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. Hogervorst, Matti A. Rookus, J. Margriet Collée, 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, Paweł Blecharz, Heli Nevanlinna, Kristiina Aittomäki, 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 Chan, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Catherine Phelan, Steven Narod, Esther M. John, John L. Hopper, Saundra S. Buys, Mary B. Daly, Melissa C. Southey, Mary Beth Terry, Nadine Tung, Thomas V O Hansen, Ana Osorio, Javier Benitez, Mercedes Durán, 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 Hodgson, Patrick J. Morrison, Mary 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, Bert Gold

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)685-699
Number of pages15
JournalHuman Genetics
Volume130
Issue number5
DOIs
StatePublished - Nov 2011

Fingerprint

Jews
Haplotypes
Mutation
Linkage Disequilibrium
Chromosomes
Population
Genetic Drift
Population Density
Genomics
Gene Frequency
Constriction
Ovarian Neoplasms
Genotype
Demography
Genome
Breast Neoplasms

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Im, K. M., Kirchhoff, T., Wang, X., Green, T., Chow, C. Y., Vijai, J., ... Gold, B. (2011). Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. Human Genetics, 130(5), 685-699. https://doi.org/10.1007/s00439-011-1003-z

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; Pankratz, V. Shane; 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.

In: Human Genetics, Vol. 130, No. 5, 11.2011, p. 685-699.

Research output: Contribution to journalArticle

Im, KM, Kirchhoff, T, Wang, X, Green, T, Chow, CY, Vijai, J, Korn, J, Gaudet, MM, Fredericksen, Z, Pankratz, VS, Guiducci, C, Crenshaw, A, McGuffog, L, Kartsonaki, C, Morrison, J, Healey, S, Sinilnikova, OM, Mai, PL, Greene, MH, Piedmonte, M, Rubinstein, WS, Hogervorst, FB, Rookus, MA, Collée, JM, Hoogerbrugge, N, Van Asperen, CJ, Meijers-Heijboer, HEJ, 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, Devilee, P, Olopade, OI, Neuhausen, SL, Peissel, B, Bonanni, B, Peterlongo, P, Singer, CF, Rennert, G, Lejbkowicz, F, Andrulis, IL, Glendon, G, Ozcelik, H, Toland, AE, Caligo, MA, Beattie, MS, Chan, S, 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, TVO, Osorio, A, Benitez, J, Durán, M, Weitzel, JN, Garber, J, Hamann, U, 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 2011, 'Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers', Human Genetics, vol. 130, no. 5, pp. 685-699. https://doi.org/10.1007/s00439-011-1003-z
Im KM, Kirchhoff T, Wang X, Green T, Chow CY, Vijai J et al. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. Human Genetics. 2011 Nov;130(5):685-699. https://doi.org/10.1007/s00439-011-1003-z
Im, Kate M. ; Kirchhoff, Tomas ; Wang, Xianshu ; Green, Todd ; Chow, Clement Y. ; Vijai, Joseph ; Korn, Joshua ; Gaudet, Mia M. ; Fredericksen, Zachary ; Pankratz, V. Shane ; 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. / Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. In: Human Genetics. 2011 ; Vol. 130, No. 5. pp. 685-699.
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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.",
author = "Im, {Kate M.} and Tomas Kirchhoff and Xianshu Wang and Todd Green and Chow, {Clement Y.} and Joseph Vijai and Joshua Korn and Gaudet, {Mia M.} and Zachary Fredericksen and Pankratz, {V. Shane} and Candace Guiducci and Andrew Crenshaw and Lesley McGuffog and Christiana Kartsonaki and Jonathan Morrison and Sue Healey and Sinilnikova, {Olga M.} and Mai, {Phuong L.} and Greene, {Mark H.} and Marion Piedmonte and Rubinstein, {Wendy S.} and Hogervorst, {Frans B.} and Rookus, {Matti A.} and Coll{\'e}e, {J. Margriet} and Nicoline Hoogerbrugge and {Van Asperen}, {Christi J.} and Meijers-Heijboer, {Hanne E J} and {Van Roozendaal}, {Cees E.} and Trinidad Caldes and Pedro Perez-Segura and Anna Jakubowska and Jan Lubinski and Tomasz Huzarski and Paweł Blecharz and Heli Nevanlinna and Kristiina Aittom{\"a}ki and Conxi Lazaro and Ignacio Blanco and Barkardottir, {Rosa B.} and Marco Montagna and Emma D'Andrea and Peter Devilee and Olopade, {Olufunmilayo I.} and Neuhausen, {Susan L.} and Bernard Peissel and Bernardo Bonanni and Paolo Peterlongo and Singer, {Christian F.} and Gad Rennert and Flavio Lejbkowicz and Andrulis, {Irene L.} and Gord Glendon and Hilmi Ozcelik and Toland, {Amanda Ewart} and Caligo, {Maria Adelaide} and Beattie, {Mary S.} and Salina Chan and Domchek, {Susan M.} and Nathanson, {Katherine L.} and Rebbeck, {Timothy R.} and Catherine Phelan and Steven Narod 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 Nadine Tung and Hansen, {Thomas V O} and Ana Osorio and Javier Benitez and Mercedes Dur{\'a}n and Weitzel, {Jeffrey N.} and Judy Garber and Ute Hamann and Susan Peock and Margaret Cook and Oliver, {Clare T.} and Debra Frost and Radka Platte and Evans, {D. Gareth} and Ros Eeles and Louise Izatt and Joan Paterson and Carole Brewer and Shirley Hodgson and Morrison, {Patrick J.} and Mary Porteous and Lisa Walker and Rogers, {Mark T.} and Side, {Lucy E.} and Godwin, {Andrew K.} and Schmutzler, {Rita K.} and Barbara Wappenschmidt and Yael Laitman and Alfons Meindl and Helmut Deissler and Raymonda Varon-Mateeva and Sabine Preisler-Adams and Karin Kast and Laurence Venat-Bouvet and Dominique Stoppa-Lyonnet and Georgia Chenevix-Trench and Easton, {Douglas F.} and Klein, {Robert J.} and Daly, {Mark J.} and Eitan Friedman and Michael Dean and Clark, {Andrew G.} and Altshuler, {David M.} and Antoniou, {Antonis C.} and Couch, {Fergus J} and Kenneth Offit and Bert Gold",
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TY - JOUR

