Human Genetics

, Volume 130, Issue 5, pp 685–699

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
  • Wendy S. Rubinstein
  • HEBON
  • 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
  • kConFab
  • 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
  • Ontario Cancer Genetics Network
  • Amanda Ewart Toland
  • Maria Adelaide Caligo
  • SWE-BRCA
  • Mary S. Beattie
  • Salina Chan
  • UKFOCR
  • 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
  • EMBRACE
  • 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
Original Investigation

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.

Abbreviations

AJ

Ashkenazi Jews

CIMBA

Consortium of Investigators of Modifiers of BRCA1 and BRCA2

CNJ

Caucasian non-Jews

LD

Linkage disequilibrium

MAF

Minor allele frequency

MJ

Median joining

PCA

Principal components analysis

SNP

Single nucleotide polymorphism

IBD

Identity by descent

Supplementary material

439_2011_1003_MOESM1_ESM.eps (7.4 mb)
Supplementary material 1 (EPS 7541 kb)
439_2011_1003_MOESM2_ESM.eps (887 kb)
Supplementary material 2 (EPS 887 kb)
439_2011_1003_MOESM3_ESM.eps (2.3 mb)
Supplementary material 3 (EPS 2386 kb)
439_2011_1003_MOESM4_ESM.docx (15 kb)
Supplementary material 4 (DOCX 14 kb)

