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

Nature Genetics volume 39, pages 1321–1328 (2007)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Elinor K Karlsson, Claire M Wade, Michael C Zody, Nathan Anderson, Tara M Biagi, Nick Patterson, Edward J Kulbokas III, Jill P Mesirov, Eric S Lander & Kerstin Lindblad-Toh

  2. Bioinformatics Program, Boston University, 44 Cummington Street, Boston, 02215, Massachusetts, USA

    Elinor K Karlsson & Jill P Mesirov

  3. Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Biomedical centre, Box 597, Uppsala, SE-751 24, Sweden

    Izabella Baranowska, Nicolette H C Salmon Hillbertz, Göran Andersson & Leif Andersson

  4. Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Claire M Wade

  5. Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, Uppsala, SE-751 24, Sweden

    Gerli Rosengren Pielberg, Leif Andersson & Kerstin Lindblad-Toh

  6. Department of Urology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Kenine E Comstock & Evan T Keller

  7. Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, SE-750 07, Sweden

    Henrik von Euler & Åke Hedhammar

  8. Department of Medical Sciences, University Hospital, Uppsala University, Uppsala, SE-751 85, Sweden

    Olle Kämpe

  9. Whitehead Institute for Biomedical Research, Cambridge, 02142, Massachusetts, USA

    Eric S Lander

  10. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Eric S Lander

  11. Department of Systems Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Eric S Lander

Authors
  1. Elinor K Karlsson
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  2. Izabella Baranowska
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  3. Claire M Wade
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  12. Evan T Keller
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  13. Jill P Mesirov
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Corresponding authors

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

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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

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