Haplotype structure and selection of the MDM2 oncogene in humans

Atwal, G. S., Bond, G. L., Metsuyanim, S., Papa, M., Friedman, E., Distelman-Menachem, T., Ben Asher, E., Lancet, D., Ross, D. A., Sninsky, J., White, T. J., Levine, A. J., Yarden, R. (2007) Haplotype structure and selection of the MDM2 oncogene in humans. Proc Natl Acad Sci U S A, 104 (11). pp. 4524-9. ISSN 0027-8424 (Print) 0027-8424 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/17360557
DOI: 10.1073/pnas.0610998104

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.

Item Type: Paper
Uncontrolled Keywords: African Continental Ancestry Group Alleles Entropy European Continental Ancestry Group Gene Frequency Genotype Haplotypes Humans Jews Linkage Disequilibrium Models, Genetic Monte Carlo Method Polymorphism, Single Nucleotide Proto-Oncogene Proteins c-mdm2 genetics/ physiology Tumor Suppressor Protein p53/metabolism
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > MDM2
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > SNP
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > ubiquitin ligase
CSHL Authors:
Communities: CSHL labs > Atwal lab
Depositing User: CSHL Librarian
Date Deposited: 02 Dec 2011 17:04
Last Modified: 19 Dec 2016 21:46
PMCID: PMC1838634
Related URLs:
URI: http://repository.cshl.edu/id/eprint/22964

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