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

Nature Genetics 39, 1321–1328 (2007) | Download Citation

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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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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

  1. Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), 7 Cambridge Center, Cambridge, Massachusetts 02142, 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, Massachusetts 02215, USA.

    • Elinor K Karlsson
    •  & Jill P Mesirov

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

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

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

    • Claire M Wade

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

    • Gerli Rosengren Pielberg
    • , Leif Andersson
    •  & Kerstin Lindblad-Toh

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

    • Kenine E Comstock
    •  & Evan T Keller

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

    • Henrik von Euler
    •  & Åke Hedhammar

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

    • Olle Kämpe

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

    • Eric S Lander

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

    • Eric S Lander

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

    • Eric S Lander

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

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DOI

https://doi.org/10.1038/ng.2007.10

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