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Science 325 (5943): 995-998

Copyright © 2009 by the American Association for the Advancement of Science

An Expressed Fgf4 Retrogene Is Associated with Breed-Defining Chondrodysplasia in Domestic Dogs

Heidi G. Parker,1 Bridgett M. VonHoldt,2 Pascale Quignon,1 Elliott H. Margulies,3 Stephanie Shao,1 Dana S. Mosher,1 Tyrone C. Spady,1 Abdel Elkahloun,1 Michele Cargill,4,* Paul G. Jones,5 Cheryl L. Maslen,6 Gregory M. Acland,7,8 Nathan B. Sutter,8 Keiichi Kuroki,9 Carlos D. Bustamante,10 Robert K. Wayne,2 Elaine A. Ostrander1,{dagger}

Abstract: Retrotransposition of processed mRNAs is a common source of novel sequence acquired during the evolution of genomes. Although the vast majority of retroposed gene copies, or retrogenes, rapidly accumulate debilitating mutations that disrupt the reading frame, a small percentage become new genes that encode functional proteins. By using a multibreed association analysis in the domestic dog, we demonstrate that expression of a recently acquired retrogene encoding fibroblast growth factor 4 (fgf4) is strongly associated with chondrodysplasia, a short-legged phenotype that defines at least 19 dog breeds including dachshund, corgi, and basset hound. These results illustrate the important role of a single evolutionary event in constraining and directing phenotypic diversity in the domestic dog.

1 Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2 Department of Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA.
3 Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
4 Affymetrix Corporation, 3420 Central Expressway, Santa Clara, CA 95051, USA.
5 The WALTHAM Centre for Pet Nutrition, Waltham on the Wolds, Leicestershire LE14 4RT, UK.
6 Division of Cardiovascular Medicine, Oregon Health and Science University, Portland, OR 97239, USA.
7 Baker Institute for Animal Health, Cornell University, Ithaca, NY 14853, USA.
8 College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
9 Comparative Orthopaedic Laboratory, University of Missouri, Columbia, MO 65211, USA.
10 Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA.

* Present address: Genetics Navigenics, Foster City, CA 94404, USA.

{dagger} To whom correspondence should be addressed. E-mail: eostrand{at}mail.nih.gov

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