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Kate M. Im
    • 1
  • Tomas Kirchhoff
    • 2
  • Xianshu Wang
    • 3
  • Todd Green
    • 4
    • 5
    • 6
  • Clement Y. Chow
    • 7
  • Joseph Vijai
    • 2
  • Joshua Korn
    • 4
    • 5
    • 6
  • Mia M. Gaudet
    • 8
  • Zachary Fredericksen
    • 3
  • V. Shane Pankratz
    • 3
  • Candace Guiducci
    • 4
    • 5
    • 6
  • Andrew Crenshaw
    • 4
    • 5
    • 6
  • Lesley McGuffog
    • 9
  • Christiana Kartsonaki
    • 9
  • Jonathan Morrison
    • 9
  • Sue Healey
    • 10
  • Olga M. Sinilnikova
    • 11
    • 12
  • Phuong L. Mai
    • 13
  • Mark H. Greene
    • 13
  • Marion Piedmonte
    • 14
  • Wendy S. Rubinstein
    • 15
  • HEBON
    • 16
  • Frans B. Hogervorst
    • 16
  • Matti A. Rookus
    • 17
  • J. Margriet Collée
    • 18
  • Nicoline Hoogerbrugge
    • 19
  • Christi J. van Asperen
    • 20
  • Hanne E. J. Meijers-Heijboer
    • 21
  • Cees E. Van Roozendaal
    • 22
  • Trinidad Caldes
    • 23
  • Pedro Perez-Segura
    • 23
  • Anna Jakubowska
    • 24
  • Jan Lubinski
    • 24
  • Tomasz Huzarski
    • 24
  • Paweł Blecharz
    • 25
  • Heli Nevanlinna
    • 26
  • Kristiina Aittomäki
    • 27
  • Conxi Lazaro
    • 28
  • Ignacio Blanco
    • 28
  • Rosa B. Barkardottir
    • 29
    • 30
  • Marco Montagna
    • 31
  • Emma D’Andrea
    • 31
    • 32
  • kConFab
    • 33
  • Peter Devilee
    • 34
  • Olufunmilayo I. Olopade
    • 35
  • Susan L. Neuhausen
    • 36
  • Bernard Peissel
    • 37
  • Bernardo Bonanni
    • 38
  • Paolo Peterlongo
    • 39
    • 40
  • Christian F. Singer
    • 41
    • 42
  • Gad Rennert
    • 43
  • Flavio Lejbkowicz
    • 43
  • Irene L. Andrulis
    • 44
    • 45
    • 46
    • 47
  • Gord Glendon
    • 45
  • Hilmi Ozcelik
    • 44
    • 45
    • 46
  • Ontario Cancer Genetics Network
    • 45
  • Amanda Ewart Toland
    • 48
  • Maria Adelaide Caligo
    • 49
  • SWE-BRCA
    • 50
  • Mary S. Beattie
    • 51
  • Salina Chan
    • 52
  • UKFOCR
    • 53
  • Susan M. Domchek
    • 54
  • Katherine L. Nathanson
    • 54
  • Timothy R. Rebbeck
    • 54
  • Catherine Phelan
    • 55
  • Steven Narod
    • 56
  • Esther M. John
    • 57
  • John L. Hopper
    • 58
  • Saundra S. Buys
    • 59
  • Mary B. Daly
    • 60
  • Melissa C. Southey
    • 61
  • Mary-Beth Terry
    • 62
  • Nadine Tung
    • 63
  • Thomas v. O. Hansen
    • 64
  • Ana Osorio
    • 65
    • 66
  • Javier Benitez
    • 66
    • 67
  • Mercedes Durán
    • 68
  • Jeffrey N. Weitzel
    • 69
  • Judy Garber
    • 70
  • Ute Hamann
    • 71
  • EMBRACE
    • 9
  • Susan Peock
    • 9
  • Margaret Cook
    • 9
  • Clare T. Oliver
    • 9
  • Debra Frost
    • 9
  • Radka Platte
    • 9
  • D. Gareth Evans
    • 72
  • Ros Eeles
    • 73
  • Louise Izatt
    • 74
  • Joan Paterson
    • 75
  • Carole Brewer
    • 76
  • Shirley Hodgson
    • 77
  • Patrick J. Morrison
    • 78
  • Mary Porteous
    • 79
  • Lisa Walker
    • 80
  • Mark T. Rogers
    • 81
  • Lucy E. Side
    • 82
  • Andrew K. Godwin
    • 83
  • Rita K. Schmutzler
    • 84
  • Barbara Wappenschmidt
    • 84
  • Yael Laitman
    • 87
  • Alfons Meindl
    • 88
  • Helmut Deissler
    • 89
  • Raymonda Varon-Mateeva
    • 90
  • Sabine Preisler-Adams
    • 91
  • Karin Kast
    • 92
  • Laurence Venat-Bouvet
    • 85
  • Dominique Stoppa-Lyonnet
    • 86
  • Georgia Chenevix-Trench
    • 10
  • Douglas F. Easton
    • 9
  • Robert J. Klein
    • 2
  • Mark J. Daly
    • 4
    • 5
    • 6
  • Eitan Friedman
    • 87
  • Michael Dean
    • 1
  • Andrew G. Clark
    • 7
  • David M. Altshuler
    • 4
    • 5
    • 6
  • Antonis C. Antoniou
    • 9
  • Fergus J. Couch
    • 3
  • Kenneth Offit
    • 2
  • Bert Gold
    • 1
    • 93
  1. 1.Center for Cancer Research, Cancer Inflammation Program, Human Genetics SectionNational Cancer InstituteFrederickUSA
  2. 2.Clinical Genetics Service, Department of Medicine, Program in Cancer Prevention and Population Research, Program in Cancer Biology and Genetics (RJK)Memorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA
