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.
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 cer...
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2021
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oai:doaj.org-article:bc00abd03f7a4a5eb45034df9811c21d2021-12-02T20:03:04ZThe 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.1553-73901553-740410.1371/journal.pgen.1009726https://doaj.org/article/bc00abd03f7a4a5eb45034df9811c21d2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009726https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Selective 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.Erik AxelssonIngrid LjungvallPriyasma BhoumikLaura Bas ConnEva MurenÅsa OhlssonLisbeth Høier OlsenKarolina EngdahlRagnvi HagmanJeanette HansonDmytro KryvokhyzhaMats PetterssonOlivier GrenetJonathan MoggsAlberto Del Rio-EspinolaChristian EpeBruce TaillonNilesh TawariShrinivas ManeTroy HawkinsÅke HedhammarPhilippe GruetJens HäggströmKerstin Lindblad-TohPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 9, p e1009726 (2021) |
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| collection |
DOAJ |
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Genetics QH426-470 |
| spellingShingle |
Genetics QH426-470 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 Hawkins Åke Hedhammar Philippe Gruet Jens Häggström Kerstin Lindblad-Toh 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. |
| description |
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. |
| format |
article |
| author |
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 Hawkins Åke Hedhammar Philippe Gruet Jens Häggström Kerstin Lindblad-Toh |
| author_facet |
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 Hawkins Åke Hedhammar Philippe Gruet Jens Häggström Kerstin Lindblad-Toh |
| author_sort |
Erik Axelsson |
| title |
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. |
| title_short |
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. |
| title_full |
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. |
| title_fullStr |
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. |
| title_full_unstemmed |
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. |
| title_sort |
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. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/bc00abd03f7a4a5eb45034df9811c21d |
| work_keys_str_mv |
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