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Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers

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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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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

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Acknowledgments

This work was supported in part by federal funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. We also acknowledge the support of the Starr Foundation, the Breast Cancer Research Foundation and the Sabin Family Fund. The content of this publication does not necessarily reflect the views of the Department of Health and Human Services nor does its mention of trade names, commercial products or organizations imply endorsement by the US government. The authors wish to thank Dr. Colm O’hUigin, who provided valuable comments on an early version of this manuscript.

UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Paul Pharoah, Simon Gayther, Susan Ramus, Carole Pye and Patricia Harrington for their contributions toward the UKFOCR.

The GEMO study (Cancer Genetics Network “Groupe Génétique et Cancer”, Fédération Nationale des Centres de Lutte Contre le Cancer, France) is supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association “Le cancer du sein, parlons-en!” Award.

We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, & UMR5201 CNRS, Université de Lyon, Lyon: Olga Sinilnikova, Laure Barjhoux, Sophie Giraud, Mélanie Léone, Sylvie Mazoyer; and INSERM U509, Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Audrey Remenieras, Véronique Byrde, Olivier Caron, Gilbert Lenoir. Centre Jean Perrin, Clermont–Ferrand: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona. Centre François Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, François Eisinger. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Françoise Révillion, Philippe Vennin, Claude Adenis. Centre René Huguenin, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung. CHU de Dijon: Cécile Cassini, Laurence Faivre. CHU de St-Etienne: Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frénay. CHU de Limoges: Laurence Vénat-Bouvet. Creighton University, Omaha, USA: Henry T. Lynch.

For kConFab, we wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinic and the Clinical Follow Up Study (funded 2001–2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contributed to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia.

The CONSIT TEAM study (Consorzio degli Studi Italiani Tumori Ereditari Alla Mammella), acknowledges Marco Pierotti, Siranoush Manoukian, Daniela Zaffaroni, Carla B. Ripamonti and Paolo Radice of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Monica Barile of the Istituto Europeo di Oncologia, Milan, Italy and Loris Bernard of the Cogentech, Consortium for Genomic Technologies, Milan, Italy. We thank all patients and families who participated in this study. This study was supported by funds from Italian citizens who allocated the 5 × 1,000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 × 1,000’).

For the Mayo Study, the authors would like to acknowledge funding from the Breast Cancer Research Foundation, Komen Foundation, and NIHCA116167.

The Cancer Prevention Institute of California was supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and P.I.s. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Cancer Family Registry (CFR), nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the CFR.

The SWE-BRCA study acknowledge the study collaborators: Per Karlsson, Margareta Nordling, Annika Bergman and Zakaria Einbeigi, Gothenburg, Sahlgrenska University Hospital; Marie Stenmark-Askmalm and Sigrun Liedgren Linköping University Hospital; Åke Borg, Niklas Loman, Håkan Olsson, Ulf Kristoffersson, Helena Jernström, Katja Harbst and Karin Henriksson, Lund University Hospital; Annika Lindblom, Brita Arver, Anna von Wachenfeldt, Annelie Liljegren, Gisela Barbany-Bustinza and Johanna Rantala, Stockholm, Karolinska University Hospital; Beatrice Melin, Henrik Grönberg, Eva-Lena Stattin and Monica Emanuelsson, Umeå University Hospital; Hans Ehrencrona, Richard Rosenquist Brandell and Niklas Dahl, Uppsala University Hospital. The HCSC study was supported by RD06/0020/0021 from ISCIII.

The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Collaborating Centers are Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.B.L. Hogervorst, S. Verhoef, M. Verheus, L.J. van ‘t Veer, F.E. van Leeuwen, M.A. Rookus; Erasmus Medical Center, Rotterdam, NL: M. Collée, A.M.W. van den Ouweland, A. Jager, M.J. Hooning, M.M.A. Tilanus-Linthorst, C. Seynaeve; Leiden University Medical Center, NL, Leiden: C.J. van Asperen, J.T. Wijnen, M.P. Vreeswijk, R.A. Tollenaar, P. Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: M.J. Ligtenberg, N. Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: M.G. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL: C.M. Aalfs, T.A. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: E.B. Gomez-Garcia, C.E. van Roozendaal, Marinus J. Blok, B. Caanen; University Medical Center Groningen University, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088 and NKI2007-3756.

