Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Efficient mapping of mendelian traits in dogs through genome-wide association


With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with 27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only 20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of 100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genome structure in dog breeds determined using a genome-wide 27,000 SNP array.
Figure 2: Genome-wide association mapping of two mendelian-inherited traits.
Figure 3: Fine-mapping of coat color in boxers and bull terriers.
Figure 4: Alleles by breed for the two candidate mutations.


  1. Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005).

    Article  CAS  Google Scholar 

  2. Sutter, N.B. et al. Extensive and breed-specific linkage disequilibrium in Canis familiaris. Genome Res. 14, 2388–2396 (2004).

    Article  CAS  Google Scholar 

  3. Wade, C.M., Karlsson, E.K., Mikkelsen, T.S., Zody, M.C. & Lindblad-Toh, K. The dog genome: sequence, evolution and haplotype structure. in The Dog and Its Genome (eds. Ostrander, E.A., Giger, U. & Lindblad-Toh, K.) 179–207 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2006).

    Google Scholar 

  4. Hartl, D.L. & Clark, A.G. Principles of Population Genetics (Sinauer Associates, Sunderland, MA, 2007).

  5. Keinan, A., Mullikin, J.C., Patterson, N. & Reich, D. Measurement of the human allele frequency spectrum demonstrates greater genetic drift in East Asians than in Europeans. Nat. Genet. 39, 1251–1255 (2007).

    Article  CAS  Google Scholar 

  6. Parker, H.G. et al. Genetic structure of the purebred domestic dog. Science 304, 1160–1164 (2004).

    Article  CAS  Google Scholar 

  7. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    Article  Google Scholar 

  8. Hillbertz, N.H. & Andersson, G. Autosomal dominant mutation causing the dorsal ridge predisposes for dermoid sinus in Rhodesian ridgeback dogs. J. Small Anim. Pract. 47, 184–188 (2006).

    Article  Google Scholar 

  9. Copp, A.J., Greene, N.D. & Murdoch, J.N. The genetic basis of mammalian neurulation. Nat. Rev. Genet. 4, 784–793 (2003).

    Article  Google Scholar 

  10. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  11. Karabagli, H., Karabagli, P., Ladher, R.K. & Schoenwolf, G.C. Comparison of the expression patterns of several fibroblast growth factors during chick gastrulation and neurulation. Anat. Embryol. (Berl.) 205, 365–370 (2002).

    Article  CAS  Google Scholar 

  12. Ladher, R.K., Wright, T.J., Moon, A.M., Mansour, S.L. & Schoenwolf, G.C. FGF8 initiates inner ear induction in chick and mouse. Genes Dev. 19, 603–613 (2005).

    Article  CAS  Google Scholar 

  13. Salmon Hillbertz, N.H.C. et al. A duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Nat. Genet. advance online publication 30 September 2007 (doi:10:1038/ng.2007.4).

  14. Dourmishev, A.L., Dourmishev, L.A., Schwartz, R.A. & Janniger, C.K. Waardenburg syndrome. Int. J. Dermatol. 38, 656–663 (1999).

    Article  CAS  Google Scholar 

  15. Tietz, W. A syndrome of deaf-mutism associated with albinism showing dominant autosomal inheritance. Am. J. Hum. Genet. 15, 259–264 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Little, C.C. The Inheritance of Coat Color in Dogs (Comstock Publishing Associates, Ithaca, NY, 1957).

  17. Metallinos, D. & Rine, J. Exclusion of EDNRB and KIT as the basis for white spotting in Border Collies. Genome Biol. 1 research0004.1–research0004.4 (2000).

  18. van Hagen, M.A. et al. Analysis of the inheritance of white spotting and the evaluation of KIT and EDNRB as spotting loci in Dutch boxer dogs. J. Hered. 95, 526–531 (2004).

    Article  CAS  Google Scholar 

  19. Smith, S.D., Kelley, P.M., Kenyon, J.B. & Hoover, D. Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF. J. Med. Genet. 37, 446–448 (2000).

