The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Elaine A Ostrander - One of the best experts on this subject based on the ideXlab platform.
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Hair of the Dog: Identification of a Cis-Regulatory Module Predicted to Influence Canine Coat Composition
MDPI AG, 2019Co-Authors: Thad D. Whitaker, Elaine A OstranderAbstract:Each domestic Dog Breed is characterized by a strict set of physical and behavioral characteristics by which Breed members are judged and rewarded in conformation shows. One defining feature of particular interest is the coat, which is comprised of either a double- or single-layer of hair. The top coat contains coarse guard hairs and a softer undercoat, similar to that observed in wolves and assumed to be the ancestral state. The undercoat is absent in single-coated Breeds which is assumed to be the derived state. We leveraged single nucleotide polymorphism (SNP) array and whole genome sequence (WGS) data to perform genome-wide association studies (GWAS), identifying a locus on chromosome (CFA) 28 which is strongly associated with coat number. Using WGS data, we identified a locus of 18.4 kilobases containing 62 significant variants within the intron of a long noncoding ribonucleic acid (lncRNA) upstream of ADRB1. Multiple lines of evidence highlight the locus as a potential cis-regulatory module. Specifically, two variants are found at high frequency in single-coated Dogs and are rare in wolves, and both are predicted to affect transcription factor (TF) binding. This report is among the first to exploit WGS data for both GWAS and variant mapping to identify a Breed-defining trait
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genomic analyses reveal the influence of geographic origin migration and hybridization on modern Dog Breed development
Cell Reports, 2017Co-Authors: Heidi G Parker, Maud Rimbault, Dayna L Dreger, Brian W Davis, Alexandra B Mullen, Gretchen Carpinteroramirez, Elaine A OstranderAbstract:There are nearly 400 modern domestic Dog Breeds with a unique histories and genetic profiles. To track the genetic signatures of Breed development, we have assembled the most diverse dataset of Dog Breeds, reflecting their extensive phenotypic variation and heritage. Combining genetic distance, migration, and genome-wide haplotype sharing analyses, we uncover geographic patterns of development and independent origins of common traits. Our analyses reveal the hybrid history of Breeds and elucidate the effects of immigration, revealing for the first time a suggestion of New World Dog within some modern Breeds. Finally, we used cladistics and haplotype sharing to show that some common traits have arisen more than once in the history of the Dog. These analyses characterize the complexities of Breed development, resolving longstanding questions regarding individual Breed origination, the effect of migration on geographically distinct Breeds, and, by inference, transfer of trait and disease alleles among Dog Breeds.
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a genetic dissection of Breed composition and performance enhancement in the alaskan sled Dog
BMC Genetics, 2010Co-Authors: Heidi G Parker, Jonathan Runstadler, Heather J Huson, Elaine A OstranderAbstract:The Alaskan sled Dog offers a rare opportunity to investigate the development of a Dog Breed based solely on performance, rather than appearance, thus setting the Breed apart from most others. Several established Breeds, many of which are recognized by the American Kennel Club (AKC), have been introduced into the sled Dog population to enhance racing performance. We have used molecular methods to ascertain the constitutive Breeds used to develop successful sled Dog lines, and in doing so, determined the Breed origins of specific performance-related behaviors. One hundred and ninety-nine Alaskan sled Dogs were genotyped using 96 microsatellite markers that span the canine genome. These data were compared to that from 141 similarly genotyped purebred Dog Breeds. Sled Dogs were evaluated for Breed composition based on a variety of performance phenotypes including speed, endurance and work ethic, and the data stratified based on population structure. We observe that the Alaskan sled Dog has a unique molecular signature and that the genetic profile is sufficient for identifying Dogs bred for sprint versus distance. When evaluating contributions of existing Breeds we find that the Alaskan Malamute and Siberian Husky contributions are associated with enhanced endurance; Pointer and Saluki are associated with enhanced speed and the Anatolian Shepherd demonstrates a positive influence on work ethic. We have established a genetic Breed profile for the Alaskan sled Dog, identified profile variance between sprint and distance Dogs, and established Breeds associated with enhanced performance attributes. These data set the stage for mapping studies aimed at finding genes that are associated with athletic attributes integral to the high performing Alaskan sled Dog.
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A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote Dogs.
