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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.

There are important genetic influences on the tendency to dizygotic (DZ) twinning and it is a plausible hypothesis that these reside in one or more of the genes coding for the major reproductive hormones. We used Southern analysis of DNA from 50 young (< 32) mothers of DZ twins, who also had a family history of DZ twinning, and 50 controls, to examine allele frequencies of five restriction fragment length polymorphisms (RFLPs) in four hormone genes coding for follicle stimulating hormone beta (FSH beta), chorionic gonadotropin beta (CG beta), inhibin beta B and gonadotropin releasing hormone (GnRH). Comparison of allele frequencies revealed no significant differences between DZ twin mothers and controls. However this does not rule out the role of these genes in the hereditary tendency of multiple ovulation in humans, since absence of linkage disequilibrium does not imply absence of linkage.