The Ohio State University Clinical Cancer Genetics (OSU CCG) study is supported by the OSU Comprehensive Cancer Center. We thank Leigha Senter and Kevin Sweet for patient accrual, sample ascertainment and database management. The Human Genetics Sample bank processed the samples.

This work was supported by Cancer Care Ontario and the US National Cancer Institute, National Institutes of Health under RFA # CA- 06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and principal investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the BCFR. We wish to thank Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study.

Epidemiological study of BRCA1 and BRCA2 mutation carriers (EMBRACE).

Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centers are Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy’s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins, Kashmir Randhawa. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell, Nafisa Patel. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D’Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D’Mello are also supported by Cancer Research UK Grant C5047/A8385.

CBCS: We thank Bent Ejlertsen, Mette K. Andersen, Anne-Marie Gerdes and Susanne Kjaergaard for clinical data. Moreover, we thank the NEYE foundation for financial support.

Conflict of interest

The authors report no conflicts of interest.

Author information

Authors and Affiliations

  1. Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute, Frederick, MD, USA

    Kate M. Im, Michael Dean & Bert Gold

  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 Center, New York, NY, USA

    Tomas Kirchhoff, Joseph Vijai, Robert J. Klein & Kenneth Offit

  3. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Xianshu Wang, Zachary Fredericksen, V. Shane Pankratz & Fergus J. Couch

  4. Department of Genetics and of Medicine, Harvard Medical School, Boston, MA, USA

    Todd Green, Joshua Korn, Candace Guiducci, Andrew Crenshaw, Mark J. Daly & David M. Altshuler

  5. Program in Medical and Population Genetics, Broad Institute of Harvard University and MIT, Cambridge, USA

    Todd Green, Joshua Korn, Candace Guiducci, Andrew Crenshaw, Mark J. Daly & David M. Altshuler

  6. Department of Molecular Biology, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA

    Todd Green, Joshua Korn, Candace Guiducci, Andrew Crenshaw, Mark J. Daly & David M. Altshuler

  7. Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA

    Clement Y. Chow & Andrew G. Clark

  8. Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA

    Mia M. Gaudet

  9. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Lesley McGuffog, Christiana Kartsonaki, Jonathan Morrison, Susan Peock, Margaret Cook, Clare T. Oliver, Debra Frost, Radka Platte, Douglas F. Easton & Antonis C. Antoniou

