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Title: Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.
Authors: 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
Journal: Hum Genet
Date: 2011 Nov
Branches: CGB, GEB, HREB
PubMed ID: 21597964
PMC ID: PMC3196382
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.