Haplotype structure and selection of the MDM2 oncogene in humans

Gurinder Singh Atwal*, Gareth L. Bond, Sally Metsuyanim, Moshe Papa, Eitan Friedman, Tal Distelman-Menachem, Edna Ben Asher, Doron Lancet, David A. Ross, John Sninsky, Tomas J. White, Arnold J. Levine, Ronit Yarden

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4524-4529
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number11
DOIs
StatePublished - 13 Mar 2007
Externally publishedYes

Keywords

  • Cancer
  • Entropy
  • Population genetics
  • SNP
  • p53

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