  4. 4.Department of Genetics and of MedicineHarvard Medical SchoolBostonUSA
  5. 5.Program in Medical and Population GeneticsBroad Institute of Harvard University and MITCambridgeUSA
  6. 6.Department of Molecular Biology, Center for Human Genetic ResearchMassachusetts General HospitalBostonUSA
  7. 7.Department of Molecular Biology and GeneticsCornell UniversityIthacaUSA
  8. 8.Epidemiology Research ProgramAmerican Cancer SocietyAtlantaUSA
  9. 9.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary CareUniversity of CambridgeCambridgeUK
  10. 10.Genetics and Population Health DivisionQueensland Institute of Medical ResearchBrisbaneAustralia
  11. 11.Unité Mixte de Génétique Constitutionnelle des Cancers FréquentsCentre Hospitalier Universitaire de Lyon/Centre Léon BérardLyonFrance
  12. 12.Centre Léon BérardUniversité de LyonLyonFrance
  13. 13.Clinical Genetics BranchNational Cancer InstituteRockvilleUSA
  14. 14.GOG Statistical and Data CenterRoswell Park Cancer InstituteBuffaloUSA
  15. 15.NorthShore University Health SystemEvanstonUSA
  16. 16.Family Cancer ClinicNetherlands Cancer InstituteAmsterdamThe Netherlands
  17. 17.Department of EpidemiologyNetherlands Cancer InstituteAmsterdamThe Netherlands
  18. 18.Department of Clinical Genetics, Family Cancer ClinicErasmus University Medical CenterRotterdamThe Netherlands
  19. 19.Hereditary Cancer ClinicRadboud University Nijmegen Medical CenterNijmegenThe Netherlands
  20. 20.Department of Clinical GeneticsLeiden University Medical CenterLeidenThe Netherlands
  21. 21.Department of Clinical GeneticsVU Medical CenterAmsterdamThe Netherlands
  22. 22.Department of Clinical GeneticsUniversity Medical CenterMaastrichtThe Netherlands
  23. 23.Molecular Oncology LaboratoryHospital Clinico San CarlosMadridSpain
  24. 24.International Hereditary Cancer Center, Department of Genetics and PathologyPomeranian Medical UniversitySzczecinPoland
  25. 25.Center of OncologyMaria Sklodowska-Curie Memorial InstituteKrakówPoland
  26. 26.Department of Obstetrics and GynecologyHelsinki University Central HospitalHelsinkiFinland
  27. 27.Department of Clinical GeneticsHelsinki University Central HospitalHelsinkiFinland
  28. 28.Hereditary Cancer ProgramCatalan Institute of Oncology-IDIBELLBarcelonaSpain
  29. 29.Department of PathologyLandspitali–LSHReykjavikIceland
  30. 30.Faculty of MedicineUniversity of IcelandReykjavikIceland
  31. 31.Immunology and Molecular Oncology UnitIstituto Oncologico Veneto IOV, IRCCSPaduaItaly
  32. 32.Department of Oncology and Surgical SciencesUniversity of PaduaPaduaItaly
  33. 33.Kathleen Cuningham Foundation Consortium for Research into Familial Breast CancerPeter MacCallum Cancer CentreMelbourneAustralia
  34. 34.Department of Human Genetics and PathologyLeiden University Medical CenterLeidenThe Netherlands
  35. 35.Center for Clinical Cancer Genetics and Global Health, Department of MedicineUniversity of Chicago Medical CenterChicagoUSA
  36. 36.Department of Population SciencesThe Beckman Research Institute of the City of HopeDuarteUSA
  37. 37.Unit of Medical Genetics, Department of Preventive and Predictive MedicineFondazione IRCCS Istituto Nazionale dei Tumori (INT)MilanItaly
  38. 38.Division of Cancer Prevention and GeneticsIstituto Europeo di Oncologia (IEO)MilanItaly
  39. 39.Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular MedicineFondazione IRCCS Istituto Nazionale Tumori (INT)MilanItaly
  40. 40.IFOMFondazione Istituto FIRC di Oncologia MolecolareMilanItaly
  41. 41.Department of Obstetrics and GynecologyUniversity of ViennaViennaAustria
  42. 42.Comprehensive Cancer Medical CenterUniversity of ViennaViennaAustria
  43. 43.CHS National Cancer Control Center and Department of Community Medicine and EpidemiologyCarmel Medical Center and Technion Faculty of MedicineHaifaIsrael
  44. 44.Samuel Lunenfeld Research InstituteMount Sinai HospitalTorontoCanada
  45. 45.Cancer Care OntarioUniversity of TorontoTorontoCanada
  46. 46.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  47. 47.Department of Molecular GeneticsUniversity of TorontoTorontoCanada
