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Research article - Peer-reviewed, 2021

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

Axelsson, Erik; Ljungvall, Ingrid; Bhoumik, Priyasma; Conn, Laura Bas; Muren, Eva; Ohlsson, Asa; Olsen, Lisbeth Hoier; Engdahl, Karolina; Hagman, Ragnvi; Hanson, Jeanette; Kryvokhyzha, Dmytro; Pettersson, Mats; Grenet, Olivier; Moggs, Jonathan; Del Rio-Espinola, Alberto; Epe, Christian; Taillon, Bruce; Tawari, Nilesh; Mane, Shrinivas; Hawkins, Troy;
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Abstract

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 similar to 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 heartderived 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.

Published in

PLOS GENETICS

2021, volume: 17, number: 9
Publisher: PUBLIC LIBRARY SCIENCE

Authors' information

Axelsson, Erik
Uppsala University
Swedish University of Agricultural Sciences, Department of Clinical Sciences
Bhoumik, Priyasma
ETH Zurich
Conn, Laura Bas
Uppsala University
Muren, Eva
Uppsala University
Swedish University of Agricultural Sciences, Department of Animal Breeding and Genetics
Olsen, Lisbeth Hoier
University of Copenhagen
Swedish University of Agricultural Sciences, Department of Clinical Sciences
Swedish University of Agricultural Sciences, Department of Clinical Sciences
Swedish University of Agricultural Sciences, Department of Clinical Sciences
Kryvokhyzha, Dmytro
Uppsala University
Pettersson, Mats
Uppsala University
Grenet, Olivier
Novartis
Moggs, Jonathan
Novartis
Del Rio-Espinola, Alberto
Novartis
Epe, Christian
Boehringer Ingelheim
Taillon, Bruce
Elanco Animal Health
Tawari, Nilesh
Elanco Animal Health
Mane, Shrinivas
Elanco Animal Health
Hawkins, Troy
Elanco Animal Health
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UKÄ Subject classification

Animal and Dairy Science

Publication Identifiers

DOI: https://doi.org/10.1371/journal.pgen.1009726

URI (permanent link to this page)

https://res.slu.se/id/publ/113588