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 Piedmonte & 31 others Wendy 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, HEBON, Zofia Miedzybrodzka

Research output: Contribution to journalArticle

11 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
Pages (from-to)685-699
Number of pages15
JournalHuman Genetics
Volume130
Issue number5
DOIs
Publication statusPublished - 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

Keywords

  • arthritis
  • BRCA1 protein
  • BRCA2 protein
  • base sequence
  • computer simulation
  • deafness
  • female
  • founder effect
  • genotype
  • haplotypes
  • heterozygote
  • humans
  • Jews
  • polychondritis, relapsing
  • sequence deletion

Cite this

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; 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; HEBON ; Miedzybrodzka, Zofia.

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, Shane Pankratz, V, 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, HEBON & Miedzybrodzka, Z 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 ; 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 ; HEBON ; Miedzybrodzka, Zofia. / 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.",
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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 - Shane Pankratz, V

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 - HEBON

AU - Miedzybrodzka, Zofia

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.

KW - arthritis

KW - BRCA1 protein

KW - BRCA2 protein

KW - base sequence

KW - computer simulation

KW - deafness

KW - female

KW - founder effect

KW - genotype

KW - haplotypes

KW - heterozygote

KW - humans

KW - Jews

KW - polychondritis, relapsing

KW - sequence deletion

U2 - 10.1007/s00439-011-1003-z

DO - 10.1007/s00439-011-1003-z

M3 - Article

VL - 130

SP - 685

EP - 699

JO - Human Genetics

JF - Human Genetics

SN - 0340-6717

IS - 5

ER -