Publications by authors named "Claire M Wade"

60 Publications

Author Correction: Mapping the genetic basis of diabetes mellitus in the Australian Burmese cat (Felis catus).

Sci Rep 2021 Feb 17;11(1):4375. Epub 2021 Feb 17.

Faculty of Science, Sydney School of Veterinary Science, University of Sydney, Sydney, NSW, Australia.

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http://dx.doi.org/10.1038/s41598-021-83769-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889845PMC
February 2021

Inbreeding levels in an open-registry pedigreed dog breed: The Australian working kelpie.

Vet J 2021 Mar 15;269:105609. Epub 2021 Jan 15.

School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia.

The depletion in genetic diversity of closed-pedigree dog breeds can be a contentious topic and can lead to calls for open-registry. However, strong evidence in support of proposed open-registry solutions is lacking, with the reproductive isolation of these breeds unlikely to be the sole cause of elevated inbreeding levels. Human-induced limitations, such as popular sire effects, are unlikely to be confined to closed-registry breeds and conceivably play an important role in maintaining genetic diversity within all breeds. Consequently, the aim of the current study was to explore inbreeding levels in an open-registry breed and determine the impact open-registry has on genetic diversity. Complete pedigree records on all Australian working kelpies (AWKs) were provided by the Working Kelpie Council with the cleaned pedigree consisting of 86,671 individuals with a median pedigree depth of 6.6 generations. The average inbreeding coefficient in the AWK population was 0.049 with an increase in inbreeding coefficient of 0.0016/year. This demonstrates that opening a breed registry can have a beneficial impact on the level of inbreeding within a population over the longer-term. However, allowing for a generation length of 5.1 years yielded an effective population size of 61 for AWKs and demonstrated a pattern consistent with closed-registry dog populations of comparable size.
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http://dx.doi.org/10.1016/j.tvjl.2021.105609DOI Listing
March 2021

Mapping the genetic basis of diabetes mellitus in the Australian Burmese cat (Felis catus).

Sci Rep 2020 11 5;10(1):19194. Epub 2020 Nov 5.

Faculty of Science, Sydney School of Veterinary Science, University of Sydney, Sydney, NSW, Australia.

Diabetes mellitus, a common endocrinopathy affecting domestic cats, shares many clinical and pathologic features with type 2 diabetes in humans. In Australia and Europe, diabetes mellitus is almost four times more common among Burmese cats than in other breeds. As a genetically isolated population, the diabetic Australian Burmese cat provides a spontaneous genetic model for studying diabetes mellitus in humans. Studying complex diseases in pedigreed breeds facilitates tighter control of confounding factors including population stratification, allelic frequencies and environmental heterogeneity. We used the feline SNV array and whole genome sequence data to undertake a genome wide-association study and runs of homozygosity analysis, of a case-control cohort of Australian and European Burmese cats. Our results identified diabetes-associated haplotypes across chromosomes A3, B1 and E1 and selective sweeps across the Burmese breed on chromosomes B1, B3, D1 and D4. The locus on chromosome B1, common to both analyses, revealed coding and splice region variants in candidate genes, ANK1, EPHX2 and LOX2, implicated in diabetes mellitus and lipid dysregulation. Mapping this condition in Burmese cats has revealed a polygenic spectrum, implicating loci linked to pancreatic beta cell dysfunction, lipid dysregulation and insulin resistance in the pathogenesis of diabetes mellitus in the Burmese cat.
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http://dx.doi.org/10.1038/s41598-020-76166-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644637PMC
November 2020

A large deletion on CFA28 omitting ACSL5 gene is associated with intestinal lipid malabsorption in the Australian Kelpie dog breed.

Sci Rep 2020 10 26;10(1):18223. Epub 2020 Oct 26.

School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Camperdown, NSW, 2006, Australia.

Inborn errors of metabolism are genetic conditions that can disrupt intermediary metabolic pathways and cause defective absorption and metabolism of dietary nutrients. In an Australian Kelpie breeding population, 17 puppies presented with intestinal lipid malabsorption. Juvenile dogs exhibited stunted postnatal growth, steatorrhea, abdominal distension and a wiry coat. Using genome-wide association analysis, an associated locus on CFA28 (P = 2.87E) was discovered and validated in a closely related population (P = 1.75E). A 103.3 kb deletion NC_006610.3CFA28:g.23380074_23483377del, containing genes Acyl-CoA Synthetase Long Chain Family Member 5 (ACSL5) and Zinc Finger DHHC-Type Containing 6 (ZDHHC6), was characterised using whole transcriptomic data. Whole transcriptomic sequencing revealed no expression of ACSL5 and disrupted splicing of ZDHHC6 in jejunal tissue of affected Kelpies. The ACSL5 gene plays a key role in long chain fatty acid absorption, a phenotype similar to that of our affected Kelpies has been observed in a knockout mouse model. A PCR-based diagnostic test was developed and confirmed fully penetrant autosomal recessive mode of inheritance. We conclude the structural variant causing a deletion of the ACSL5 gene is the most likely cause for intestinal lipid malabsorption in the Australian Kelpie.
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http://dx.doi.org/10.1038/s41598-020-75243-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589484PMC
October 2020

Characterization of A Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as A Risk Factor for Disorders of Sex Development and Reproduction.

