Human Molecular Genetics Advance Access originally published online on February 19, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 8 783-797
DOI: 10.1093/hmg/ddh099
Human Molecular Genetics, Vol. 13, No. 8 © Oxford University Press 2004; all rights reserved
Genomic evidence for recent positive selection at the human MDR1 gene locus
1Department of Biochemistry, 2Department of Pharmacology and 3Department of Pediatrics and Obstetrics/Gynecology, National University of Singapore, Singapore, 4Division of Medical Sciences, National Cancer Center, Singapore and 5Department of Pediatrics and Gynecology/Obstetrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
Received August 21, 2003; Accepted February 10, 2004
The MDR1 multidrug transporter regulates the traffic of drugs, peptides and xenobiotics into the body as well as sensitive tissues like the brain, germ cells and the developing fetus. Hence, it may influence an individual's response to drugs as well as his/her susceptibility to complex diseases in which environmental factors, especially xenobiotics, play a role. Polymorphisms within this gene, especially single-nucleotide polymorphism e26/3435(C/T), have been variously associated with differences in MDR1 expression, function, drug response and disease susceptibility. Here, we report the detailed characterization of the haplotype and linkage disequilibrium architecture of the entire 200 kb of the MDR1 gene in five world populations, namely, Chinese, Malays, Indians, Caucasians and African-Americans. We observed varied haplotype diversity across the entire gene in the different populations. The major haplotype mh5, which contains the subhaplotype e12/1236T–e21/2677T–e26/3435T, is highly represented among the four non-African populations, while mh7, which contains the subhaplotype e12/1236C–e21/2677G–e26/3435C, accounts for over a third of African-American chromosomes. These observations are inconsistent with a simple population evolution model, but instead are suggestive of recent historical events that have maintained such long range linkage disequilibrium. Using a modified long-range haplotype test, we found statistically significant evidence of recent positive selection for the e21/2677T and e26/3435T alleles in the Chinese population, and for the e26/3435T allele in the Malay population. Interestingly, we also detected evidence for positive selection of the alternative allele e26/3435C in the African-American population. These data suggest that independent mutational events may have occurred on the mh5 and mh7 haplotypes of the MDR1 gene to confer positive selection in the non-African and African-American populations, respectively.
* To whom correspondence should be addressed at: Division of Medical Sciences, National Cancer Center, Level 6, Lab 5, 11 Hospital Drive, Singapore 169610. Tel: +65 64368353; Fax: +65 62241778; Email: bchleec{at}nus.edu.sg
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