Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

Kate M. Im, Tomas Kirchhoff, Xianshu Wang, Todd Green, Clement Y. Chow, Joseph Vijai, Joshua Korn, Mia M. Gaudet, Zachary Fredericksen, V. Shane Pankratz, Candace Guiducci, Andrew Crenshaw, Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Sue Healey, Olga M. Sinilnikova, Phuong L. Mai, Mark H. Greene, Marion PiedmonteWendy S. Rubinstein, Frans B. L. Hogervorst, Matti A. Rookus, Margriet J. Collee, Nicoline Hoogerbrugge, Christi J. van Asperen, Hanne E. J. Meijers-Heijboer, Cees E. van Roozendaal, Trinidad Caldes, Pedro Perez Segura, Anna Jakubowska, Jan Lubinski, Tomasz Huzarski, Pawel Blecharz, Heli Nevanlinna, Kristiina Aittomaki, Conxi Lazaro, Ignacio Blanco, Rosa B. Barkardottir, Marco Montagna, Emma D'Andrea, Peter Devilee, Olufunmilayo I. Olopade, Susan L. Neuhausen, Bernard Peissel, Bernardo Bonanni, Paolo Peterlongo, Christian F. Singer, Gad Rennert, Flavio Lejbkowicz, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Amanda Ewart Toland, Maria Adelaide Caligo, Mary S. Beattie, Salina B. Chan, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Catherine M. Phelan, Steven A. Narod, Esther M. John, John L. Hopper, Saundra Buys, Mary B. Daly, Melissa C. Southey, Mary Beth Terry, Nadine Tung, Thomas V. O. Hansen, Ana Osorio, Javier Benitez, Mercedes Duran, Jeffrey N. Weitzel, Judy Garber, Ute Hamann, Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte, D. Gareth Evans, Ros Eeles, Louise Izatt, Joan Paterson, Carole Brewer, Shirley V. Hodgson, Patrick J. Morrison, Mary E. Porteous, Lisa Walker, Mark T. Rogers, Lucy E. Side, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Yael Laitman, Alfons Meindl, Helmut Deissler, Raymonda Varon-Mateeva, Sabine Preisler-Adams, Karin Kast, Laurence Venat-Bouvet, Dominique Stoppa-Lyonnet, Georgia Chenevix-Trench, Douglas F. Easton, Robert J. Klein, Mark J. Daly, Eitan Friedman, Michael Dean, Andrew G. Clark, David M. Altshuler, Antonis C. Antoniou, Fergus J. Couch, Kenneth Offit, Encarna Gomez Garcia, Marinus Blok, Bert Gold*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)685-699
JournalHuman Genetics
Issue number5
Publication statusPublished - Nov 2011

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