Genes (Basel) 2020 02 27;11(3). Epub 2020 Feb 27.

College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843-4458, USA.

Disorders of sex development (DSD) and reproduction are not uncommon among horses, though knowledge about their molecular causes is sparse. Here we characterized a ~200 kb homozygous deletion in chromosome 29 at 29.7-29.9 Mb. The region contains genes which function as ketosteroid reductases in steroid hormone biosynthesis, including androgens and estrogens. Mutations in genes are associated with human DSDs. Deletion boundaries, sequence properties and gene content were studied by PCR and whole genome sequencing of select deletion homozygotes and control animals. Deletion analysis by PCR in 940 horses, including 622 with DSDs and reproductive problems and 318 phenotypically normal controls, detected 67 deletion homozygotes of which 79% were developmentally or reproductively abnormal. Altogether, 8-9% of all abnormal horses were homozygous for the deletion, with the highest incidence (9.4%) among cryptorchids. The deletion was found in ~4% of our phenotypically normal cohort, ~1% of global warmblood horses and ponies, and ~7% of draught breeds of general horse population as retrieved from published data. Based on the abnormal phenotype of the carriers, the functionally relevant gene content, and the low incidence in general population, we consider the deletion in chromosome 29 as a risk factor for equine DSDs and reproductive disorders.
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http://dx.doi.org/10.3390/genes11030251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140900PMC
February 2020

Association between coat colour and the behaviour of Australian Labrador retrievers.

Canine Genet Epidemiol 2019 30;6:10. Epub 2019 Nov 30.

The University of Sydney, Camperdown, NSW 2006 Australia.

Background: Making assumptions regarding temperament and intelligence based on the physical appearance of dogs can be a conscious or unconscious human act. Labrador retrievers with chocolate-coloured coats are anecdotally considered to be less trainable and more hyperactive and aggressive than their black or yellow peers. To test these assertions, we analysed the owner-reported behavioural traits of Labradors in relation to both their observable coat colour, and their and genotypes.

Results: We used the results of an owner-based questionnaire to determine scores for 21 behavioural traits and test whether these scores varied with coat colour ( = 225). was the only trait that was found to vary significantly with coat colour ( = 0.013). Yellow Labradors had a higher score than chocolate Labradors, even when corrected for multiple testing ( = 0.021).We repeated the analyses for a subset of 63 Labradors with available genotyping data for the genes (MC1R and TYRP1) that are known to determine the primary coat colours in Labradors. scores varied with both the observed coat colour and genotype. Dogs homozygous for recessive allele (with yellow coat colour) scored higher for than either black or chocolate Labradors. However, no association maintained significance when incorporating Bonferroni correction. Dog scores decreased additively as the number of recessive brown alleles for increased. This allelic association was independent of the observable coat colour. Dogs homozygous for the brown allele were considered less trainable than dogs with no brown alleles ( = 0.030).

Conclusions: Our results do not support that chocolate-coloured Labradors are more hyperactive or aggressive than either black or yellow Labradors. Trainability scores varied with genotype but not the observable coat colour. Further validation is required.
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http://dx.doi.org/10.1186/s40575-019-0078-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884874PMC
November 2019

Genomic Characterization of External Morphology Traits in Kelpies Does Not Support Common Ancestry with the Australian Dingo.

Genes (Basel) 2019 05 3;10(5). Epub 2019 May 3.

School of Life and Environmental Sciences, the University of Sydney, NSW 2006, Australia.

The Kelpie is a breed developed in Australia for use as a livestock herding dog. It has been proposed that the development of the breed included gene flow from the Australian Dingo (), a canid species present on the Australian continent for around 4000 years. The Kelpie breed is split between working and conformation types that have readily recognizable differences in external morphology. We characterize known gene variants relating to external morphology in sequenced representatives of both Kelpie types (Australian Kelpie-conformation; Australian Working Kelpie-herding) and compare the variants present with those in sequenced Australian Dingoes, including 25 canids with locus-constrained data and one with a whole genome sequence. Variants assessed include identified coat color and ear morphology variants. We describe a new variant site in the transcribed region of methionine sulfoxide reductase 3 that may relate to ear phenotype. None of the morphology variants analyzed offer support for co-ancestry of the Kelpie breed with the Australian Dingo.
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http://dx.doi.org/10.3390/genes10050337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563003PMC
May 2019

Work-type influences perceived livestock herding success in Australian Working Kelpies.

Canine Genet Epidemiol 2018 13;5. Epub 2018 Aug 13.

Faculty of Science, University of Sydney, Camperdown, NSW 2006 Australia.

Background: Working dog handlers and breeders have very different behavioural requirements in the animals that they employ for managing livestock. The Australian Working Kelpie breed may be used in several working contexts, notably yards, paddocks and a combination of both. The working context influences the skillsets required and gives rise to three corresponding work-types: and Kelpies. In particular, dogs used for working stock in the confines of yards and trucks interact with stock more forcefully than those mustering in larger areas (paddocks) where they can herd stock effectively from a greater distance. This article explores owner assessments of dog working quality and assessment of genomic similarity by multidimensional scaling, to ask whether it is sufficient for breeders to aim for a multipurpose breeding objective, or whether breeding only specialist lines maximises user satisfaction for yard and paddock work.

Results: Reported owner perceptions of 298 dogs assessed with the Livestock Herding Dog assessment tool showed that dog handlers across all working types were very happy with their dogs' level of general skills.Compared with both and Kelpies, Kelpies had significantly lower trait scores for (pressure applied by the dog to move livestock), willingness to the stock (run along a sheep's dorsum) and (frequency of using the mouth to grab or bite the livestock). Meanwhile, compared with both Paddock and Kelpies, the Kelpies had significantly higher scores for hyperactivity and excitability (both with and without stock) and impulsiveness without stock. As one would predict for all-rounders, Kelpies had intermediate scores for all behaviours and working traits.

Conclusions: Specialist characteristics were displayed by dogs in the Kelpie and Kelpie groups. In particular, Kelpies demonstrate higher excitability, willingness to the stock, and a higher tendency to and the stock. Conversely, Kelpies rarely display these characteristics. Kelpies, as the name suggests, are intermediate between the other two groups and display the characteristics of both. Genetic analysis suggests that the Yard, Utility and Paddock Kelpies are not distinguishable at a DNA level. In conclusion, at this time there is no suggestion of a breed split in the Australian Working Kelpie generated by selection for work type. A common breeding objective should enable dogs to be produced that fulfil all potential working requirements. This reinforces the importance of breeder skill in recognising the phenotypic potential of pups in order to place them in appropriate working contexts.
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http://dx.doi.org/10.1186/s40575-018-0063-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090621PMC
August 2018

Umbilical tissue as a sampling technique for DNA testing in neonate dogs.

Anim Genet 2018 Oct 5;49(5):499-500. Epub 2018 Aug 5.

School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Camperdown, NSW, 2006, Australia.

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http://dx.doi.org/10.1111/age.12706DOI Listing
October 2018

Exclusion of known gene loci for cerebellar abiotrophy in the Australian Working Kelpie.

Anim Genet 2017 Dec 29;48(6):730-732. Epub 2017 Aug 29.

School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Camperdown, NSW, 2145, Australia.

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http://dx.doi.org/10.1111/age.12594DOI Listing
December 2017

Developing a 670k genotyping array to tag ~2M SNPs across 24 horse breeds.

BMC Genomics 2017 07 27;18(1):565. Epub 2017 Jul 27.

Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, USA.

Background: To date, genome-scale analyses in the domestic horse have been limited by suboptimal single nucleotide polymorphism (SNP) density and uneven genomic coverage of the current SNP genotyping arrays. The recent availability of whole genome sequences has created the opportunity to develop a next generation, high-density equine SNP array.

Results: Using whole genome sequence from 153 individuals representing 24 distinct breeds collated by the equine genomics community, we cataloged over 23 million de novo discovered genetic variants. Leveraging genotype data from individuals with both whole genome sequence, and genotypes from lower-density, legacy SNP arrays, a subset of ~5 million high-quality, high-density array candidate SNPs were selected based on breed representation and uniform spacing across the genome. Considering probe design recommendations from a commercial vendor (Affymetrix, now Thermo Fisher Scientific) a set of ~2 million SNPs were selected for a next-generation high-density SNP chip (MNEc2M). Genotype data were generated using the MNEc2M array from a cohort of 332 horses from 20 breeds and a lower-density array, consisting of ~670 thousand SNPs (MNEc670k), was designed for genotype imputation.

Conclusions: Here, we document the steps taken to design both the MNEc2M and MNEc670k arrays, report genomic and technical properties of these genotyping platforms, and demonstrate the imputation capabilities of these tools for the domestic horse.
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http://dx.doi.org/10.1186/s12864-017-3943-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530493PMC
July 2017

A Coding Variant in the Gene Bardet-Biedl Syndrome 4 () Is Associated with a Novel Form of Canine Progressive Retinal Atrophy.

