Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage disequilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.National Institutes of Health, National Cancer Institute, Center for Cancer Research Starr Foundation Breast Cancer Research Foundation Sabin Family Fund CRUK Ligue National Contre le Cancer Association for International Cancer Research AICR-07-0454 Association "Le cancer du sein, parlons-en" NHMRC National Breast Cancer Foundation Cancer Australia 628333 Queensland Cancer Fund Cancer Councils of New South Wales, Victoria, Tasmania and South Australia Cancer Foundation of Western Australia Italian citizens Fondazione IRCCS Istituto Nazionale Tumori Komen Foundation National Cancer Institute, National Institutes of Health RFA-CA-06-503 ISCIII RD06/0020/0021 Dutch Cancer Society NKI1998-1854 NKI2004-3088 NKI2007-3756 OSU Comprehensive Cancer Center Cancer Care Ontario US National Cancer Institute, National Institutes of Health RFA CA-06-503 Cancer Research UK C1287/A10118 C1287/A11990 C5047/A8385 NIHR Biomedical Research Centre, Manchester Biomedical Research Centre at The Institute of Cancer Research Royal Marsden NHS Foundation Trust NEYE foundation NIHCA11616