The genetic consequences of dog breed formation-Accumulation of deleterious genetic variation and fixation of mutations associated with myxomatous mitral valve disease in cavalier King Charles spaniels

PLoS Genet. 2021 Sep 2;17(9):e1009726. doi: 10.1371/journal.pgen.1009726. eCollection 2021 Sep.


Selective breeding for desirable traits in strictly controlled populations has generated an extraordinary diversity in canine morphology and behaviour, but has also led to loss of genetic variation and random entrapment of disease alleles. As a consequence, specific diseases are now prevalent in certain breeds, but whether the recent breeding practice led to an overall increase in genetic load remains unclear. Here we generate whole genome sequencing (WGS) data from 20 dogs per breed from eight breeds and document a ~10% rise in the number of derived alleles per genome at evolutionarily conserved sites in the heavily bottlenecked cavalier King Charles spaniel breed (cKCs) relative to in most breeds studied here. Our finding represents the first clear indication of a relative increase in levels of deleterious genetic variation in a specific breed, arguing that recent breeding practices probably were associated with an accumulation of genetic load in dogs. We then use the WGS data to identify candidate risk alleles for the most common cause for veterinary care in cKCs-the heart disease myxomatous mitral valve disease (MMVD). We verify a potential link to MMVD for candidate variants near the heart specific NEBL gene in a dachshund population and show that two of the NEBL candidate variants have regulatory potential in heart-derived cell lines and are associated with reduced NEBL isoform nebulette expression in papillary muscle (but not in mitral valve, nor in left ventricular wall). Alleles linked to reduced nebulette expression may hence predispose cKCs and other breeds to MMVD via loss of papillary muscle integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Dog Diseases / genetics*
  • Dogs / genetics*
  • Electrophoretic Mobility Shift Assay
  • Gene Expression
  • Genetic Variation*
  • Heart Valve Diseases / genetics
  • Heart Valve Diseases / veterinary*
  • Mitral Valve / pathology*
  • Mutation*

Grants and funding

Funding from Elanco (previously Novartis Animal Health) to KLT covered the generation of WGS data and parts of EA’s salary. Elanco (previously Novartis Animal Health) influenced the choice of dog breeds sequenced in this study, participated in data analysis and edited and reviewed the manuscript. Two grants from the Agria and SKK Research Foundation, one to IL (19969) and one to RH (P2011-0021), provided funding for sampling of dogs. EA was funded by a grant from the Swedish Research council (2016-03826) and a grant from FORMAS (2016-01312), both of which contributed to EA’s salary. KLT is a Distinguished Professor at the Swedish Research Council (D0816101). PB’s salary was funded by a Novartis postdoctoral fellowship ( With the exception of Elanco (see above) the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.