G3 (Bethesda) 2017 07 5;7(7):2327-2335. Epub 2017 Jul 5.

School of Life and Environmental Sciences, Faculty of Science, University of Sydney, 2006, Australia

Progressive retinal atrophy is a common cause of blindness in the dog and affects >100 breeds. It is characterized by gradual vision loss that occurs due to the degeneration of photoreceptor cells in the retina. Similar to the human counterpart retinitis pigmentosa, the canine disorder is clinically and genetically heterogeneous and the underlying cause remains unknown for many cases. We use a positional candidate gene approach to identify putative variants in the Hungarian Puli breed using genotyping data of 14 family-based samples (CanineHD BeadChip array, Illumina) and whole-genome sequencing data of two proband and two parental samples (Illumina HiSeq 2000). A single nonsense SNP in exon 2 of (c.58A > T, p.Lys20*) was identified following filtering of high quality variants. This allele is highly associated ( = 3.425, = 103) and segregates perfectly with progressive retinal atrophy in the Hungarian Puli. In humans, is known to cause Bardet-Biedl syndrome which includes a retinitis pigmentosa phenotype. From the observed coding change we expect that no functional BBS4 can be produced in the affected dogs. We identified canine phenotypes comparable with -null mice including obesity and spermatozoa flagella defects. Knockout mice fail to form spermatozoa flagella. In the affected Hungarian Puli spermatozoa flagella are present, however a large proportion of sperm are morphologically abnormal and <5% are motile. This suggests that BBS4 contributes to flagella motility but not formation in the dog. Our results suggest a promising opportunity for studying Bardet-Biedl syndrome in a large animal model.
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http://dx.doi.org/10.1534/g3.117.043109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499139PMC
July 2017

Exclusion of known progressive retinal atrophy genes for blindness in the Hungarian Puli.

Anim Genet 2017 Aug 5;48(4):500-501. Epub 2017 Apr 5.

School of Life and Environmental Sciences, Faculty of Veterinary Science, University of Sydney, Camperdown, NSW, 2145, Australia.

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http://dx.doi.org/10.1111/age.12553DOI Listing
August 2017

Variants in the host genome may inhibit tumour growth in devil facial tumours: evidence from genome-wide association.

Sci Rep 2017 03 24;7(1):423. Epub 2017 Mar 24.

School of Life and Environmental Sciences, Faculty of Veterinary Science, University of Sydney, Sydney, NSW, Australia.

Devil facial tumour disease (DFTD) has decimated wild populations of Tasmanian devils (Sarcophilus harrisii) due to its ability to avoid immune detection and pass from host to host by biting. A small number of devils have been observed to spontaneously recover from the disease which is otherwise fatal. We have sequenced the genomes of these rare cases and compared them to the genomes of devils who succumbed to the disease. Genome-wide association, based on this limited sampling, highlighted two key genomic regions potentially associated with ability to survive DFTD. Following targeted genotyping in additional samples, both of these loci remain significantly different between cases and controls, with the PAX3 locus retaining significance at the 0.001 level, though genome-wide significance was not achieved. We propose that PAX3 may be involved in a regulatory pathway that influences the slowing of tumour growth and may allow more time for an immune response to be mounted in animals with regressed tumours. This provides an intriguing hypothesis for further research and could provide a novel route of treatment for this devastating disease.
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http://dx.doi.org/10.1038/s41598-017-00439-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428454PMC
March 2017

Digging for known genetic mutations underlying inherited bone and cartilage characteristics and disorders in the dog and cat.

Vet Comp Orthop Traumatol 2016 Jul 18;29(4):269-76. Epub 2016 May 18.

Prof. Claire M. Wade, School of Life and Environmental Sciences, Faculty of Veterinary Science, University of Sydney, Regimental Drive, B19-301 RMC Gunn, Sydney, NSW 2006, Australia, Phone +61 29351 8097, Fax +61 29351 3957, E-mail:

Gene mapping projects for many traits in both dogs and cats have yielded new knowledge. Both researchers and the public alike have been fascinated by the inheritance of breed characteristic phenotypes and sporadic disorders. It has been proposed that selective breeding practices have on occasion generated alterations in structure that might be harmful. In this review, simply inherited disorders and characteristics affecting bone and cartilage for which a putative mutation is known are collected. A better understanding of the known inherited basis of skeletal conditions and disorders will assist veterinarians to improve their diagnoses and increase their effectiveness on advising clients on the prevention, management, prognosis and possible treatment of the conditions.
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http://dx.doi.org/10.3415/VCOT-16-02-0037DOI Listing
July 2016

Inheritance of chronic superficial keratitis in Australian Greyhounds.