  10. Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia

    Sue Healey & Georgia Chenevix-Trench

  11. Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, Lyon, France

    Olga M. Sinilnikova

  12. Centre Léon Bérard, Université de Lyon, Lyon, France

    Olga M. Sinilnikova

  13. Clinical Genetics Branch, National Cancer Institute, Rockville, MD, USA

    Phuong L. Mai & Mark H. Greene

  14. GOG Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY, USA

    Marion Piedmonte

  15. NorthShore University Health System, Evanston, IL, USA

    Wendy S. Rubinstein

  16. Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Frans B. Hogervorst

  17. Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Matti A. Rookus

  18. Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands

    J. Margriet Collée

  19. Hereditary Cancer Clinic, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Nicoline Hoogerbrugge

  20. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Christi J. van Asperen

  21. Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands

    Hanne E. J. Meijers-Heijboer

  22. Department of Clinical Genetics, University Medical Center, Maastricht, The Netherlands

    Cees E. Van Roozendaal

  23. Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain

    Trinidad Caldes & Pedro Perez-Segura

  24. International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

    Anna Jakubowska, Jan Lubinski & Tomasz Huzarski

  25. Center of Oncology, Maria Sklodowska-Curie Memorial Institute, Kraków, Poland

    Paweł Blecharz

  26. Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland

    Heli Nevanlinna

  27. Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland

    Kristiina Aittomäki

  28. Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, Barcelona, Spain

    Conxi Lazaro & Ignacio Blanco

  29. Department of Pathology, Landspitali–LSH, Reykjavik, Iceland

    Rosa B. Barkardottir

  30. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Rosa B. Barkardottir

  31. Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV, IRCCS, Padua, Italy

    Marco Montagna & Emma D’Andrea

  32. Department of Oncology and Surgical Sciences, University of Padua, Padua, Italy

    Emma D’Andrea

  33. Department of Human Genetics and Pathology, Leiden University Medical Center, Leiden, The Netherlands

    Peter Devilee

  34. Center for Clinical Cancer Genetics and Global Health, Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA

    Olufunmilayo I. Olopade

  35. Department of Population Sciences, The Beckman Research Institute of the City of Hope, Duarte, CA, USA

    Susan L. Neuhausen

  36. Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy

    Bernard Peissel

  37. Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy

    Bernardo Bonanni

  38. Unit of Genetic Susceptibility to Cancer, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy

    Paolo Peterlongo

  39. IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy

    Paolo Peterlongo

  40. Department of Obstetrics and Gynecology, University of Vienna, Vienna, Austria

    Christian F. Singer

  41. Comprehensive Cancer Medical Center, University of Vienna, Vienna, Austria

    Christian F. Singer

  42. CHS National Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel

    Gad Rennert & Flavio Lejbkowicz

  43. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

    Irene L. Andrulis & Hilmi Ozcelik

  44. Cancer Care Ontario, University of Toronto, Toronto, ON, Canada

    Irene L. Andrulis, Gord Glendon & Hilmi Ozcelik

  45. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Irene L. Andrulis & Hilmi Ozcelik

  46. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Irene L. Andrulis

  47. Department of Molecular Virology Immunology, and Medical Genetics and Internal Medicine, The Ohio State University, Columbus, OH, USA

    Amanda Ewart Toland

  48. Section of Genetic Oncology, Department of Laboratory Medicine, University of Pisa and Santa Chiara University Hospital, Pisa, Italy

    Maria Adelaide Caligo

  49. Division of General Internal Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    Mary S. Beattie

  50. Cancer Risk Program, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA

    Salina Chan

  51. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Susan M. Domchek, Katherine L. Nathanson & Timothy R. Rebbeck

  52. Moffitt Cancer Center, Tampa, FL, USA

    Catherine Phelan

  53. Women’s College Research Institute, Toronto, ON, Canada

    Steven Narod

  54. Cancer Prevention Institute of California, Fremont, CA, USA

    Esther M. John

  55. Centre for Genetic Epidemiology, University of Melbourne, Victoria, Australia

    John L. Hopper

  56. Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    Saundra S. Buys

  57. Fox Chase Cancer Center, Philadelphia, PA, USA

    Mary B. Daly

  58. Department of Pathology, The University of Melbourne, Victoria, 3010, Australia

    Melissa C. Southey

  59. Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA

    Mary-Beth Terry

  60. Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Brookline Avenue, Boston, MA, USA