  48. 48.Department of Molecular Virology Immunology, and Medical Genetics and Internal MedicineThe Ohio State UniversityColumbusUSA
  49. 49.Section of Genetic Oncology, Department of Laboratory MedicineUniversity of Pisa and Santa Chiara University HospitalPisaItaly
  50. 50.Department of OncologyLund UniversityLundSweden
  51. 51.Division of General Internal Medicine, Department of MedicineUniversity of California San FranciscoSan FranciscoUSA
  52. 52.Cancer Risk ProgramUniversity of California San Francisco, Helen Diller Family Comprehensive Cancer CenterSan FranciscoUSA
  53. 53.Department of OncologyUniversity of CambridgeCambridgeUK
  54. 54.Abramson Cancer CenterUniversity of PennsylvaniaPhiladelphiaUSA
  55. 55.Moffitt Cancer CenterTampaUSA
  56. 56.Women’s College Research InstituteTorontoCanada
  57. 57.Cancer Prevention Institute of CaliforniaFremontUSA
  58. 58.Centre for Genetic EpidemiologyUniversity of MelbourneVictoriaAustralia
  59. 59.Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA
  60. 60.Fox Chase Cancer CenterPhiladelphiaUSA
  61. 61.Department of PathologyThe University of MelbourneVictoriaAustralia
  62. 62.Department of Epidemiology, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  63. 63.Division of Hematology-OncologyBeth Israel Deaconess Medical CenterBostonUSA
  64. 64.Genomic Medicine, Department of Clinical Biochemistry, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
  65. 65.Human Genetics Group, Human Cancer Genetics ProgrammeSpanish National Cancer Research CentreMadridSpain
  66. 66.Spanish Network on Rare Diseases (CIBERER)MadridSpain
  67. 67.Human Genetics Group and Genotyping Unit, Human Cancer Genetics ProgrammeSpanish National Cancer Research CentreMadridSpain
  68. 68.Institute of Biology and Molecular GeneticsUniversidad de Valladolid (IBGM-UVA)ValladolidSpain
  69. 69.Division of Clinical Cancer GeneticsCity of Hope Cancer CenterDuarteUSA
  70. 70.Dana Farber Cancer InstituteHarvard UniversityBostonUSA
  71. 71.Molecular Genetics of Breast CancerDeutsches Krebsforschungszentrum (DKFZ)HeidelbergGermany
  72. 72.Genetic Medicine, Manchester Academic Health Sciences CentreCentral Manchester University Hospitals NHS Foundation TrustManchesterUK
  73. 73.Oncogenetics TeamThe Institute of Cancer Research and Royal Marsden NHS Foundation TrustSurreyUK
  74. 74.Clinical Genetics, Guy’s and St. Thomas’ NHS Foundation TrustLondonUK
  75. 75.Department of Clinical Genetics, East Anglian Regional Genetics ServiceAddenbrookes HospitalCambridgeUK
  76. 76.Department of Clinical GeneticsRoyal Devon & Exeter HospitalExeterUK
  77. 77.Clinical Genetics Department, St Georges HospitalUniversity of LondonLondonUK
  78. 78.Northern Ireland Regional Genetics CentreBelfast City HospitalBelfastUK
  79. 79.South East of Scotland Regional Genetics ServiceWestern General HospitalEdinburghUK
  80. 80.Oxford Regional Genetics ServiceChurchill HospitalOxfordUK
  81. 81.All Wales Medical Genetics ServicesUniversity Hospital of WalesCardiffUK
  82. 82.North East Thames Regional Genetics ServiceGreat Ormond Street Hospital for Children NHS TrustLondonUK
  83. 83.Department of Pathology and LaboratoryUniversity of Kansas Medical CenterKansas CityUSA
  84. 84.University Hospital of CologneCologneGermany
  85. 85.Department of Medical OncologyCentre Hospitalier Universitaire DupuytrenLimogesFrance
  86. 86.INSERM U509, Service de Génétique Oncologique, Institut CurieUniversité Paris-DescartesParisFrance
  87. 87.The Susan Levy Gertner Oncogenetics unit, Institute of GeneticsSheba Medical CenterTel HashomerIsrael
  88. 88.Technical University MunichMunichGermany
  89. 89.University Hospital UlmUlmGermany
  90. 90.Institute of Human GeneticsCharite Campus Virchow KlinikumBerlinGermany
  91. 91.Institute of Human GeneticsUniversity of MünsterMünsterGermany
  92. 92.Department of Gynaecology and ObstetricsUniversity Hospital Carl Gustav, Technical University DresdenDresdenGermany
  93. 93.NCI-FrederickFrederickUSA

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