Anim Genet 2016 Oct 5;47(5):629. Epub 2016 May 5.

School of Life and Environmental Sciences, Faculty of Veterinary Science, University of Sydney, Camperdown, NSW, 2006, Australia.

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http://dx.doi.org/10.1111/age.12446DOI Listing
October 2016

Congenital vestibular disease in captive Sumatran tigers (Panthera tigris ssp. sumatrae) in Australasia.

Vet J 2015 Nov 9;206(2):178-82. Epub 2015 Sep 9.

Faculty of Veterinary Science, University of Sydney, Sydney, NSW 2006, Australia. Electronic address:

The Sumatran tiger (Panthera tigris ssp. sumatrae) is a critically endangered species in the wild. To ensure that demographic and genetic integrity are maintained in the longer term, those Sumatran tigers held in captivity are managed as a global population under a World Association of Zoos and Aquariums Global Species Management Plan (GSMP). A retrospective study, including segregation and pedigree analysis, was conducted to investigate potential cases of congenital vestibular disease (CVD) in captive Sumatran tigers in Australasian zoos using medical and husbandry records, as well as video footage obtained from 50 tigers between 1975 and 2013. Data from the GSMP Sumatran tiger studbook were made available for pedigree and segregation analysis. Fourteen cases of CVD in 13 Sumatran tiger cubs and one hybrid cub (Panthera tigris ssp. sumatrae × Panthera tigris) were identified. Vestibular signs including head tilt, circling, ataxia, strabismus and nystagmus were observed between birth and 2 months of age. These clinical signs persisted for a median of 237 days and had resolved by 2 years of age in all cases. Pedigree analysis revealed that all affected tigers were closely related and shared a single common ancestor in the last four generations. A genetic cause for the disease is suspected and, based on pedigree and segregation analysis, an autosomal dominant mode of inheritance is likely. Further investigations to determine the world-wide prevalence and underlying pathology of this disorder are warranted.
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http://dx.doi.org/10.1016/j.tvjl.2015.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128761PMC
November 2015

Strong selection for behavioural resilience in Australian stock working dogs identified by selective sweep analysis.

Canine Genet Epidemiol 2015 7;2. Epub 2015 May 7.

Faculty of Veterinary Science, University of Sydney, Camperdown, NSW 2006 Australia.

Background: Working dog handlers and breeders have strong opinions on characteristics that are desirable in the breeds that they use to handle stock. Most of these characteristics are related to conformation or behaviour. This study explored whether the genetics underlying desirable working behaviour traits might be identified by selective sweep analysis; a method that identifies long regions of strong homozygosity combined with allelic divergence from a comparison group. For this analysis, we compared genomic haplotype architecture in two breeds derived from common founder stock but subjected to divergent selective pressures. The breeds studied were the Australian Kelpie, which is registered with the Australian National Kennel Council, and the Australian Working Kelpie, which is registered with the Working Kelpie Council.

Results: A selective sweep spanning 3 megabases on chromosome 3 was identified in the Australian Working Kelpie. This region is the location of genes related to fear-memory formation and pain perception. Selective sweep loci of similar magnitude were observed in the Australian Kelpie. On chromosome 8 is a locus which may be related to behavioural excitability and on chromosome 30 is a smaller locus which most likely is related to morphology.

Conclusions: Active working stock dogs of the Australian Working Kelpie breed have been bred primarily for gene loci influencing pain perception and fear memory formation. By contrast Australian Kelpies are commonly maintained in urban environments where these characteristics are not required and have been affected by selection for conformation and coat colour. The identified loci may aid in the identification of superior working dogs.
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http://dx.doi.org/10.1186/s40575-015-0017-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579362PMC
September 2015

Genome-wide association studies in dogs and humans identify ADAMTS20 as a risk variant for cleft lip and palate.

PLoS Genet 2015 03 23;11(3):e1005059. Epub 2015 Mar 23.

Department of Population Health and Reproduction, School of Veterinary Medicine University of California, Davis, Davis, California, United States of America.

Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR) breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10(-13); adjusted p= 2.2 x 10(-3)). Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 - 10.73 Mb) segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS) in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)), which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM) of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10-6) with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans.
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http://dx.doi.org/10.1371/journal.pgen.1005059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370697PMC
March 2015

X-linked myotubular myopathy in Rottweiler dogs is caused by a missense mutation in Exon 11 of the MTM1 gene.

Skelet Muscle 2015 27;5(1). Epub 2015 Jan 27.

Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 USA.