Public Library of Science (PLoS), 2007Co-Authors: Dana S Mosher, Cathryn S Mellersh, Heidi G Parker, Pascale Quignon, Nathan B Sutter, Carlos D Bustamante, Elaine A OstranderAbstract:Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin (MSTN) gene (previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet Dog Breed that results in a double-muscled phenotype known as the "bully" whippet. Individuals with this phenotype carry two copies of a two-base-pair deletion in the third exon of MSTN leading to a premature stop codon at amino acid 313. Individuals carrying only one copy of the mutation are, on average, more muscular than wild-type individuals (p = 7.43 x 10(-6); Kruskal-Wallis Test) and are significantly faster than individuals carrying the wild-type genotype in competitive racing events (Kendall's nonparametric measure, tau = 0.3619; p approximately 0.00028). These results highlight the utility of performance-enhancing polymorphisms, marking the first time a mutation in MSTN has been quantitatively linked to increased athletic performance
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a mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote Dogs
PLOS Genetics, 2005Co-Authors: Dana S Mosher, Cathryn S Mellersh, Heidi G Parker, Pascale Quignon, Carlos Bustamante, Nathan B Sutter, Elaine A OstranderAbstract:Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin (MSTN) gene (previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet Dog Breed that results in a double-muscled phenotype known as the “bully” whippet. Individuals with this phenotype carry two copies of a two-base-pair deletion in the third exon of MSTN leading to a premature stop codon at amino acid 313. Individuals carrying only one copy of the mutation are, on average, more muscular than wild-type individuals (p = 7.43 × 10−6; Kruskal-Wallis Test) and are significantly faster than individuals carrying the wild-type genotype in competitive racing events (Kendall's nonparametric measure, τ = 0.3619; p ≈ 0.00028). These results highlight the utility of performance-enhancing polymorphisms, marking the first time a mutation in MSTN has been quantitatively linked to increased athletic performance.
Cathryn S Mellersh - One of the best experts on this subject based on the ideXlab platform.
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an inversion disrupting fam134b is associated with sensory neuropathy in the border collie Dog Breed
G3: Genes Genomes Genetics, 2016Co-Authors: Oliver P. Forman, Rebekkah J. Hitti, Christopher A. Jenkins, Luisa De Risio, Louise Pettitt, Dennis P Obrien, Diane G Shelton, Rodrigo Gutierrez Quintana, Elsa Beltran, Cathryn S MellershAbstract:Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 Breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie Breed population.
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genome sequencing reveals a splice donor site mutation in the snx14 gene associated with a novel cerebellar cortical degeneration in the hungarian vizsla Dog Breed
BMC Genetics, 2016Co-Authors: Joe Fenn, Patrick J. Kenny, Mike Boursnell, Rebekkah J. Hitti, Christopher A. Jenkins, Rebecca L. Terry, Cathryn S Mellersh, Simon L Priestnall, Oliver P. FormanAbstract:Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many Dog Breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different Breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several Breeds, allowing screening for selective Breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas. Two full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one Dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one Dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both Dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population. This is the first report of CCD in Hungarian Vizsla Dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected.
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Missense Mutation in CAPN1 Is Associated with Spinocerebellar Ataxia in the Parson Russell Terrier Dog Breed
PloS one, 2013Co-Authors: Oliver P. Forman, Luisa De Risio, Cathryn S MellershAbstract:Spinocerebellar ataxia (SCA) in the Parson Russell Terrier (PRT) Dog Breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected Dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected Dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain), was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans.
