Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

Human genetics ·Vol. 130 ·No. 5 ·2011-12-08

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

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.

Article Info

Journal

Human genetics

Abbr.

Hum Genet

ISSN

0340-6717

Published

2011-12-08

Indexed

2011-10-14

Updated

2016-11-22

Language

English

Country/Region

Germany

NLM ID

7613873

External Links

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Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.

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