Background: Congenital and inherited myopathies in dogs are faithful models of human muscle diseases and are being recognized with increasing frequency. In fact, canine models of dystrophin deficient muscular dystrophy and X-linked myotubular myopathy are of tremendous value in the translation of new and promising therapies for the treatment of these diseases. We have recently identified a family of Australian Rottweilers in which male puppies were clinically affected with severe muscle weakness and atrophy that resulted in early euthanasia or death. X-linked myotubular myopathy was suspected based on the early and severe clinical presentation and histopathological changes within muscle biopsies. The aim of this study was to determine the genetic basis for myopathy in these dogs and compare and contrast the clinical presentation, histopathology, ultrastructure, and mutation in this family of Rottweiler dogs with the previously described myotubular myopathy in Labrador retrievers.

Results: Histopathology, histochemistry, and ultrastructural examination of muscle biopsies from affected Rottweiler puppies were consistent with an X-linked myotubular myopathy. An unusual finding that differed from the previously reported Labradors and similar human cases was the presence of excessive autophagy and prominent autophagic vacuoles. Molecular investigations confirmed a missense mutation in exon 11 of MTM1 that was predicted to result in a non-functional phosphatase activity. Although the clinical presentations and histopathology were similar, the MTM1 p.(Q384P) mutation is different from the p.(N155K) mutation in exon 7 affecting Labrador retrievers with X-linked myotubular myopathy.

Conclusions: Here we describe a second pathogenic mutation in MTM1 causing X-linked myotubular myopathy in dogs. Our findings suggest a variety of MTM1 mutations in dogs as seen in human patients. The number of MTM1 mutations resulting in similar severe and progressive clinical myopathy and histopathological changes are likely to increase as canine myopathies are further characterized.
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http://dx.doi.org/10.1186/s13395-014-0025-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320619PMC
February 2015

Canine disorder mirrors human disease: exonic deletion in HES7 causes autosomal recessive spondylocostal dysostosis in miniature Schnauzer dogs.

PLoS One 2015 6;10(2):e0117055. Epub 2015 Feb 6.

Faculty of Veterinary Science, University of Sydney, Sydney, NSW, Australia.

Spondylocostal dysostosis is a congenital disorder of the axial skeleton documented in human families from diverse racial backgrounds. The condition is characterised by truncal shortening, extensive hemivertebrae and rib anomalies including malalignment, fusion and reduction in number. Mutations in the Notch signalling pathway genes DLL3, MESP2, LFNG, HES7 and TBX6 have been associated with this defect. In this study, spondylocostal dysostosis in an outbred family of miniature schnauzer dogs is described. Computed tomography demonstrated that the condition mirrors the skeletal defects observed in human cases, but unlike most human cases, the affected dogs were stillborn or died shortly after birth. Through gene mapping and whole genome sequencing, we identified a single-base deletion in the coding region of HES7. The frameshift mutation causes loss of functional domains essential for the oscillatory transcriptional autorepression of HES7 during somitogenesis. A restriction fragment length polymorphism test was applied within the immediate family and supported a highly penetrant autosomal recessive mode of inheritance. The mutation was not observed in wider testing of 117 randomly sampled adult miniature schnauzer and six adult standard schnauzer dogs; providing a significance of association of Praw = 4.759e-36 (genome-wide significant). Despite this apparently low frequency in the Australian population, the allele may be globally distributed based on its presence in two unrelated sires from geographically distant locations. While isolated hemivertebrae have been observed in a small number of other dog breeds, this is the first clinical and genetic diagnosis of spontaneously occurring spondylocostal dysostosis in a non-human mammal and offers an excellent model in which to study this devastating human disorder. The genetic test can be utilized by dog breeders to select away from the disease and avoid unnecessary neonatal losses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0117055PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319916PMC
March 2015

Simple, rapid and accurate genotyping-by-sequencing from aligned whole genomes with ArrayMaker.

Bioinformatics 2015 Feb 21;31(4):599-601. Epub 2014 Oct 21.

Faculty of Veterinary Science and School of Information Technologies, University of Sydney, Sydney, New South Wales 2006, Australia.

Summary: Whole-genome sequencing has revolutionized the study of genetics. Genotyping-by-sequencing is now a viable method of genotyping, yet the bioinformatics involved can be daunting if not prohibitive for some laboratories. Here we present ArrayMaker, a user-friendly tool that extracts accurate single nucleotide polymorphism genotypes at pre-defined loci from whole-genome alignments and presents them in a standard genotyping format compatible with association analysis software and datasets genotyped on commercial array platforms. Using this tool, geneticists with only basic computing ability can genotype samples at any desired list of markers, facilitating genome-wide association analysis, fine mapping, candidate variant assessment, data sharing and compatibility of data sourced from multiple technologies.

Availability And Implementation: ArrayMaker is licensed under The MIT License and can be freely obtained at https://github.com/cw2014/ArrayMaker/. The program is implemented in Perl and runs on Linux operating systems.