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parallel mapping and simultaneous sequencing reveals deletions in bcan and fam83h associated with discrete inherited disorders in a domestic Dog Breed
PLOS Genetics, 2012Co-Authors: Oliver P. Forman, Jacques Penderis, Claudia Hartley, Louisa J Hayward, Sally L Ricketts, Cathryn S MellershAbstract:The domestic Dog (Canis familiaris) segregates more naturally-occurring diseases and phenotypic variation than any other species and has become established as an unparalled model with which to study the genetics of inherited traits. We used a genome-wide association study (GWAS) and targeted resequencing of DNA from just five Dogs to simultaneously map and identify mutations for two distinct inherited disorders that both affect a single Breed, the Cavalier King Charles Spaniel. We investigated episodic falling (EF), a paroxysmal exertion-induced dyskinesia, alongside the phenotypically distinct condition congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), commonly known as dry eye curly coat syndrome. EF is characterised by episodes of exercise-induced muscular hypertonicity and abnormal posturing, usually occurring after exercise or periods of excitement. CKCSID is a congenital disorder that manifests as a rough coat present at birth, with keratoconjunctivitis sicca apparent on eyelid opening at 10-14 days, followed by hyperkeratinisation of footpads and distortion of nails that develops over the next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a common set of 38 controls and identified statistically associated signals for EF and CKCSID on chromosome 7 (P(raw) 1.9×10(-14); P(genome) = 1.0×10(-5)) and chromosome 13 (P(raw) 1.2×10(-17); P(genome) = 1.0×10(-5)), respectively. We resequenced both the EF and CKCSID disease-associated regions in just five Dogs and identified a 15,724 bp deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in FAM83H associated with CKCSID. Neither BCAN or FAM83H have been associated with equivalent disease phenotypes in any other species, thus demonstrating the ability to use the domestic Dog to study the genetic basis of more than one disease simultaneously in a single Breed and to identify multiple novel candidate genes in parallel.
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A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote Dogs.
Public Library of Science (PLoS), 2007Co-Authors: Dana S Mosher, Cathryn S Mellersh, Heidi G Parker, Pascale Quignon, Nathan B Sutter, Carlos D Bustamante, Elaine A OstranderAbstract:Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin (MSTN) gene (previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet Dog Breed that results in a double-muscled phenotype known as the "bully" whippet. Individuals with this phenotype carry two copies of a two-base-pair deletion in the third exon of MSTN leading to a premature stop codon at amino acid 313. Individuals carrying only one copy of the mutation are, on average, more muscular than wild-type individuals (p = 7.43 x 10(-6); Kruskal-Wallis Test) and are significantly faster than individuals carrying the wild-type genotype in competitive racing events (Kendall's nonparametric measure, tau = 0.3619; p approximately 0.00028). These results highlight the utility of performance-enhancing polymorphisms, marking the first time a mutation in MSTN has been quantitatively linked to increased athletic performance
Heidi G Parker - One of the best experts on this subject based on the ideXlab platform.
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genetic analysis of the modern australian labradoodle Dog Breed reveals an excess of the poodle genome
PLOS Genetics, 2020Co-Authors: Heidi G Parker, Thad D. Whitaker, Muhammad Basil Ali, Jacquelyn M Evans, Jaemin Kim, Susan E Pearcekelling, Jocelyn Plassais, Qaiser Mahmood KhanAbstract:The genomic diversity of the domestic Dog is an invaluable resource for advancing understanding of mammalian biology, evolutionary biology, morphologic variation, and behavior. There are approximately 350 recognized Breeds in the world today, many established through hybridization and selection followed by intense Breeding programs aimed at retaining or enhancing specific traits. As a result, many Breeds suffer from an excess of particular diseases, one of many factors leading to the recent trend of "designer Breed" development, i.e. crossing purebred Dogs from existing Breeds in the hope that offspring will be enriched for desired traits and characteristics of the parental Breeds. We used a dense panel of 150,106 SNPs to analyze the population structure of the Australian labradoodle (ALBD), to understand how such Breeds are developed. Haplotype and admixture analyses show that Breeds other than the poodle (POOD) and Labrador retriever (LAB) contributed to ALBD formation, but that the Breed is, at the genetic level, predominantly POOD, with all small and large varieties contributing to its construction. Allele frequency analysis reveals that the Breed is enhanced for variants associated with a poodle-like coat, which is perceived by Breeders to have an association with hypoallergenicity. We observed little enhancement for LAB-specific alleles. This study provides a blueprint for understanding how Dog Breeds are formed, highlighting the limited scope of desired traits in defining new Breeds.
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genomic analyses reveal the influence of geographic origin migration and hybridization on modern Dog Breed development
Cell Reports, 2017Co-Authors: Heidi G Parker, Maud Rimbault, Dayna L Dreger, Brian W Davis, Alexandra B Mullen, Gretchen Carpinteroramirez, Elaine A OstranderAbstract:There are nearly 400 modern domestic Dog Breeds with a unique histories and genetic profiles. To track the genetic signatures of Breed development, we have assembled the most diverse dataset of Dog Breeds, reflecting their extensive phenotypic variation and heritage. Combining genetic distance, migration, and genome-wide haplotype sharing analyses, we uncover geographic patterns of development and independent origins of common traits. Our analyses reveal the hybrid history of Breeds and elucidate the effects of immigration, revealing for the first time a suggestion of New World Dog within some modern Breeds. Finally, we used cladistics and haplotype sharing to show that some common traits have arisen more than once in the history of the Dog. These analyses characterize the complexities of Breed development, resolving longstanding questions regarding individual Breed origination, the effect of migration on geographically distinct Breeds, and, by inference, transfer of trait and disease alleles among Dog Breeds.
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a genetic dissection of Breed composition and performance enhancement in the alaskan sled Dog
BMC Genetics, 2010Co-Authors: Heidi G Parker, Jonathan Runstadler, Heather J Huson, Elaine A OstranderAbstract:The Alaskan sled Dog offers a rare opportunity to investigate the development of a Dog Breed based solely on performance, rather than appearance, thus setting the Breed apart from most others. Several established Breeds, many of which are recognized by the American Kennel Club (AKC), have been introduced into the sled Dog population to enhance racing performance. We have used molecular methods to ascertain the constitutive Breeds used to develop successful sled Dog lines, and in doing so, determined the Breed origins of specific performance-related behaviors. One hundred and ninety-nine Alaskan sled Dogs were genotyped using 96 microsatellite markers that span the canine genome. These data were compared to that from 141 similarly genotyped purebred Dog Breeds. Sled Dogs were evaluated for Breed composition based on a variety of performance phenotypes including speed, endurance and work ethic, and the data stratified based on population structure. We observe that the Alaskan sled Dog has a unique molecular signature and that the genetic profile is sufficient for identifying Dogs bred for sprint versus distance. When evaluating contributions of existing Breeds we find that the Alaskan Malamute and Siberian Husky contributions are associated with enhanced endurance; Pointer and Saluki are associated with enhanced speed and the Anatolian Shepherd demonstrates a positive influence on work ethic. We have established a genetic Breed profile for the Alaskan sled Dog, identified profile variance between sprint and distance Dogs, and established Breeds associated with enhanced performance attributes. These data set the stage for mapping studies aimed at finding genes that are associated with athletic attributes integral to the high performing Alaskan sled Dog.
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A mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote Dogs.
Public Library of Science (PLoS), 2007Co-Authors: Dana S Mosher, Cathryn S Mellersh, Heidi G Parker, Pascale Quignon, Nathan B Sutter, Carlos D Bustamante, Elaine A OstranderAbstract:Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin (MSTN) gene (previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet Dog Breed that results in a double-muscled phenotype known as the "bully" whippet. Individuals with this phenotype carry two copies of a two-base-pair deletion in the third exon of MSTN leading to a premature stop codon at amino acid 313. Individuals carrying only one copy of the mutation are, on average, more muscular than wild-type individuals (p = 7.43 x 10(-6); Kruskal-Wallis Test) and are significantly faster than individuals carrying the wild-type genotype in competitive racing events (Kendall's nonparametric measure, tau = 0.3619; p approximately 0.00028). These results highlight the utility of performance-enhancing polymorphisms, marking the first time a mutation in MSTN has been quantitatively linked to increased athletic performance
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a mutation in the myostatin gene increases muscle mass and enhances racing performance in heterozygote Dogs
PLOS Genetics, 2005Co-Authors: Dana S Mosher, Cathryn S Mellersh, Heidi G Parker, Pascale Quignon, Carlos Bustamante, Nathan B Sutter, Elaine A OstranderAbstract:Double muscling is a trait previously described in several mammalian species including cattle and sheep and is caused by mutations in the myostatin (MSTN) gene (previously referred to as GDF8). Here we describe a new mutation in MSTN found in the whippet Dog Breed that results in a double-muscled phenotype known as the “bully” whippet. Individuals with this phenotype carry two copies of a two-base-pair deletion in the third exon of MSTN leading to a premature stop codon at amino acid 313. Individuals carrying only one copy of the mutation are, on average, more muscular than wild-type individuals (p = 7.43 × 10−6; Kruskal-Wallis Test) and are significantly faster than individuals carrying the wild-type genotype in competitive racing events (Kendall's nonparametric measure, τ = 0.3619; p ≈ 0.00028). These results highlight the utility of performance-enhancing polymorphisms, marking the first time a mutation in MSTN has been quantitatively linked to increased athletic performance.
Oliver P. Forman - One of the best experts on this subject based on the ideXlab platform.
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an inversion disrupting fam134b is associated with sensory neuropathy in the border collie Dog Breed
G3: Genes Genomes Genetics, 2016Co-Authors: Oliver P. Forman, Rebekkah J. Hitti, Christopher A. Jenkins, Luisa De Risio, Louise Pettitt, Dennis P Obrien, Diane G Shelton, Rodrigo Gutierrez Quintana, Elsa Beltran, Cathryn S MellershAbstract:Sensory neuropathy in the Border Collie is a severe neurological disorder caused by the degeneration of sensory and, to a lesser extent, motor nerve cells with clinical signs starting between 2 and 7 months of age. Using a genome-wide association study approach with three cases and 170 Breed matched controls, a suggestive locus for sensory neuropathy was identified that was followed up using a genome sequencing approach. An inversion disrupting the candidate gene FAM134B was identified. Genotyping of additional cases and controls and RNAseq analysis provided strong evidence that the inversion is causal. Evidence of cryptic splicing resulting in novel exon transcription for FAM134B was identified by RNAseq experiments. This investigation demonstrates the identification of a novel sensory neuropathy associated mutation, by mapping using a minimal set of cases and subsequent genome sequencing. Through mutation screening, it should be possible to reduce the frequency of or completely eliminate this debilitating condition from the Border Collie Breed population.
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genome sequencing reveals a splice donor site mutation in the snx14 gene associated with a novel cerebellar cortical degeneration in the hungarian vizsla Dog Breed
BMC Genetics, 2016Co-Authors: Joe Fenn, Patrick J. Kenny, Mike Boursnell, Rebekkah J. Hitti, Christopher A. Jenkins, Rebecca L. Terry, Cathryn S Mellersh, Simon L Priestnall, Oliver P. FormanAbstract:Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many Dog Breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different Breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several Breeds, allowing screening for selective Breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas. Two full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one Dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one Dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both Dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population. This is the first report of CCD in Hungarian Vizsla Dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected.
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A Novel Genome-Wide Association Study Approach Using Genotyping by Exome Sequencing Leads to the Identification of a Primary Open Angle Glaucoma Associated Inversion Disrupting ADAMTS17
2015Co-Authors: Oliver P. Forman, Louise Pettitt, András M. Komáromy, Peter Bedford, Cathryn MellershAbstract:Closed Breeding populations in the Dog in conjunction with advances in gene mapping and sequencing techniques facilitate mapping of autosomal recessive diseases and identification of novel disease-causing variants, often using unorthodox experimental designs. In our investigation we demonstrate successful mapping of the locus for primary open angle glaucoma in the Petit Basset Griffon Vendéen Dog Breed with 12 cases and 12 controls, using a novel genotyping by exome sequencing approach. The resulting genome-wide association signal was followed up by genome sequencing of an individual case, leading to the identification of an inversion with a breakpoint disrupting the ADAMTS17 gene. Genotyping of additional controls and expression analysis provide strong evidence that the inversion is disease causing. Evidence of cryptic splicing resulting in novel exon transcription as a consequence of the inversion in ADAMTS17 is identified through RNAseq experiments. This investigation demonstrates how a novel genotyping by exome sequencing approach can be used to map an autosomal recessive disorder in the Dog, with the use of genome sequencing to facilitate identification of a disease-associated variant.
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Missense Mutation in CAPN1 Is Associated with Spinocerebellar Ataxia in the Parson Russell Terrier Dog Breed
PloS one, 2013Co-Authors: Oliver P. Forman, Luisa De Risio, Cathryn S MellershAbstract:Spinocerebellar ataxia (SCA) in the Parson Russell Terrier (PRT) Dog Breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected Dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected Dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain), was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans.
