Hum Genet. 2011 Nov;130(5):685-99. doi: 10.1007/s00439-011-1003-z. Epub 2011 May 20.
Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers.
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;
HEBON,
Hogervorst FB,
Rookus MA,
Collée JM,
Hoogerbrugge N,
van Asperen CJ,
Meijers-Heijboer HE,
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;
kConFab,
Devilee P,
Olopade OI,
Neuhausen SL,
Peissel B,
Bonanni B,
Peterlongo P,
Singer CF,
Rennert G,
Lejbkowicz F,
Andrulis IL,
Glendon G,
Ozcelik H;
Ontario Cancer Genetics Network,
Toland AE,
Caligo MA;
SWE-BRCA,
Beattie MS,
Chan S;
UKFOCR,
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 TV,
Osorio A,
Benitez J,
Durán M,
Weitzel JN,
Garber J,
Hamann U;
EMBRACE,
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.
Stoppa-Lyonnet D, Gauthier-Villars M, Houdayer C, Moncoutier V, Belotti M, de Pauw A, Bressac-de-Paillerets B, Remenieras A, Byrde V, Caron O, Lenoir G, Bignon YJ, Uhrhammer N, Lasset C, Bonadona V, Hardouin A, Berthet P, Sobol H, Bourdon V, Noguchi T, Eisinger F, Coulet F, Colas C, Soubrier F, Coupier I, Peyrat JP, Fournier J, Révillion F, Vennin P, Adenis C, Rouleau E, Lidereau R, Demange L, Nogues C, Muller D, Fricker JP, Longy M, Sevenet N, Toulas C, Guimbaud R, Gladieff L, Feillel V, Leroux D, Dreyfus H, Rebischung C, Cassini C, Faivre L, Prieur F, Ferrer SF, Frénay M, Vénat-Bouvet L, Lynch HT, Thorne H, Niedermayr E, Pierotti M, Manoukian S, Zaffaroni D, Ripamonti CB, Radice P, Barile M, Bernard L, Karlsson P, Nordling M, Bergman A, Einbeigi Z, Stenmark-Askmalm M, Liedgren S, Borg Å, Loman N, Olsson H, Kristoffersson U, Jernström H, Harbst K, Henriksson K, Lindblom A, Arver B, von Wachenfeldt A, Liljegren A, Barbany-Bustinza G, Rantala J, Melin B, Grönberg H, Stattin EL, Emanuelsson M, Ehrencrona H, Brandell RR, Dahl N, Hogervorst FB, Verhoef S, Verheus M, van 't Veer LJ, van Leeuwen FE, Rookus MA, Collée M, van den Ouweland AM, Jager A, Hooning MJ, Tilanus-Linthorst MM, Seynaeve C, van Asperen CJ, Wijnen JT, Vreeswijk MP, Tollenaar RA, Devilee P, Ligtenberg MJ, Hoogerbrugge N, Ausems MG, van der Luijt RB, Aalfs CM, van Os TA, Gille JJ, Waisfisz Q, Meijers-Heijboer HE, Gomez-Garcia EB, van Roozendaal CE, Blok MJ, Caanen B, Oosterwijk JC, van der Hout AH, Mourits MJ, Vasen HF, Easton DF, Peock S, Cook M, Oliver CT, Frost D, Platte R, Miedzybrodzka Z, Gregory H, Morrison P, Jeffers L, Cole T, Ong KR, Hoffman J, Donaldson A, James M, Paterson J, Downing S, Taylor A, Murray A, Rogers MT, McCann E, Kennedy MJ, Barton D, Porteous M, Drummond S, Brewer C, Kivuva E, Searle A, Goodman S, Hill K, Davidson R, Murday V, Bradshaw N, Snadden L, Longmuir M, Watt C, Gibson S, Haque E, Tobias E, Duncan A, Izatt L, Jacobs C, Langman C, Whaite A, Dorkins H, Randhawa K, Barwell J, Patel N, Adlard J, Chu C, Miller J, Ellis I, Houghton C, Evans DG, Lalloo F, Taylor J, Side L, Male A, Berlin C, Eason J, Collier R, Douglas F, Claber O, Jobson I, Walker L, McLeod D, Halliday D, Durell S, Stayner B, Eeles R, Shanley S, Rahman N, Houlston R, Bancroft E, D'Mello L, Page E, Ardern-Jones A, Kohut K, Wiggins J, Castro E, Mitra A, Robertson L, Cook J, Quarrell O, Bardsley C, Hodgson S, Brice G, Winchester L, Eddy C, Tripathi V, Attard V, Eccles D, Lucassen A, Crawford G, McBride D, Smalley S.
Source
Center for Cancer Research, Cancer Inflammation Program, Human Genetics Section, National Cancer Institute, Frederick, MD, USA.
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.
- PMID:
- 21597964
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3196382
Free PMC ArticleFig. 1
Linkage disequilibrium across a 570-kb region in 372 Ashkenazi women. a Haploview output showing LD blocks across region. Black block represents the core haplotype. b Haplotypes estimated using SNPHAP for each of the LD blocks. Haplotypes observed in at least 1% of chromosomes are shown in order of frequency (most frequent first)
Hum Genet. 2011 November;130(5):685-699.
Fig. 2
Extended haplotype structure observed in (a) 372 Ashkenazi women across a 2.1-Mb region and (b) 1441 Caucasian, non-Jewish women across an 805-kb region. Each row represents an individual. Tick marks show SNP locations, red triangles mark the boundaries of the 8-SNP core BRCA2 haplotype, and blue triangles mark the boundaries of the (a) 1.4 Mb extended haplotype and (b) 715 kb extended haplotype in the AJ and CNJ, respectively. Long horizontal red lines represent the core haplotype, while interruptions in that haplotype observed in the data by the presence of frequent alternative alleles are colored in green
Hum Genet. 2011 November;130(5):685-699.
Fig. 3
Population differentiation among Ashkenazi and CNJ women. a FST between 372 Ashkenazi and 1,441 Caucasian, non-Jewish women across chromosome 13. b FST between 613 Ashkenazi (carriers of the 185delAG and 5382insC founder mutations) and 2,186 Caucasian, non-Jewish (carriers of non-founder mutations) women across chromosome 17. The peaks of FST occur in the region surrounding BRCA2 and BRCA1 in (a) and (b), respectively, represented by the black boxes
Hum Genet. 2011 November;130(5):685-699.
Fig. 4
Genome-wide distribution of Tajima's D in 372 AJ women. D statistics were estimated for 100-kb sliding windows
Hum Genet. 2011 November;130(5):685-699.
Fig. 5
Haplotype network results from analyzing the eight SNPs that make up the core BRCA2 haplotype. Diagrams constructed using haplotypes observed at a frequency of at least 1% are labeled. The dark gray sphere (H1) represents the core haplotype. a Network for AJ chromosomes. b Network for CNJ chromosomes. Frequency of each haplotype can be found in Supplementary Table 1. The size of each sphere is proportional to its frequency in the sample
Hum Genet. 2011 November;130(5):685-699.
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