Abstract
The identification of candidate genes for significant traits is crucial. In this study, we developed and tested effective and systematic methods based on linkage disequilibrium (LD) for the identification of candidate regions for genes with Mendelian inheritance and those associated with complex traits. Our approach entailed the combination of primary screening using pooled DNA samples based on ΔTAC, secondary screening using an individual typing method and tertiary screening using a permutation test based on the differences in the haplotype frequency between two neighbouring microsatellites. This series of methods was evaluated using horse coat colour traits (chestnut/non-chestnut) as a simple Mendelian inheritance model. In addition, the methods were evaluated using a complex trait model constructed by mixing samples from chestnut and non-chestnut horses. Using both models, the methods could detect the expected regions for the horse coat colour trait. The results revealed that LD extends up to several centimorgans in horses, indicating that whole-genome LD screening in horses could be performed systematically and efficiently by combining the above-mentioned methods. Since genetic maps based on microsatellites have been constructed for many other species, the approaches present here could have wide applicability.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ahmed ZM, Morell RJ, Riazuddin S, Gropman A, Shaukat S, Ahmad MM, Mohiddin SA, Fananapazir L, Caruso RC, Husnain T, Khan SN, Riazuddin S, Griffith AJ, Friedman TB, Wilcox ER (2003) Mutations of MYO6 are associated with recessive deafness, DFNB37. Am J Hum Genet 72:1315–1322
Cader ZM, Noble-Topham S, Dyment DA, Cherny SS, Brown JD, Rice GP, Ebers GC (2003) Significant linkage to migraine with aura on chromosome 11q24. Hum Mol Genet 12:2511–2517
Chowdhary BP, Raudsepp T, Kata SR, Goh G, Millon LV, Allan V, Piumi F, Guérin G, Swinburne J, Binns M, Lear TL, Mickelson J, Murray J, Antczak DF, Womack JE, Skow LC (2003) The first-generation wgole-genome radiation hybrid map in the horse identifies conserved segments in human and mouse genomes. Genome Res 13:742–751
Collins HE, Li H, Inda SE, Anderson J, Laiho K, Tuomilehto J, Seldin MF (2000) A simple and accurate method for determination of microsatellite total allele content differences between DNA pools. Hum Genet 106:218–226
Cunningham EP, Dooley JJ, Splan RK, Bradley DG (2001) Microsatellite diversity, pedigree relatedness and the contributions of founder lineages to Thoroughbred horses. Anim Genet 32:360–364
Funayama M, Hasegawa K, Kowa H, Saito M Tsuji S, Obata F (2002) A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 51:296–301
Goedde R, Sawcer S, Boehringer S, Miterski B, Sindern E, Haupts M, Schimrigk S, Compston A, Epplen JT (2002) A genome screen for linkage disequilibrium in HLA-DRB1*15-positive Germans with multiple sclerosis based on 4666 microsatellite markers. Hum Genet 111:270–277
Hedrick PW (1987) Gametic disequilibrium measures, proceed with caution. Genetics 117:331–341
Henner J, Poncet P-A, Guérin G, Hagger C, Stranzinger G, Rieder S (2002) Genetic mapping of the (G)-locus, responsible for the coat color phenotype “progressive greying with age” in horses (Equus caballus). Mamm Genome 13:535–537
Hill EW, Bradley DG, Al-Barody M, Ertugrul O, Splan RK, Zakharov I, Cunningham EP (2002) History and integrity of Thoroughbred dam lines revealed in equine mtDNA variation. Anim Genet 33:287–294
Hyun C, Filippich LJ, Lea RA, Shepherd G, Hughes IP, Griffiths LR (2003) Prospects for whole genome linkage disequilibrium mapping in domestic dog breeds. Mamm Genome 14:640–649
Leeb T, Vogl C, Zhu B, de Jong PJ, Binns MM, Chowdhary BP, Scharfe M, Jarek M, Nordsiek G, Schrader F, Blocker H (2006) A human–horse comparative map based on equine BAC end sequences. Genomics 87:772–776
Lewontin RC (1964) The interaction of selection and linkage II, Optimal model. Genetics 50:757–782
Locke MM, Ruth LS, Millon LV, Penedo MC, Murray JD, Bowling AT (2001) The cream dilution gene, responsible for the palomino and buckskin coat colours, maps to horse chromosome 21. Anim Genet 32:340–243
Locke MM, Penedo MCT, SJ Bricker SJ, Millon LV, Murray JD (2002) Linkage of the grey coat colour locus to microsatellites on horse chromosome 25. Anim Genet 33:329–337
McRae AF, McEwan JC, Dodds KG, Wilson T, Crawford AM, Slate J (2002) Linkage disequilibrium in domestic sheep. Genetics 160:1113–1122
Odani M, Narita A, Watanabe T, Yokouchi K, Sugimoto Y, Fujita T, Oguni T, Matsumoto M, Sasaki Y (2006) Genome-wide linkage disequilibrium in two Japanese beef cattle breeds. Anim Genet 37:139–144
Penedo MC, Millon LV, Bernoco D, Bailey E, Binns M, Cholewinski G, Ellis N, Flynn J, Gralak B, Guthrie A, Hasegawa T, Lindgren G, Lyons LA, Roed KH, Swinburne JE, Tozaki T (2005) International equine gene mapping workshop report: a comprehensive linkage map constructed with data from new markers and by merging four mapping resources. Cytogenet Genome Res 111:5–15
Rahman N, Dunstan M, Teare MD, Hank S, Douglas J, Coleman K, Bottomly WE, Campbell ME, Berglund B, Nordenskjold M, Forssell B, Burrows N, Lunt P, Young I, Williams N, Bignell GR, Futreal PA, Pope FM (2003) Ehlers-Danlos syndrome with severe early-onset periodontal disease (EDS-VIII) is a distinct, heterogeneous disorder with one predisposition gene at chromosome 12p13. Am J Hum Genet 73:198–204
Rieder S, Taourit S, Mariat D, Langlois B, Guérin G (2001) Mutations in the agouti (ASIP), the extention (MC1R), and the brown (TYRP1) loci and their association to coat phenotypes in horses (Equus caballus). Mamm Genome 12:450–455
Swinburne JE, Hopkins A, Binns M (2002) Assignment of the horse grey coat colour gene to ECA25 using whole genome scanning. Anim Genet 33:338–342
Swinburne JE, Boursnell M, Hill G, Pettitt L, Allen T, Chowdhary B, Hasegawa T, Kurosawa M Leeb T, Mashima S, Mickelson JR, Raudsepp T, Tozaki T, Binns M (2006) Single linkage group per chromosome genetic linkage map for the horse, based on two three-generation, full-sibling, crossbred horse reference families. Genomics 87:1–29
Tamiya G, Shinya M, Imanishi T, Ikuta T, Makino S, Okamoto K, Furugaki K, Matsumoto T, Mano S, Ando S, Nozaki Y, Yukawa W, Nakashige R, Yamaguchi D, Ishibashi H, Yonekura M, Nakami Y, Takayama S, Endo T, Saruwatari T, Yagura M, Yoshikawa Y, Fujimoto K, Oka A, Chiku S, Linsen SE, Giphart MJ, Kulski JK, Fukazawa T, Hashimoto H, Kimura M, Hoshina Y, Suzuki Y, Hotta T, Mochida J, Minezaki T, Komai K, Shiozawa S, Taniguchi A, Yamanaka H, Kamatani N, Gojobori T, Bahram S, Inoko H (2005) Whole genome association study of rheumatoid arthritis using 27039 microsatellites. Hum Mol Genet 14:2305–2321
Terry RB, Archer S, Brooks S, Bernoco D, Bailey E (2004) Assignment of the appaloosa coat colour gene (LP) to equine chromosome 1. Anim Genet 35:134–137
Toda T, Momose Y, Murata M, Tamiya G, Yamamoto M, Hattori N, Inoko H (2003) Toward identification of susceptibility genes for sporadic Parkinson’s disease. J Neurol 250(Suppl 3):III40–III43
Tozaki T, Mashima S, Hirota K, Miura N, Choi-Miura N, Tomita M (2001) Characterization of equine microsatellites and microsatellite-linked repetitive elements (eMLREs) by efficient cloning and genotyping methods. DNA Res 8:33–45
Tozaki T, Penedo MC, Oliveira RP, Katz JP, Millon LV, Ward T, Pettigrew DC, Brault LS, Tomita M, Kurosawa M, Hasegawa T, Hirota K (2004) Isolation, characterization and chromosome assignment of 341 newly isolated equine TKY microsatellite markers. Anim Genet 35:487–496
Tozaki T, Hirota K, Hasegawa T, Tomita M, Kurosawa M (2005) Prospects for whole genome linkage disequilibrium mapping in Thoroughbreds. Gene 14:127–132
Tozaki T, Swinburne J, Hirota K, Hasegawa T, Ishida N, Tobe T (2007) Improved resolution of the comparative horse–human map: investigating markers with in silico and linkage mapping approaches. Gene (in press)
Valdes AM, Thomson G (1997) Detecting disease-predisposing variants: the haplotype method. Am J Hum Genet 60:703–716
van Swieten JC, Brusse E, de Graaf BM, Krieger E, van de Graaf R, de Koning I, Maat-Kievit A, Leegwater P, Dooijes D, Oostra BA, Heutink P (2003) A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia. Am J Hum Genet 72:191–199
Wagner H-J, Reissmann M (2000) New polymorphism detected in the horse MC1R gene. Anim Genet 31:289–290
Acknowledgments
We thank Keiko Tanaka (Laboratory of Racing Chemistry) for expert technical assistance. We would also like to thank the Japan Racing Association, which provided samples from horses for this study and supported it with a grant-in-aid (2005–2006).
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by S. Hohmann.
Rights and permissions
About this article
Cite this article
Tozaki, T., Hirota, Ki., Hasegawa, T. et al. Whole-genome linkage disequilibrium screening for complex traits in horses. Mol Genet Genomics 277, 663–672 (2007). https://doi.org/10.1007/s00438-007-0216-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00438-007-0216-2