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

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 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. 4

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

  5. 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).

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

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

    Article  Google Scholar 

  8. 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. 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. 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).

    CAS  Article  Google Scholar 

  11. 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).

    CAS  Article  Google Scholar 

  12. 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).

    CAS  Article  Google Scholar 

  13. 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. 14

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

    CAS  Article  Google Scholar 

  15. 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. 16

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

  17. 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. 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).

    CAS  Article  Google Scholar 

  19. 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).

    CAS  Article  Google Scholar 

  20. 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).

    CAS  Article  Google Scholar 

  21. 21

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

    CAS  Article  Google Scholar 

  22. 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).

    CAS  Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 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).

    CAS  Article  Google Scholar 

  25. 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).

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 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).

    CAS  Article  Google Scholar 

  28. 28

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

    Google Scholar 

  29. 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).

    CAS  Article  Google Scholar 

  30. 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. 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. 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).

    CAS  Article  Google Scholar 

  33. 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).

    CAS  Article  Google Scholar 

  34. 34

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

    CAS  Article  Google Scholar 

  35. 35

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

    Google Scholar 

  36. 36

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

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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

Affiliations

Authors

Corresponding authors

Correspondence to Elinor K Karlsson or 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). https://doi.org/10.1038/ng.2007.10

Download citation

Further reading

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing