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: [+ correction]
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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 : [+ correction]. / Axelsson, Erik; Ljungvall, Ingrid; Bhoumik, Priyasma; Conn, Laura Bas; Muren, Eva; Ohlsson, Åsa; Olsen, Lisbeth Høier; 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; Hedhammar, Åke; Gruet, Philippe; Häggström, Jens; Lindblad-Toh, Kerstin.
In: PLOS Genetics, Vol. 17, No. 9, e1009726, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - 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
T2 - [+ correction]
AU - Axelsson, Erik
AU - Ljungvall, Ingrid
AU - Bhoumik, Priyasma
AU - Conn, Laura Bas
AU - Muren, Eva
AU - Ohlsson, Åsa
AU - Olsen, Lisbeth Høier
AU - Engdahl, Karolina
AU - Hagman, Ragnvi
AU - Hanson, Jeanette
AU - Kryvokhyzha, Dmytro
AU - Pettersson, Mats
AU - Grenet, Olivier
AU - Moggs, Jonathan
AU - Del Rio-Espinola, Alberto
AU - Epe, Christian
AU - Taillon, Bruce
AU - Tawari, Nilesh
AU - Mane, Shrinivas
AU - Hawkins, Troy
AU - Hedhammar, Åke
AU - Gruet, Philippe
AU - Häggström, Jens
AU - Lindblad-Toh, Kerstin
N1 - Correction: 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 DOI: 10.1371/journal.pgen.1010039 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.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
UR - https://doi.org/10.1371/journal.pgen.1010039
U2 - 10.1371/journal.pgen.1009726
DO - 10.1371/journal.pgen.1009726
M3 - Journal article
C2 - 34473707
AN - SCOPUS:85114433751
VL - 17
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 9
M1 - e1009726
ER -
ID: 279636331