title: Haplotype structure and selection of the MDM2 oncogene in humans.
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.
authors.affiliation: Institute for Advanced Study, Simons Center for Systems Biology, Princeton, NJ 08540, USA. atwal@ias.edu
authors.forename: Gurinder Singh
authors.initials: GS
authors.lastname: Atwal
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Bond
authors.forename: Sally
authors.initials: S
authors.lastname: Metsuyanim
authors.forename: Moshe
authors.initials: M
authors.lastname: Papa
authors.forename: Eitan
authors.initials: E
authors.lastname: Friedman
authors.forename: Tal
authors.initials: T
authors.lastname: Distelman-Menachem
authors.forename: Edna
authors.initials: E
authors.lastname: Ben Asher
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
authors.forename: David A
authors.initials: DA
authors.lastname: Ross
authors.forename: John
authors.initials: J
authors.lastname: Sninsky
authors.forename: Tomas J
authors.initials: TJ
authors.lastname: White
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.forename: Ronit
authors.initials: R
authors.lastname: Yarden
mesh_terms: D000483:Alleles; D044383:Black People; D019277:Entropy; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007585:Jews; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D009010:Monte Carlo Method; D020641:Polymorphism, Single Nucleotide; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044465:White People; D001741:Black or African American
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2