    Nadine Tung

  61. Genomic Medicine, Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Thomas v. O. Hansen

  62. Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain

    Ana Osorio

  63. Spanish Network on Rare Diseases (CIBERER), Madrid, Spain

    Ana Osorio & Javier Benitez

  64. Human Genetics Group and Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain

    Javier Benitez

  65. Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain

    Mercedes Durán

  66. Division of Clinical Cancer Genetics, City of Hope Cancer Center, Duarte, CA, USA

    Jeffrey N. Weitzel

  67. Dana Farber Cancer Institute, Harvard University, Boston, MA, USA

    Judy Garber

  68. Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

    Ute Hamann

  69. Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

    D. Gareth Evans

  70. Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey, UK

    Ros Eeles

  71. Clinical Genetics, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

    Louise Izatt

  72. Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, UK

    Joan Paterson

  73. Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK

    Carole Brewer

  74. Clinical Genetics Department, St Georges Hospital, University of London, London, UK

    Shirley Hodgson

  75. Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK

    Patrick J. Morrison

  76. South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK

    Mary Porteous

  77. Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK

    Lisa Walker

  78. All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK

    Mark T. Rogers

  79. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK

    Lucy E. Side

  80. Department of Pathology and Laboratory, University of Kansas Medical Center, Kansas City, KS, USA

    Andrew K. Godwin

  81. University Hospital of Cologne, Cologne, Germany

    Rita K. Schmutzler & Barbara Wappenschmidt

  82. Department of Medical Oncology, Centre Hospitalier Universitaire Dupuytren, Limoges, France

    Laurence Venat-Bouvet

  83. INSERM U509, Service de Génétique Oncologique, Institut Curie, Université Paris-Descartes, Paris, France

    Dominique Stoppa-Lyonnet

  84. The Susan Levy Gertner Oncogenetics unit, Institute of Genetics, Sheba Medical Center, Tel Hashomer, Israel

    Yael Laitman & Eitan Friedman

  85. Technical University Munich, Munich, Germany

    Alfons Meindl

  86. University Hospital Ulm, Ulm, Germany

    Helmut Deissler

  87. Institute of Human Genetics, Charite Campus Virchow Klinikum, Berlin, Germany

    Raymonda Varon-Mateeva

  88. Institute of Human Genetics, University of Münster, Münster, Germany

    Sabine Preisler-Adams

  89. Department of Gynaecology and Obstetrics, University Hospital Carl Gustav, Technical University Dresden, Dresden, Germany

    Karin Kast

  90. NCI-Frederick, Box B, Boyles Street Fort Detrick, Frederick, MD, 21702, USA

    Bert Gold

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HEBON

kConFab

Ontario Cancer Genetics Network

SWE-BRCA

UKFOCR

EMBRACE

Corresponding author

Correspondence to Bert Gold.

Electronic supplementary material

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Supplementary material 1 (EPS 7541 kb)

Supplementary material 2 (EPS 887 kb)

Supplementary material 3 (EPS 2386 kb)

Supplementary material 4 (DOCX 14 kb)

Supplementary Fig. 1 Pattern of linkage disequilibrium across BRCA1 in 216 Ashkenazi women with the founder 185delAG mutation. This is a portion of the plot generated by Haploview. The asterisk (*) marks the haplotype block used as the core to determine haplotype structure. Note: LD for women carrying the 5382insC mutation looks nearly identical (data not shown).

Supplementary Fig. 2 Recombination landscape across 2.1-Mb region surrounding BRCA2. LDHat with a block penalty of ten was used to estimate population recombination rates (4Nr, where N is the effective population size and r is the recombination fraction) in 372 Ashkenazi women. The Markov chain was updated 1 million times and estimates were sampled every 2000 iterations. Gray bar is the location of the BRCA2 gene.

Supplementary Fig. 3 The inbreeding coefficient (FIS) among 372 Ashkenazi women across chromosome 13. Positive values reflect a deficiency of heterozygosity compared to what is expected under Hardy–Weinberg equilibrium. Black lines represent the mean F IS ± 3 SD along chromosome 13. Black box marks the location of the 2.1 Mb BRCA2 region on chromosome 13.

Appendix A—msHOT command

Appendix A—msHOT command

/mshot 412 1 -r 1.0 2087508 -s 545 -v 30 46440 55764 92.72 94074 101467 172.87 116262 120708 84.46 158286 166715 60.34 188386 195853 69.08 203508 207586 27.50 408508 419950 23.61 425890 436582 14.86 531508 540447 22.26 661931 673793 120.99 770385 780441 29.47 815508 819627 29.47 824410 832053 71.03 896479 899758 92.66 907490 914508 66.72 927238 930508 5.91 951526 958508 33.76 967928 979794 50.26 996275 999508 107.56 1084508 1088508 28.62 1091504 1098508 126.14 1616508 1619571 340.72 1621508 1627508 15.09 1660329 1663531 623.28 1675309 1679508 35.42 1686508 1706508 5.02 1850331 1854508 65.25 1883508 1887508 237.76 1962482 1967508 38.82 2055476 2087508 53.91 -G 2355557.4 -eG 0.0000018 0.0000571 -eN 0.0000018 0.095.

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Im, K.M., Kirchhoff, T., Wang, X. et al. Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. Hum Genet 130, 685–699 (2011). https://doi.org/10.1007/s00439-011-1003-z

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