Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

• Published in: Human genetics 2011-11, Vol.130 (5), p.685-699
• Main Authors: Im, Kate M., Kirchhoff, Tomas, Wang, Xianshu, Green, Todd, Chow, Clement Y., 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, Meijers-Heijboer, Hanne E. J., Van Roozendaal, Cees E., Perez-Segura, Pedro, Jakubowska, Anna, Huzarski, Tomasz, Blecharz, Paweł, Nevanlinna, Heli, Aittomäki, Kristiina, Lazaro, Conxi, Blanco, Ignacio, Barkardottir, Rosa B., D’Andrea, Emma, Devilee, Peter, Olopade, Olufunmilayo I., Peissel, Bernard, Bonanni, Bernardo, Peterlongo, Paolo, Singer, Christian F., Rennert, Gad, Lejbkowicz, Flavio, Andrulis, Irene L., 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., Southey, Melissa C., Terry, Mary-Beth, Tung, Nadine, Hansen, Thomas v. O., Benitez, Javier, Weitzel, Jeffrey N., Garber, Judy, Hamann, Ute, Peock, Susan, Cook, Margaret, Oliver, Clare T., Frost, Debra, Eeles, Ros, Izatt, Louise, Paterson, Joan, Brewer, Carole, Hodgson, Shirley, Porteous, Mary, Walker, Lisa, Rogers, Mark T., Side, Lucy E., Godwin, Andrew K., Wappenschmidt, Barbara, Laitman, Yael, 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
• Format: Article
• Language: English
• Subjects: Arthritis; Arthritis - genetics; Base Sequence; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; BRCA1 Protein; BRCA1 Protein - genetics; BRCA2 Protein; BRCA2 Protein - genetics; Breast cancer; Cancer; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chromosomes; Classical genetics, quantitative genetics, hybrids; Computer Simulation; Cromosomes; Deafness; Deafness - genetics; Demography; Epidemiology; Female; Founder Effect; Fundamental and applied biological sciences. Psychology; Gene frequency; Gene Function; Gene mutations; Genetic aspects; Genetic drift; Genetic research; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomics; Genotype; Genotypes; Haplotypes; Haplotypes - genetics; Heterozygote; Human; Human Genetics; Humans; Jewish people; Jews; Jews - genetics; Life Sciences; Linkage disequilibrium; Medical research; Metabolic Diseases; Molecular and cellular biology; Molecular biology; Molecular Medicine; Mutation; Original Investigation; Ovarian cancer; Polychondritis, Relapsing; Polychondritis, Relapsing - genetics; Population; Population genetics; Sequence Deletion; Statistics; Toy industry; Womens health
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-011-1003-z

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.