Supplementary Information: Supplementary data are available at Bioinformatics online.

Contact: cali.willet@sydney.edu.au.
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http://dx.doi.org/10.1093/bioinformatics/btu691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325546PMC
February 2015

Environmental factors associated with success rates of Australian stock herding dogs.

PLoS One 2014 19;9(8):e104457. Epub 2014 Aug 19.

Faculty of Veterinary Science, University of Sydney, Sydney, Australia.

This study investigated the current management practices associated with stock herding dogs on Australian farms. A parallel goal was to determine whether these practices and the characteristics of the dog handlers were associated with success rates. Success rate refers to the proportion of dogs acquired by the farmer that were retained as working dogs. Data on a total of 4,027 dogs were obtained through The Farm Dog Survey which gathered information from 812 herding dog owners around Australia. Using logistic regression, significant associations were identified between success rate and seven variables: dog breed, housing method, trial participation, age of the dog at acquisition, electric collar use, hypothetical maximum treatment expenditure and the conscientiousness score of the owner's personality. These findings serve as a guide to direct further research into ways of optimising herding dog performance and welfare. They emphasise the importance of not only examining the genetic predispositions of the working dog but also the impact the handler can have on a dog's success in the workplace.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104457PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138039PMC
October 2015

From the phenotype to the genotype via bioinformatics.

Methods Mol Biol 2014 ;1168:1-16

Faculty of Veterinary Science, University of Sydney, Sydney, NSW, 2006, Australia.

Moving a project from the status of observing a trait of interest to identifying the underlying causal variant is a challenging task requiring a series of bioinformatics procedures and ideally the availability of a suitable reference genome sequence and its associated resources. We visit common practices for discovering the biology underlying observed traits in mammals.
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http://dx.doi.org/10.1007/978-1-4939-0847-9_1DOI Listing
January 2015

A LINE-1 insertion in DLX6 is responsible for cleft palate and mandibular abnormalities in a canine model of Pierre Robin sequence.

PLoS Genet 2014 Apr 3;10(4):e1004257. Epub 2014 Apr 3.

Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, California, United States of America.

Cleft palate (CP) is one of the most commonly occurring craniofacial birth defects in humans. In order to study cleft palate in a naturally occurring model system, we utilized the Nova Scotia Duck Tolling Retriever (NSDTR) dog breed. Micro-computed tomography analysis of CP NSDTR craniofacial structures revealed that these dogs exhibit defects similar to those observed in a recognizable subgroup of humans with CP: Pierre Robin Sequence (PRS). We refer to this phenotype in NSDTRs as CP1. Individuals with PRS have a triad of birth defects: shortened mandible, posteriorly placed tongue, and cleft palate. A genome-wide association study in 14 CP NSDTRs and 72 unaffected NSDTRs identified a significantly associated region on canine chromosome 14 (24.2 Mb-29.3 Mb; p(raw )= 4.64 × 10(-15)). Sequencing of two regional candidate homeobox genes in NSDTRs, distal-less homeobox 5 (DLX5) and distal-less homeobox 6 (DLX6), identified a 2.1 kb LINE-1 insertion within DLX6 in CP1 NSDTRs. The LINE-1 insertion is predicted to insert a premature stop codon within the homeodomain of DLX6. This prompted the sequencing of DLX5 and DLX6 in a human cohort with CP, where a missense mutation within the highly conserved DLX5 homeobox of a patient with PRS was identified. This suggests the involvement of DLX5 in the development of PRS. These results demonstrate the power of the canine animal model as a genetically tractable approach to understanding naturally occurring craniofacial birth defects in humans.
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http://dx.doi.org/10.1371/journal.pgen.1004257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974639PMC
April 2014

Holding back the genes: limitations of research into canine behavioural genetics.

Canine Genet Epidemiol 2014 10;1. Epub 2014 Jun 10.

Faculty of Veterinary Science, University of Sydney, Sydney, NSW 2006 Australia.

Canine behaviours that are both desirable and undesirable to owners have a demonstrable genetic component. Some behaviours are breed-specific, such as the livestock guarding by maremmas and flank sucking seen in Dobermanns. While the identification of genes responsible for common canine diseases is rapidly advancing, those genes underlying behaviours remain elusive. The challenges of accurately defining and measuring behavioural phenotypes remain an obstacle, and the use of variable phenotyping methods has prevented meta-analysis of behavioural studies. International standardised testing protocols and terminology in canine behavioural evaluations should facilitate selection against behavioural disorders in the modern dog and optimise breeding success and performance in working dogs. This review examines the common hurdles faced by researchers of behavioural genetics and the current state of knowledge.
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http://dx.doi.org/10.1186/2052-6687-1-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579367PMC
September 2015

Genetic correlations among canine hip dysplasia radiographic traits in a cohort of Australian German Shepherd Dogs, and implications for the design of a more effective genetic control program.