    Article  CAS  Google Scholar 

  20. Tassabehji, M., Newton, V.E. & Read, A.P. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat. Genet. 8, 251–255 (1994).

    Article  CAS  Google Scholar 

  21. Steingrimsson, E., Copeland, N.G. & Jenkins, N.A. Melanocytes and the microphthalmia transcription factor network. Annu. Rev. Genet. 38, 365–411 (2004).

    Article  CAS  Google Scholar 

  22. Widlund, H.R. & Fisher, D.E. Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival. Oncogene 22, 3035–3041 (2003).

    Article  CAS  Google Scholar 

  23. Levy, C., Khaled, M. & Fisher, D.E. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol. Med. 12, 406–414 (2006).

    Article  CAS  Google Scholar 

  24. Saito, H. et al. Melanocyte-specific microphthalmia-associated transcription factor isoform activates its own gene promoter through physical interaction with lymphoid-enhancing factor 1. J. Biol. Chem. 277, 28787–28794 (2002).

    Article  CAS  Google Scholar 

  25. Jacquemin, P. et al. The transcription factor onecut-2 controls the microphthalmia-associated transcription factor gene. Biochem. Biophys. Res. Commun. 285, 1200–1205 (2001).

    Article  CAS  Google Scholar 

  26. Bondurand, N. et al. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Hum. Mol. Genet. 9, 1907–1917 (2000).

    Article  CAS  Google Scholar 

  27. Udono, T. et al. Structural organization of the human microphthalmia-associated transcription factor gene containing four alternative promoters. Biochim. Biophys. Acta 1491, 205–219 (2000).

    Article  CAS  Google Scholar 

  28. Burns, M. & Fraser, M.N. Genetics of the Dog: the Basis of Successful Breeding (Oliver & Boyd, Edinburgh, London, 1966).

    Google Scholar 

  29. Motohashi, H., Hozawa, K., Oshima, T., Takeuchi, T. & Takasaka, T. Dysgenesis of melanocytes and cochlear dysfunction in mutant microphthalmia (mi) mice. Hear. Res. 80, 10–20 (1994).

    Article  CAS  Google Scholar 

  30. Yoshida, H., Kunisada, T., Kusakabe, M., Nishikawa, S. & Nishikawa, S.I. Distinct stages of melanocyte differentiation revealed by analysis of nonuniform pigmentation patterns. Development 122, 1207–1214 (1996).

    CAS  PubMed  Google Scholar 

  31. Strain, G.M. Deafness prevalence and pigmentation and gender associations in dog breeds at risk. Vet. J. 167, 23–32 (2004).

    Article  Google Scholar 

  32. Jordan, S.A. & Jackson, I.J. A late wave of melanoblast differentiation and rostrocaudal migration revealed in patch and rump-white embryos. Mech. Dev. 92, 135–143 (2000).

    Article  CAS  Google Scholar 

  33. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  34. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  35. Felsenstein, J. PHYLIP, phylogeny inference package (version 3.2). Cladistics 5, 164–166 (1989).

    Google Scholar 

  36. Karolchik, D. et al. The UCSC Genome Browser Database. Nucleic Acids Res. 31, 51–54 (2003).

    Article  CAS  Google Scholar 

Download references


We thank the Genetic Analysis Platform at the Broad Institute of MIT and Harvard for performing the SNP array genotyping, and L. Gaffney for assistance with figures. The work was supported by the AKC/Canine Health Foundation (grant 373), the Foundation for Strategic Research, and the Donald and Jo Ann Petersen Endowed Research Fund of the University of Michigan Comprehensive Cancer Center.

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Elinor K Karlsson, Leif Andersson or Kerstin Lindblad-Toh.

Supplementary information

Supplementary Text and Figures

Supp Tables 1–3, Supp Figures 1–4, Supp Methods (PDF 4574 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Karlsson, E., Baranowska, I., Wade, C. et al. Efficient mapping of mendelian traits in dogs through genome-wide association. Nat Genet 39, 1321–1328 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing