Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

Abstract

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.

Fig. 1

Linkage disequilibrium across a 570-kb region in 372 Ashkenazi women. a Haploview output showing LD blocks across region. Black block represents the core haplotype. b Haplotypes estimated using SNPHAP for each of the LD blocks. Haplotypes observed in at least 1% of chromosomes are shown in order of frequency (most frequent first)

Fig. 2

Extended haplotype structure observed in (a) 372 Ashkenazi women across a 2.1-Mb region and (b) 1441 Caucasian, non-Jewish women across an 805-kb region. Each row represents an individual. Tick marks show SNP locations, red triangles mark the boundaries of the 8-SNP core BRCA2 haplotype, and blue triangles mark the boundaries of the (a) 1.4 Mb extended haplotype and (b) 715 kb extended haplotype in the AJ and CNJ, respectively. Long horizontal red lines represent the core haplotype, while interruptions in that haplotype observed in the data by the presence of frequent alternative alleles are colored in green

Fig. 3

Population differentiation among Ashkenazi and CNJ women. a F_ST between 372 Ashkenazi and 1,441 Caucasian, non-Jewish women across chromosome 13. b F_ST between 613 Ashkenazi (carriers of the 185delAG and 5382insC founder mutations) and 2,186 Caucasian, non-Jewish (carriers of non-founder mutations) women across chromosome 17. The peaks of F_ST occur in the region surrounding BRCA2 and BRCA1 in (a) and (b), respectively, represented by the black boxes

Fig. 4

Genome-wide distribution of Tajima's D in 372 AJ women. D statistics were estimated for 100-kb sliding windows

Fig. 5

Haplotype network results from analyzing the eight SNPs that make up the core BRCA2 haplotype. Diagrams constructed using haplotypes observed at a frequency of at least 1% are labeled. The dark gray sphere (H1) represents the core haplotype. a Network for AJ chromosomes. b Network for CNJ chromosomes. Frequency of each haplotype can be found in Supplementary Table 1. The size of each sphere is proportional to its frequency in the sample