Cargando…
Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs
Congenital laryngeal paralysis (CLP) is an inherited disorder that affects the ability of the dog to exercise and precludes it from functioning as a working sled dog. Though CLP is known to occur in Alaskan sled dogs (ASDs) since 1986, the genetic mutation underlying the disease has not been reporte...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9602090/ https://www.ncbi.nlm.nih.gov/pubmed/36292693 http://dx.doi.org/10.3390/genes13101808 |
_version_ | 1784817227067817984 |
---|---|
author | Srikanth, Krishnamoorthy von Pfeil, Dirsko J. F. Stanley, Bryden J. Griffitts, Caroline Huson, Heather J. |
author_facet | Srikanth, Krishnamoorthy von Pfeil, Dirsko J. F. Stanley, Bryden J. Griffitts, Caroline Huson, Heather J. |
author_sort | Srikanth, Krishnamoorthy |
collection | PubMed |
description | Congenital laryngeal paralysis (CLP) is an inherited disorder that affects the ability of the dog to exercise and precludes it from functioning as a working sled dog. Though CLP is known to occur in Alaskan sled dogs (ASDs) since 1986, the genetic mutation underlying the disease has not been reported. Using a genome-wide association study (GWAS), we identified a 708 kb region on CFA 18 harboring 226 SNPs to be significantly associated with CLP. The significant SNPs explained 47.06% of the heritability of CLP. We narrowed the region to 431 kb through autozygosity mapping and found 18 of the 20 cases to be homozygous for the risk haplotype. Whole genome sequencing of two cases and a control ASD, and comparison with the genome of 657 dogs from various breeds, confirmed the homozygous status of the risk haplotype to be unique to the CLP cases. Most of the dogs that were homozygous for the risk allele had blue eyes. Gene annotation and a gene-based association study showed that the risk haplotype encompasses genes implicated in developmental and neurodegenerative disorders. Pathway analysis showed enrichment of glycoproteins and glycosaminoglycans biosynthesis, which play a key role in repairing damaged nerves. In conclusion, our results suggest an important role for the identified candidate region in CLP. |
format | Online Article Text |
id | pubmed-9602090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96020902022-10-27 Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs Srikanth, Krishnamoorthy von Pfeil, Dirsko J. F. Stanley, Bryden J. Griffitts, Caroline Huson, Heather J. Genes (Basel) Article Congenital laryngeal paralysis (CLP) is an inherited disorder that affects the ability of the dog to exercise and precludes it from functioning as a working sled dog. Though CLP is known to occur in Alaskan sled dogs (ASDs) since 1986, the genetic mutation underlying the disease has not been reported. Using a genome-wide association study (GWAS), we identified a 708 kb region on CFA 18 harboring 226 SNPs to be significantly associated with CLP. The significant SNPs explained 47.06% of the heritability of CLP. We narrowed the region to 431 kb through autozygosity mapping and found 18 of the 20 cases to be homozygous for the risk haplotype. Whole genome sequencing of two cases and a control ASD, and comparison with the genome of 657 dogs from various breeds, confirmed the homozygous status of the risk haplotype to be unique to the CLP cases. Most of the dogs that were homozygous for the risk allele had blue eyes. Gene annotation and a gene-based association study showed that the risk haplotype encompasses genes implicated in developmental and neurodegenerative disorders. Pathway analysis showed enrichment of glycoproteins and glycosaminoglycans biosynthesis, which play a key role in repairing damaged nerves. In conclusion, our results suggest an important role for the identified candidate region in CLP. MDPI 2022-10-06 /pmc/articles/PMC9602090/ /pubmed/36292693 http://dx.doi.org/10.3390/genes13101808 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Srikanth, Krishnamoorthy von Pfeil, Dirsko J. F. Stanley, Bryden J. Griffitts, Caroline Huson, Heather J. Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs |
title | Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs |
title_full | Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs |
title_fullStr | Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs |
title_full_unstemmed | Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs |
title_short | Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs |
title_sort | genome wide association study with imputed whole genome sequence data identifies a 431 kb risk haplotype on cfa18 for congenital laryngeal paralysis in alaskan sled dogs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9602090/ https://www.ncbi.nlm.nih.gov/pubmed/36292693 http://dx.doi.org/10.3390/genes13101808 |
work_keys_str_mv | AT srikanthkrishnamoorthy genomewideassociationstudywithimputedwholegenomesequencedataidentifiesa431kbriskhaplotypeoncfa18forcongenitallaryngealparalysisinalaskansleddogs AT vonpfeildirskojf genomewideassociationstudywithimputedwholegenomesequencedataidentifiesa431kbriskhaplotypeoncfa18forcongenitallaryngealparalysisinalaskansleddogs AT stanleybrydenj genomewideassociationstudywithimputedwholegenomesequencedataidentifiesa431kbriskhaplotypeoncfa18forcongenitallaryngealparalysisinalaskansleddogs AT griffittscaroline genomewideassociationstudywithimputedwholegenomesequencedataidentifiesa431kbriskhaplotypeoncfa18forcongenitallaryngealparalysisinalaskansleddogs AT husonheatherj genomewideassociationstudywithimputedwholegenomesequencedataidentifiesa431kbriskhaplotypeoncfa18forcongenitallaryngealparalysisinalaskansleddogs |