T1 - Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

AU - Im, Kate M.

AU - Kirchhoff, Tomas

AU - Wang, Xianshu

AU - Green, Todd

AU - Chow, Clement Y.

AU - Vijai, Joseph

AU - Korn, Joshua

AU - Gaudet, Mia M.

AU - Fredericksen, Zachary

AU - Pankratz, V. Shane

AU - Guiducci, Candace

AU - Crenshaw, Andrew

AU - McGuffog, Lesley

AU - Kartsonaki, Christiana

AU - Morrison, Jonathan

AU - Healey, Sue

AU - Sinilnikova, Olga M.

AU - Mai, Phuong L.

AU - Greene, Mark H.

AU - Piedmonte, Marion

AU - Rubinstein, Wendy S.

AU - Hogervorst, Frans B.

AU - Rookus, Matti A.

AU - Collée, J. Margriet

AU - Hoogerbrugge, Nicoline

AU - Van Asperen, Christi J.

AU - Meijers-Heijboer, Hanne E J

AU - Van Roozendaal, Cees E.

AU - Caldes, Trinidad

AU - Perez-Segura, Pedro

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Huzarski, Tomasz

AU - Blecharz, Paweł

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Lazaro, Conxi

AU - Blanco, Ignacio

AU - Barkardottir, Rosa B.

AU - Montagna, Marco

AU - D'Andrea, Emma

AU - Devilee, Peter

AU - Olopade, Olufunmilayo I.

AU - Neuhausen, Susan L.

AU - Peissel, Bernard

AU - Bonanni, Bernardo

AU - Peterlongo, Paolo

AU - Singer, Christian F.

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Andrulis, Irene L.

AU - Glendon, Gord

AU - Ozcelik, Hilmi

AU - Toland, Amanda Ewart

AU - Caligo, Maria Adelaide

AU - Beattie, Mary S.

AU - Chan, Salina

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Rebbeck, Timothy R.

AU - Phelan, Catherine

AU - Narod, Steven

AU - John, Esther M.

AU - Hopper, John L.

AU - Buys, Saundra S.

AU - Daly, Mary B.

AU - Southey, Melissa C.

AU - Terry, Mary Beth

AU - Tung, Nadine

AU - Hansen, Thomas V O

AU - Osorio, Ana

AU - Benitez, Javier

AU - Durán, Mercedes

AU - Weitzel, Jeffrey N.

AU - Garber, Judy

AU - Hamann, Ute

AU - Peock, Susan

AU - Cook, Margaret

AU - Oliver, Clare T.

AU - Frost, Debra

AU - Platte, Radka

AU - Evans, D. Gareth

AU - Eeles, Ros

AU - Izatt, Louise

AU - Paterson, Joan

AU - Brewer, Carole

AU - Hodgson, Shirley

AU - Morrison, Patrick J.

AU - Porteous, Mary

AU - Walker, Lisa

AU - Rogers, Mark T.

AU - Side, Lucy E.

AU - Godwin, Andrew K.

AU - Schmutzler, Rita K.

AU - Wappenschmidt, Barbara

AU - Laitman, Yael

AU - Meindl, Alfons

AU - Deissler, Helmut

AU - Varon-Mateeva, Raymonda

AU - Preisler-Adams, Sabine

AU - Kast, Karin

AU - Venat-Bouvet, Laurence

AU - Stoppa-Lyonnet, Dominique

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F.

AU - Klein, Robert J.

AU - Daly, Mark J.

AU - Friedman, Eitan

AU - Dean, Michael

AU - Clark, Andrew G.

AU - Altshuler, David M.

AU - Antoniou, Antonis C.

AU - Couch, Fergus J

AU - Offit, Kenneth

AU - Gold, Bert

PY - 2011/11

Y1 - 2011/11

N2 - 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.

AB - 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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