Human Molecular Genetics Advance Access originally published online on June 8, 2005
Human Molecular Genetics 2005 14(14):2075-2087; doi:10.1093/hmg/ddi212
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A functional polymorphism within the MRP1 gene locus identified through its genomic signature of positive selection
1Department of Biochemistry, 2Department of Pharmacology, 3Department of Pediatrics and Obstetrics/Gynecology and 4Graduate Programme in Bioengineering, National University of Singapore, Singapore, 5Division of Medical Sciences, National Cancer Center, Singapore and 6Department of Pediatrics and 7Department of Gynecology and Obstetrics, McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
* To whom correspondence should be addressed at: Division of Medical Sciences, National Cancer Center, Level 6, Laboratory 5, 11 Hospital Drive, Singapore 169610, Singapore. Tel: +65 64368353; Fax: +65 62241778; Email: bchleec{at}nus.edu.sg
Received March 28, 2005; Revised May 4, 2005; Accepted June 5, 2005
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 SNP 5'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 promoter when compared with the C-containing promoter in all four 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.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Wang, A. T. C. Lee, J. Z. I. Ma, J. Wang, J. Ren, Y. Yang, E. Tantoso, K.-B. Li, L. L. P. J Ooi, P. Tan, et al. Profiling MicroRNA Expression in Hepatocellular Carcinoma Reveals MicroRNA-224 Up-regulation and Apoptosis Inhibitor-5 as a MicroRNA-224-specific Target J. Biol. Chem., May 9, 2008; 283(19): 13205 - 13215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Wang, J. Wang, E. Tantoso, B. Wang, A. Y.P. Tai, L. L.P.J. Ooi, S. S. Chong, and C. G.L. Lee Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci Hum. Mol. Genet., June 1, 2007; 16(11): 1367 - 1380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Choudhuri and C. D. Klaassen Structure, Function, Expression, Genomic Organization, and Single Nucleotide Polymorphisms of Human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) Efflux Transporters International Journal of Toxicology, July 1, 2006; 25(4): 231 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Wang, S. Ngoi, J. Wang, S. S. Chong, and C. G. L. Lee The Promoter Region of the MDR1 Gene Is Largely Invariant, but Different Single Nucleotide Polymorphism Haplotypes Affect MDR1 Promoter Activity Differently in Different Cell Lines Mol. Pharmacol., July 1, 2006; 70(1): 267 - 276. [Abstract] [Full Text] [PDF]
|
|