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Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

Im, KM; Kirchhoff, T; Wang, X; Green, T; Chow, CY; Vijai, J; Korn, J; Gaudet, MM; Fredericksen, Z; Shane Pankratz, V; et al. Im, KM; Kirchhoff, T; Wang, X; Green, T; Chow, CY; Vijai, J; Korn, J; Gaudet, MM; Fredericksen, Z; Shane Pankratz, V; Guiducci, C; Crenshaw, A; McGuffog, L; Kartsonaki, C; Morrison, J; Healey, S; Sinilnikova, OM; Mai, PL; Greene, MH; Piedmonte, M; Rubinstein, WS; HEBON, ; Hogervorst, FB; Rookus, MA; Collée, JM; Hoogerbrugge, N; van Asperen, CJ; Meijers-Heijboer, HE; Van Roozendaal, CE; Caldes, T; Perez-Segura, P; Jakubowska, A; Lubinski, J; Huzarski, T; Blecharz, P; Nevanlinna, H; Aittomäki, K; Lazaro, C; Blanco, I; Barkardottir, RB; Montagna, M; D'Andrea, E; kConFab, ; Devilee, P; Olopade, OI; Neuhausen, SL; Peissel, B; Bonanni, B; Peterlongo, P; Singer, CF; Rennert, G; Lejbkowicz, F; Andrulis, IL; Glendon, G; Ozcelik, H; Ontario Cancer Genetics Network, ; Toland, AE; Caligo, MA; SWE-BRCA, ; Beattie, MS; Chan, S; UKFOCR, ; Domchek, SM; Nathanson, KL; Rebbeck, TR; Phelan, C; Narod, S; John, EM; Hopper, JL; Buys, SS; Daly, MB; Southey, MC; Terry, MB; Tung, N; Hansen, TV; Osorio, A; Benitez, J; Durán, M; Weitzel, JN; Garber, J; Hamann, U; EMBRACE, ; Peock, S; Cook, M; Oliver, CT; Frost, D; Platte, R; Evans, DG; Eeles, R; Izatt, L; Paterson, J; Brewer, C; Hodgson, S; Morrison, PJ; Porteous, M; Walker, L; Rogers, MT; Side, LE; Godwin, AK; Schmutzler, RK; Wappenschmidt, B; Laitman, Y; Meindl, A; Deissler, H; Varon-Mateeva, R; Preisler-Adams, S; Kast, K; Venat-Bouvet, L; Stoppa-Lyonnet, D; Chenevix-Trench, G; Easton, DF; Klein, RJ; Daly, MJ; Friedman, E; Dean, M; Clark, AG; Altshuler, DM; Antoniou, AC; Couch, FJ; Offit, K; Gold, B (2011) Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. HUMAN GENETICS, 130 (5). 685 - 699 (15). ISSN 0340-6717
SGUL Authors: Hodgson, Shirley Victoria

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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 dis-equilibrium (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.

Item Type: Article
Additional Information: PubMed ID: 21597964
Keywords: Arthritis, BRCA1 Protein, BRCA2 Protein, Base Sequence, Computer Simulation, Deafness, Female, Founder Effect, Genotype, Haplotypes, Heterozygote, Humans, Jews, Polychondritis, Relapsing, Sequence Deletion, Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, GENETICS & HEREDITY, TAY-SACHS DISEASE, BREAST-CANCER, POSITIVE SELECTION, GENETIC-VARIATION, POPULATION, FREQUENCY, GENOME, JEWS, ASSOCIATION, SIGNATURES
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: HUMAN GENETICS
ISSN: 0340-6717
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1 November 2011Published
Web of Science ID: WOS:000295939900009
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