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Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture

Anterior cruciate ligament (ACL) rupture is an important condition of the human knee. Second ruptures are common and societal costs are substantial. Canine cranial cruciate ligament (CCL) rupture closely models the human disease. CCL rupture is common in the Labrador Retriever (5.79% prevalence), ~1...

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Autores principales: Binversie, Emily E., Baker, Lauren A., Engelman, Corinne D., Hao, Zhengling, Moran, John J., Piazza, Alexander M., Sample, Susannah J., Muir, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774950/
https://www.ncbi.nlm.nih.gov/pubmed/33382735
http://dx.doi.org/10.1371/journal.pone.0244075
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author Binversie, Emily E.
Baker, Lauren A.
Engelman, Corinne D.
Hao, Zhengling
Moran, John J.
Piazza, Alexander M.
Sample, Susannah J.
Muir, Peter
author_facet Binversie, Emily E.
Baker, Lauren A.
Engelman, Corinne D.
Hao, Zhengling
Moran, John J.
Piazza, Alexander M.
Sample, Susannah J.
Muir, Peter
author_sort Binversie, Emily E.
collection PubMed
description Anterior cruciate ligament (ACL) rupture is an important condition of the human knee. Second ruptures are common and societal costs are substantial. Canine cranial cruciate ligament (CCL) rupture closely models the human disease. CCL rupture is common in the Labrador Retriever (5.79% prevalence), ~100-fold more prevalent than in humans. Labrador Retriever CCL rupture is a polygenic complex disease, based on genome-wide association study (GWAS) of single nucleotide polymorphism (SNP) markers. Dissection of genetic variation in complex traits can be enhanced by studying structural variation, including copy number variants (CNVs). Dogs are an ideal model for CNV research because of reduced genetic variability within breeds and extensive phenotypic diversity across breeds. We studied the genetic etiology of CCL rupture by association analysis of CNV regions (CNVRs) using 110 case and 164 control Labrador Retrievers. CNVs were called from SNPs using three different programs (PennCNV, CNVPartition, and QuantiSNP). After quality control, CNV calls were combined to create CNVRs using ParseCNV and an association analysis was performed. We found no strong effect CNVRs but found 46 small effect (max(T) permutation P<0.05) CCL rupture associated CNVRs in 22 autosomes; 25 were deletions and 21 were duplications. Of the 46 CCL rupture associated CNVRs, we identified 39 unique regions. Thirty four were identified by a single calling algorithm, 3 were identified by two calling algorithms, and 2 were identified by all three algorithms. For 42 of the associated CNVRs, frequency in the population was <10% while 4 occurred at a frequency in the population ranging from 10–25%. Average CNVR length was 198,872bp and CNVRs covered 0.11 to 0.15% of the genome. All CNVRs were associated with case status. CNVRs did not overlap previous canine CCL rupture risk loci identified by GWAS. Associated CNVRs contained 152 annotated genes; 12 CNVRs did not have genes mapped to CanFam3.1. Using pathway analysis, a cluster of 19 homeobox domain transcript regulator genes was associated with CCL rupture (P = 6.6E-13). This gene cluster influences cranial-caudal body pattern formation during embryonic limb development. Clustered genes were found in 3 CNVRs on chromosome 14 (HoxA), 28 (NKX6-2), and 36 (HoxD). When analysis was limited to deletion CNVRs, the association was strengthened (P = 8.7E-16). This study suggests a component of the polygenic risk of CCL rupture in Labrador Retrievers is associated with small effect CNVs and may include aspects of stifle morphology regulated by homeobox domain transcript regulator genes.
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spelling pubmed-77749502021-01-11 Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture Binversie, Emily E. Baker, Lauren A. Engelman, Corinne D. Hao, Zhengling Moran, John J. Piazza, Alexander M. Sample, Susannah J. Muir, Peter PLoS One Research Article Anterior cruciate ligament (ACL) rupture is an important condition of the human knee. Second ruptures are common and societal costs are substantial. Canine cranial cruciate ligament (CCL) rupture closely models the human disease. CCL rupture is common in the Labrador Retriever (5.79% prevalence), ~100-fold more prevalent than in humans. Labrador Retriever CCL rupture is a polygenic complex disease, based on genome-wide association study (GWAS) of single nucleotide polymorphism (SNP) markers. Dissection of genetic variation in complex traits can be enhanced by studying structural variation, including copy number variants (CNVs). Dogs are an ideal model for CNV research because of reduced genetic variability within breeds and extensive phenotypic diversity across breeds. We studied the genetic etiology of CCL rupture by association analysis of CNV regions (CNVRs) using 110 case and 164 control Labrador Retrievers. CNVs were called from SNPs using three different programs (PennCNV, CNVPartition, and QuantiSNP). After quality control, CNV calls were combined to create CNVRs using ParseCNV and an association analysis was performed. We found no strong effect CNVRs but found 46 small effect (max(T) permutation P<0.05) CCL rupture associated CNVRs in 22 autosomes; 25 were deletions and 21 were duplications. Of the 46 CCL rupture associated CNVRs, we identified 39 unique regions. Thirty four were identified by a single calling algorithm, 3 were identified by two calling algorithms, and 2 were identified by all three algorithms. For 42 of the associated CNVRs, frequency in the population was <10% while 4 occurred at a frequency in the population ranging from 10–25%. Average CNVR length was 198,872bp and CNVRs covered 0.11 to 0.15% of the genome. All CNVRs were associated with case status. CNVRs did not overlap previous canine CCL rupture risk loci identified by GWAS. Associated CNVRs contained 152 annotated genes; 12 CNVRs did not have genes mapped to CanFam3.1. Using pathway analysis, a cluster of 19 homeobox domain transcript regulator genes was associated with CCL rupture (P = 6.6E-13). This gene cluster influences cranial-caudal body pattern formation during embryonic limb development. Clustered genes were found in 3 CNVRs on chromosome 14 (HoxA), 28 (NKX6-2), and 36 (HoxD). When analysis was limited to deletion CNVRs, the association was strengthened (P = 8.7E-16). This study suggests a component of the polygenic risk of CCL rupture in Labrador Retrievers is associated with small effect CNVs and may include aspects of stifle morphology regulated by homeobox domain transcript regulator genes. Public Library of Science 2020-12-31 /pmc/articles/PMC7774950/ /pubmed/33382735 http://dx.doi.org/10.1371/journal.pone.0244075 Text en © 2020 Binversie et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Binversie, Emily E.
Baker, Lauren A.
Engelman, Corinne D.
Hao, Zhengling
Moran, John J.
Piazza, Alexander M.
Sample, Susannah J.
Muir, Peter
Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture
title Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture
title_full Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture
title_fullStr Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture
title_full_unstemmed Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture
title_short Analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture
title_sort analysis of copy number variation in dogs implicates genomic structural variation in the development of anterior cruciate ligament rupture
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774950/
https://www.ncbi.nlm.nih.gov/pubmed/33382735
http://dx.doi.org/10.1371/journal.pone.0244075
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