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FGF4 retrogene on CFA12 is responsible for chondrodystrophy and intervertebral disc disease in dogs

  1. Danika L. Bannascha,d,1
  1. aDepartment of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA 95616;
  2. bDepartment of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616;
  3. cDepartment of Animal Science, University of California, Davis, CA 95616;
  4. dGenome Center, University of California, Davis, CA 95616;
  5. eBarney and Russum Animal Clinic, Fairfield, CA 94533;
  6. fDepartment of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843
  1. Edited by Harris A. Lewin, University of California, Davis, CA, and approved September 18, 2017 (received for review June 2, 2017)

Significance

Chondrodystrophy, characterized by short limbs and intervertebral disc disease (IVDD), is a common phenotype in many of the most popular dog breeds, including the dachshund, beagle, and French bulldog. Here, we report the identification of a FGF4 retrogene insertion on chromosome 12, the second FGF4 retrogene reported in the dog, as responsible for chondrodystrophy and IVDD. Identification of the causative mutation for IVDD will impact an incredibly large proportion of the dog population and provides a model for IVDD in humans, as FGF-associated mutations are responsible for IVDD and short stature in human achondroplasia. This is a report of a second retrogene copy of the same parental gene, each causing complementary disease phenotypes in a mammalian species.

Abstract

Chondrodystrophy in dogs is defined by dysplastic, shortened long bones and premature degeneration and calcification of intervertebral discs. Independent genome-wide association analyses for skeletal dysplasia (short limbs) within a single breed (PBonferroni = 0.01) and intervertebral disc disease (IVDD) across breeds (PBonferroni = 4.0 × 10?10) both identified a significant association to the same region on CFA12. Whole genome sequencing identified a highly expressed FGF4 retrogene within this shared region. The FGF4 retrogene segregated with limb length and had an odds ratio of 51.23 (95% CI = 46.69, 56.20) for IVDD. Long bone length in dogs is a unique example of multiple disease-causing retrocopies of the same parental gene in a mammalian species. FGF signaling abnormalities have been associated with skeletal dysplasia in humans, and our findings present opportunities for both selective elimination of a medically and financially devastating disease in dogs and further understanding of the ever-growing complexity of retrogene biology.

Footnotes

  • ?1To whom correspondence should be addressed. Email: dlbannasch{at}ucdavis.edu.
  • Author contributions: E.A.B. and D.L.B. designed research; E.A.B., P.J.D., T.M., B.K.S., M.A., A.E.Y., C.K., J.L., C.L.E., and D.L.B. performed research; P.J.D., B.K.S., S.V., R.P., C.T.B., T.R., and D.L.B. contributed new reagents/analytic tools; E.A.B. and D.L.B. analyzed data; and E.A.B., P.J.D., and D.L.B. wrote the paper.

  • Conflict of interest statement: The University of California, Davis, has filed a provisional patent entitled: “Methods of Diagnosing Intervertebral Disc Disease and Chondrodystrophy in Canines,” on May 30, 2017.

  • This article is a PNAS Direct Submission.

  • Data deposition: The sequence data reported in this paper has been deposited in the Sequence Read Archive (SRA Bioproject no. PRJNA377155) and in the GenBank database (accession nos. MF040221 and MF040222).

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1709082114/-/DCSupplemental.

This is an open access article distributed under the PNAS license.

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