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

Erik Axelsson, Ingrid Ljungvall, Priyasma Bhoumik, Laura Bas Conn, Eva Muren, Åsa Ohlsson, Lisbeth Høier Olsen, Karolina Engdahl, Ragnvi Hagman, Jeanette Hanson, Dmytro Kryvokhyzha, Mats Pettersson, Olivier Grenet, Jonathan Moggs, Alberto Del Rio-Espinola, Christian Epe, Bruce Taillon, Nilesh Tawari, Shrinivas Mane, Troy HawkinsÅke Hedhammar, Philippe Gruet, Jens Häggström, Kerstin Lindblad-Toh

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

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 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.

Originalspråkengelska
Artikelnummere1009726
Sidor (från-till)1-34
TidskriftPLoS Genetics
Volym17
Utgåva9
DOI
StatusPublished - 2021
Externt publiceradJa

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Publisher Copyright:
© 2021 Axelsson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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