genomic signatures of recent positive selection at this locus in ~480 individuals sampled from the Chinese, Malay, Indian, European American and African American populations. The genetic profile of SNPs at this locus revealed high haplotype diversity and weak linkage disequilibrium (LD). Despite this weak LD, major allele G of SNP5’FR/G-260C contained within a high frequency haplotype exhibited extended haplotype homozygosity across 135-kb in European Americans. Using two independent genomic tests, Long Range Haplotype (LRH) test and the FST statistic, we found statistical evidence of positive selection for this allele in the European American population. When this SNP was recapitulated in an in-vitro MRP1 promoter-reporter assay, significantly lower activity was observed from the G-containing compared to the C-containing promoter in all 4 cell-lines that we tested (P<0.01). These observations confirm the power of this strategy in identifying functionally different alleles of genes and suggest that the different alleles at this SNP locus in the MRP1 gene may account, in part, for inter-individual variations and population differences in drug response.


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