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Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

Im, Kate M; Kirchhoff, Tomas; Wang, Xianshu; Green, Todd; Chow, Clement Y; Vijai, Joseph; Korn, Joshua; Gaudet, Mia M; Fredericksen, Zachary and Shane Pankratz, V, et al. (2011) In Human Genetics 130(5). p.99-685
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.... (More)

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.

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keywords
Arthritis, BRCA1 Protein, BRCA2 Protein, Base Sequence, Computer Simulation, Deafness, Female, Founder Effect, Genotype, Haplotypes, Heterozygote, Humans, Jews, Polychondritis, Relapsing, Sequence Deletion
in
Human Genetics
volume
130
issue
5
pages
15 pages
publisher
Springer
external identifiers
  • scopus:84863778723
ISSN
1432-1203
DOI
10.1007/s00439-011-1003-z
language
English
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no
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ec985f41-4fe0-4b39-b970-72b6741ac60c
date added to LUP
2016-09-18 12:08:24
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2017-01-01 08:34:02
@article{ec985f41-4fe0-4b39-b970-72b6741ac60c,
  abstract     = {<p>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.</p>},
  author       = {Im, Kate M and Kirchhoff, Tomas and Wang, Xianshu and Green, Todd and Chow, Clement Y and Vijai, Joseph and Korn, Joshua and Gaudet, Mia M and Fredericksen, Zachary and Shane Pankratz, V and Guiducci, Candace and Crenshaw, Andrew and McGuffog, Lesley and Kartsonaki, Christiana and Morrison, Jonathan and Healey, Sue and Sinilnikova, Olga M and Mai, Phuong L and Greene, Mark H and Piedmonte, Marion and Rubinstein, Wendy S and Hogervorst, Frans B and Rookus, Matti A and Collée, J Margriet and Hoogerbrugge, Nicoline and van Asperen, Christi J and Meijers-Heijboer, Hanne E J and Van Roozendaal, Cees E and Caldes, Trinidad and Perez-Segura, Pedro and Jakubowska, Anna and Lubinski, Jan and Huzarski, Tomasz and Blecharz, Paweł and Nevanlinna, Heli and Aittomäki, Kristiina and Lazaro, Conxi and Blanco, Ignacio and Barkardottir, Rosa B and Montagna, Marco and D'Andrea, Emma and Devilee, Peter and Olopade, Olufunmilayo I and Neuhausen, Susan L and Peissel, Bernard and Bonanni, Bernardo and Peterlongo, Paolo and Singer, Christian F and Rennert, Gad and Lejbkowicz, Flavio and Andrulis, Irene L and Glendon, Gord and Ozcelik, Hilmi and Toland, Amanda Ewart and Caligo, Maria Adelaide and Beattie, Mary S and Chan, Salina and Domchek, Susan M and Nathanson, Katherine L and Rebbeck, Timothy R and Phelan, Catherine and Narod, Steven and John, Esther M and Hopper, John L and Buys, Saundra S and Daly, Mary B and Southey, Melissa C and Terry, Mary-Beth and Tung, Nadine and Hansen, Thomas V O and Osorio, Ana and Benitez, Javier and Durán, Mercedes and Weitzel, Jeffrey N and Garber, Judy and Hamann, Ute and Peock, Susan and Cook, Margaret and Oliver, Clare T and Frost, Debra and Platte, Radka and Evans, D Gareth and Eeles, Ros and Izatt, Louise and Paterson, Joan and Brewer, Carole and Hodgson, Shirley and Morrison, Patrick J and Porteous, Mary and Walker, Lisa and Rogers, Mark T and Side, Lucy E and Godwin, Andrew K and Schmutzler, Rita K and Wappenschmidt, Barbara and Laitman, Yael and Meindl, Alfons and Deissler, Helmut and Varon-Mateeva, Raymonda and Preisler-Adams, Sabine and Kast, Karin and Venat-Bouvet, Laurence and Stoppa-Lyonnet, Dominique and Chenevix-Trench, Georgia and Easton, Douglas F and Klein, Robert J and Daly, Mark J and Friedman, Eitan and Dean, Michael and Clark, Andrew G and Altshuler, David M and Antoniou, Antonis C and Couch, Fergus J and Offit, Kenneth and Gold, Bert and , },
  issn         = {1432-1203},
  keyword      = {Arthritis,BRCA1 Protein,BRCA2 Protein,Base Sequence,Computer Simulation,Deafness,Female,Founder Effect,Genotype,Haplotypes,Heterozygote,Humans,Jews,Polychondritis, Relapsing,Sequence Deletion},
  language     = {eng},
  number       = {5},
  pages        = {99--685},
  publisher    = {Springer},
  series       = {Human Genetics},
  title        = {Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers},
  url          = {http://dx.doi.org/10.1007/s00439-011-1003-z},
  volume       = {130},
  year         = {2011},
}