Haplotype structure and selection of the MDM2 oncogene in humans

被引:50
作者
Atwal, Gurinder Singh [1 ]
Bond, Gareth L.
Metsuyanim, Sally
Papa, Moshe
Friedman, Eitan
Distelman-Menachem, Tal
Ben Asher, Edna
Lancet, Doron
Ross, David A.
Sninsky, John
White, Tomas J.
Levine, Arnold J.
Yarden, Ronit
机构
[1] Simons Ctr Syst Biol, Inst Adv Study, Princeton, NJ 08540 USA
[2] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, Dept Pediat, New Brunswick, NJ 08903 USA
[3] Chaim Sheba Med Ctr, Danek Gertner Inst Human Genet, Dept Surg Oncol, Lab Genom Applicat, IL-52621 Tel Hashomer, Israel
[4] Chaim Sheba Med Ctr, Danek Gertner Inst Human Genet, Dept Surg Oncol, IL-52621 Tel Hashomer, Israel
[5] Chaim Sheba Med Ctr, Danek Gertner Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel
[6] Weizmann Inst Sci, Crown Human Genome Ctr, Dept Mol Genet, IL-76100 Rehovot, Israel
[7] Celera Diagnost, Alameda, CA 94502 USA
关键词
cancer; p53; population genetics; SNP; entropy;
D O I
10.1073/pnas.0610998104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The MDM2 protein is an ubiquitin ligase that plays a critical role in regulating the levels and activity of the p53 protein, which is a central tumor suppressor. A SNP in the human MDM2 gene (SNP309 T/G) occurs at frequencies dependent on demographic history and has been shown to have important differential effects on the activity of the MDM2 and p53 proteins and to associate with altered risk for the development of several cancers. In this report, the haplotype structure of the MDM2 gene is determined by using 14 different SNPs across the gene from three different population samples: Caucasians, African Americans, and the Ashkenazi Jewish ethnic group. The results presented in this report indicate that there is a substantially reduced variability of the deleterious SNP309 G allele haplotype in all three populations studied, whereas multiple common T allele haplotypes were found in all three populations. This observation, coupled with the relatively high frequency of the G allele haplotype in both and Caucasian and Ashkenazi Jewish population data sets, suggests that this haplotype could have undergone a recent positive selection sweep. An entropy-based selection test is presented that explicitly takes into account the correlations between different SNPs, and the analysis of MDM2 reveals a significant departure from the standard assumptions of selective neutrality.
引用
收藏
页码:4524 / 4529
页数:6
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