PLoS One 2013 7;8(11):e78929. Epub 2013 Nov 7.

Faculty of Veterinary Science, The University of Sydney, Sydney, New South Wales, Australia.

Canine hip dysplasia (CHD) is a common musculoskeletal disease in pedigree dog populations. It can cause severe pain and dysfunction which may require extensive medication and/or surgical treatment and often ultimately requires humane euthanasia. CHD has been found to be moderately heritable and, given its impact on welfare, should be considered an imperative breeding priority. The British Veterinary Association/Kennel Club scoring method is one of several measures used to assess the genetic propensity of potential breeding stock for dysplastic changes to the hips based on radiographic examination. It is a complex measure composed of nine ordinal traits, intended to evaluate both early and late dysplastic changes. It would be highly desirable if estimated breeding values (EBVs) for these nine traits were consolidated into a simpler, EBV-based, selection index more easily usable by breeders. A multivariate analysis on the phenotype scores from an Australian cohort of 13,124 German Shepherd Dogs (GSDs) returned genetic correlations between 0.48-0.97 for the nine traits which fell into two trait groups, Group 1 reflecting early changes ("laxity") and Group 2 reflecting late changes ("osteoarthritis"). Principal components analysis of the ordinal EBVs suggested the same pattern, with strong differentiation between "laxity" and "osteoarthritis" traits in the second component. Taking account of all results, we recommend interim use of two selection indexes: the first being the average of ordinal EBVs for "laxity" traits and the second being the average of ordinal EBVs for "osteoarthritis" traits. The correlation between these two selection indexes (0.771-0.774) is sufficiently less than unity enabling the selection of dogs with different genetic propensity for laxity and for osteoarthritic CHD changes in GSDs; this may also be applicable in other breeds. Dogs with low propensity for severe osteoarthritic change in the presence of laxity may be of interest both in molecular research and breeding programs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078929PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820674PMC
August 2014

Estimated breeding values for canine hip dysplasia radiographic traits in a cohort of Australian German Shepherd dogs.

PLoS One 2013 29;8(10):e77470. Epub 2013 Oct 29.

Faculty of Veterinary Science, The University of Sydney, Sydney, New South Wales, Australia.

Canine hip dysplasia (CHD) is a serious and common musculoskeletal disease of pedigree dogs and therefore represents both an important welfare concern and an imperative breeding priority. The typical heritability estimates for radiographic CHD traits suggest that the accuracy of breeding dog selection could be substantially improved by the use of estimated breeding values (EBVs) in place of selection based on phenotypes of individuals. The British Veterinary Association/Kennel Club scoring method is a complex measure composed of nine bilateral ordinal traits, intended to evaluate both early and late dysplastic changes. However, the ordinal nature of the traits may represent a technical challenge for calculation of EBVs using linear methods. The purpose of the current study was to calculate EBVs of British Veterinary Association/Kennel Club traits in the Australian population of German Shepherd Dogs, using linear (both as individual traits and a summed phenotype), binary and ordinal methods to determine the optimal method for EBV calculation. Ordinal EBVs correlated well with linear EBVs (r = 0.90-0.99) and somewhat well with EBVs for the sum of the individual traits (r = 0.58-0.92). Correlation of ordinal and binary EBVs varied widely (r = 0.24-0.99) depending on the trait and cut-point considered. The ordinal EBVs have increased accuracy (0.48-0.69) of selection compared with accuracies from individual phenotype-based selection (0.40-0.52). Despite the high correlations between linear and ordinal EBVs, the underlying relationship between EBVs calculated by the two methods was not always linear, leading us to suggest that ordinal models should be used wherever possible. As the population of German Shepherd Dogs which was studied was purportedly under selection for the traits studied, we examined the EBVs for evidence of a genetic trend in these traits and found substantial genetic improvement over time. This study suggests the use of ordinal EBVs could increase the rate of genetic improvement in this population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0077470PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812223PMC
August 2014

Accumulating mutations in series of haplotypes at the KIT and MITF loci are major determinants of white markings in Franches-Montagnes horses.

PLoS One 2013 30;8(9):e75071. Epub 2013 Sep 30.

Faculty of Veterinary Science, University of Sydney, Sydney, New South Wales, Australia ; Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.

Coat color and pattern variations in domestic animals are frequently inherited as simple monogenic traits, but a number are known to have a complex genetic basis. While the analysis of complex trait data remains a challenge in all species, we can use the reduced haplotypic diversity in domestic animal populations to gain insight into the genomic interactions underlying complex phenotypes. White face and leg markings are examples of complex traits in horses where little is known of the underlying genetics. In this study, