Abstract
There is a great deal of interest in understanding the non-random distribution of recombination events over the human genome, because it has important implications for using linkage disequilibrium (LD) to identify human disease genes. So far, only a few recombination hotspots in the human genome have been characterised and the identification of new crossover hotspots will contribute to a better understanding of the mechanisms that govern their formation and distribution. This study shows that high-density single nucleotide polymorphism (SNP) arrays, together with the presented analysis method, are an appropriate tool for generating a whole-genome recombination pattern and for detecting new crossover regions with enhanced recombination frequency. Based on the genotype data of 16 members of a Caucasian three-generation family, we identified 825 crossover regions. The average recombination frequency of females and males was 0.77 and 0.56 cM/Mb, respectively. We detected 24 crossover regions showing elevated recombination activity, which comprised known hotspots, like the MHC II region, confirming the non-random distribution of recombination events along the genome. Interestingly, 29.2% of the identified crossover hotspot regions overlapped with regions flanked by segmental duplications published by Bailey et al. (Science 297:1003–1007, 2002) suggesting that segmental duplications and crossover hotspot regions are mechanistically linked. By extrapolating the results of the present study, we conclude that it might be feasible, at least in part, to estimate to what extent the block-like pattern of LD exactly relies on the genome-wide crossover pattern using the next generation high-density SNP microarrays.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arnheim N, Calabrese P, Nordborg M (2003) Hot and cold spots of recombination in the human genome: the reason we should find them and how this can be achieved. Am J Hum Genet 73:5–16
Babcock M, Pavlicek A, Spiteri E, Kashork CD, Ioshikhes I, Shaffer LG, Jurka J, Morrow BE (2003) Shuffling of genes within low-copy repeats on 22q11 (LCR22) by Alu-mediated recombination events during evolution. Genome Res 13:2519–2532
Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, Adams MD, Myers EW, Li PW, Eichler EE (2002) Recent segmental duplications in the human genome. Science 297:1003–1007
Burwinkel B, Kilimann MW (1998) Unequal homologous recombination between LINE-1 elements as a mutational mechanism in human genetic disease. J Mol Biol 277:513–517
Cruciani F, Bernardini L, Santolamazza P, Modiano D, Torroni A, Scozzari R (2003) Linkage disequilibrium analysis of the human adenosine deaminase (ADA) gene provides evidence for a lack of correlation between hot spots of equal and unequal homologous recombination. Genomics 82:20–33
Daly MJ, Rioux JD, Schaffner SF, Hudson TJ, Lander ES (2001) High-resolution haplotype structure in the human genome. Nat Genet 29:229–232
Emanuel BS, Shaikh TH (2001) Segmental duplications: an ‘expanding’ role in genomic instability and disease. Nat Rev Genet 2:791–800
Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D (2002) The structure of haplotype blocks in the human genome. Science 296:2225–2229
Innan H, Padhukasahasram B, Nordborg M (2003) The pattern of polymorphism on human chromosome 21. Genome Res 13:1158–1168
Janson M, Larsson C, Werelius B, Jones C, Glaser T, Nakamura Y, Jones CP, Nordenskjold M (1991) Detailed physical map of human chromosomal region 11q12-13 shows high meiotic recombination rate around the MEN1 locus. Proc Natl Acad Sci USA 88:10609–10613
Jeffreys AJ, Murray J, Neumann R (1998) High-resolution mapping of crossovers in human sperm defines a minisatellite-associated recombination hotspot. Mol Cell 2:267–273
Jeffreys AJ, Ritchie A, Neumann R (2000) High-resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. Hum Mol Genet 9:725–733
Jeffreys AJ, Kauppi L, Neumann R (2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 29:217–222
Kauppi L, Jeffreys AJ, Keeney S (2004) Where the crossovers are: recombination distributions in mammals. Nat Rev Genet 5:413–424
Kennedy GC, Matsuzaki H, Dong S, Liu WM, Huang J, Liu G, Su X, Cao M, Chen W, Zhang J, Liu W, Yang G, Di X, Ryder T, He Z, Surti U, Phillips MS, Boyce-Jacino MT, Fodor SP, Jones KW (2003) Large-scale genotyping of complex DNA. Nat Biotechnol 21:1233–1237
Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247
Lopez-Correa C, Dorschner M, Brems H, Lazaro C, Clementi M, Upadhyaya M, Dooijes D, Moog U, Kehrer-Sawatzki H, Rutkowski JL, Fryns JP, Marynen P, Stephens K, Legius E (2001) Recombination hotspot in NF1 microdeletion patients. Hum Mol Genet 10:1387–1392
May CA, Shone AC, Kalaydjieva L, Sajantila A, Jeffreys AJ (2002) Crossover clustering and rapid decay of linkage disequilibrium in the Xp/Yp pseudoautosomal gene SHOX. Nat Genet 31:272–275
Nordborg M, Tavare S (2002) Linkage disequilibrium: what history has to tell us. Trends Genet 18:83–90
Patil N, Berno AJ, Hinds DA, Barrett WA, Doshi JM, Hacker CR, Kautzer CR, Lee DH, Marjoribanks C, McDonough DP, Nguyen BT, Norris MC, Sheehan JB, Shen N, Stern D, Stokowski RP, Thomas DJ, Trulson MO, Vyas KR, Frazer KA, Fodor SP, Cox DR (2001) Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21. Science 294:1719–1723
Phillips MS, Lawrence R, Sachidanandam R, Morris AP, Balding DJ, Donaldson MA, Studebaker JF, Ankener WM, Alfisi SV, Kuo FS, Camisa AL, Pazorov V, Scott KE, Carey BJ, Faith J, Katari G, Bhatti HA, Cyr JM, Derohannessian V, Elosua C, Forman AM, Grecco NM, Hock CR, Kuebler JM, Lathrop JA, Mockler MA, Nachtman EP, Restine SL, Varde SA, Hozza MJ, Gelfand CA, Broxholme J, Abecasis GR, Boyce-Jacino MT, Cardon LR (2003) Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots. Nat Genet 33:382–387
Reich DE, Schaffner SF, Daly MJ, McVean G, Mullikin JC, Higgins JM, Richter DJ, Lander ES, Altshuler D (2002) Human genome sequence variation and the influence of gene history, mutation and recombination. Nat Genet 32:135–142
Saifi GM, Szigeti K, Snipes GJ, Garcia CA, Lupski JR (2003) Molecular mechanisms, diagnosis, and rational approaches to management of and therapy for Charcot–Marie-Tooth disease and related peripheral neuropathies. J Invest Med 51:261–283
Saifi GM, Szigeti K, Wiszniewski W, Shy ME, Krajewski K, Hausmanowa-Petrusewicz I, Kochanski A, Reeser S, Mancias P, Butler I, Lupski JR (2005) SIMPLE mutations in Charcot–Marie-Tooth disease and the potential role of its protein product in protein degradation. Hum Mutat 25:372–383
Smith RA, Ho PJ, Clegg JB, Kidd JR, Thein SL (1998) Recombination breakpoints in the human beta-globin gene cluster. Blood 92:4415–4421
Sun F, Oliver-Bonet M, Liehr T, Starke H, Ko E, Rademaker A, Navarro J, Benet J, Martin RH (2004) Human male recombination maps for individual chromosomes. Am J Hum Genet 74:521–531
Tease C, Hartshorne GM, Hulten MA (2002) Patterns of meiotic recombination in human fetal oocytes. Am J Hum Genet 70:1469–1479
Twells RC, Mein CA, Payne F, Veijola R, Gilbey M, Bright M, Timms A, Nakagawa Y, Snook H, Nutland S, Rance HE, Carr P, Dudbridge F, Cordell HJ, Cooper J, Tuomilehto-Wolf E, Tuomilehto J, Phillips M, Metzker M, Hess JF, Todd JA (2003) Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes. Hum Genet 113:99–105
Wang N, Akey JM, Zhang K, Chakraborty R, Jin L (2002) Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am J Hum Genet 71:1227–1234
Yip SP, Lovegrove JU, Rana NA, Hopkinson DA, Whitehouse DB (1999) Mapping recombination hotspots in human phosphoglucomutase (PGM1). Hum Mol Genet 8:1699–1706
Acknowledgements
We are grateful to B. Frank for reviewing the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wirtenberger, M., Hemminki, K., Chen, B. et al. SNP microarray analysis for genome-wide detection of crossover regions. Hum Genet 117, 389–397 (2005). https://doi.org/10.1007/s00439-005-1323-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-005-1323-y