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parallel mapping and simultaneous sequencing reveals deletions in bcan and fam83h associated with discrete inherited disorders in a domestic Dog Breed
PLOS Genetics, 2012Co-Authors: Oliver P. Forman, Jacques Penderis, Claudia Hartley, Louisa J Hayward, Sally L Ricketts, Cathryn S MellershAbstract:The domestic Dog (Canis familiaris) segregates more naturally-occurring diseases and phenotypic variation than any other species and has become established as an unparalled model with which to study the genetics of inherited traits. We used a genome-wide association study (GWAS) and targeted resequencing of DNA from just five Dogs to simultaneously map and identify mutations for two distinct inherited disorders that both affect a single Breed, the Cavalier King Charles Spaniel. We investigated episodic falling (EF), a paroxysmal exertion-induced dyskinesia, alongside the phenotypically distinct condition congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), commonly known as dry eye curly coat syndrome. EF is characterised by episodes of exercise-induced muscular hypertonicity and abnormal posturing, usually occurring after exercise or periods of excitement. CKCSID is a congenital disorder that manifests as a rough coat present at birth, with keratoconjunctivitis sicca apparent on eyelid opening at 10-14 days, followed by hyperkeratinisation of footpads and distortion of nails that develops over the next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a common set of 38 controls and identified statistically associated signals for EF and CKCSID on chromosome 7 (P(raw) 1.9×10(-14); P(genome) = 1.0×10(-5)) and chromosome 13 (P(raw) 1.2×10(-17); P(genome) = 1.0×10(-5)), respectively. We resequenced both the EF and CKCSID disease-associated regions in just five Dogs and identified a 15,724 bp deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in FAM83H associated with CKCSID. Neither BCAN or FAM83H have been associated with equivalent disease phenotypes in any other species, thus demonstrating the ability to use the domestic Dog to study the genetic basis of more than one disease simultaneously in a single Breed and to identify multiple novel candidate genes in parallel.
Paola Valsecchi - One of the best experts on this subject based on the ideXlab platform.
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Breed sex and litter effects in 2 month old puppies behaviour in a standardised open field test
Scientific Reports, 2017Co-Authors: Shanis Barnard, Sarah Marshallpescini, Annalisa Pelosi, Chiara Passalacqua, Emanuela Pratoprevide, Paola ValsecchiAbstract:A considerable number of studies have reported differences among Dog Breeds with respect to their genetic profile, cognitive abilities or personality traits. Each Dog Breed is normally treated as a homogeneous group, however, researchers have recently questioned whether the behavioural profile of modern Breeds still reflects their historical function or if the intense divergent selective pressures and geographical barriers have created a more fragmented picture. The majority of studies attempting to assess and compare modern Breeds’ personality focused on the evaluation of adult Dogs where the potential effects of environmental/human factors on the Dogs’ behaviour are hard to discern from their genetic heritage. In the following study, we aimed at investigating between- and within-Breed differences in the personality of two-months-old puppies by direct behavioural observation of 377 puppies from 12 Breeds. Results showed that there was no effect of sex, however both Breed and litter, significantly affected all personality traits. Breed on average explained 10% of the variance, whereas the effect of litter was noticeably higher, explaining on average 23% of the variance. Taken together, our results suggest that Breed does have some influence on personality traits, but they also highlight the importance of taking litter effects into account.
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Breed sex and litter effects in 2 month old puppies behaviour in a standardised open field test
Scientific Reports, 2017Co-Authors: Shanis Barnard, Sarah Marshallpescini, Annalisa Pelosi, Chiara Passalacqua, Emanuela Pratoprevide, Paola ValsecchiAbstract:A considerable number of studies have reported differences among Dog Breeds with respect to their genetic profile, cognitive abilities or personality traits. Each Dog Breed is normally treated as a homogeneous group, however, researchers have recently questioned whether the behavioural profile of modern Breeds still reflects their historical function or if the intense divergent selective pressures and geographical barriers have created a more fragmented picture. The majority of studies attempting to assess and compare modern Breeds’ personality focused on the evaluation of adult Dogs where the potential effects of environmental/human factors on the Dogs’ behaviour are hard to discern from their genetic heritage. In the following study, we aimed at investigating between- and within-Breed differences in the personality of two-months-old puppies by direct behavioural observation of 377 puppies from 12 Breeds. Results showed that there was no effect of sex, however both Breed and litter, significantly affected all personality traits. Breed on average explained 10% of the variance, whereas the effect of litter was noticeably higher, explaining on average 23% of the variance. Taken together, our results suggest that Breed does have some influence on personality traits, but they also highlight the importance of taking litter effects into account.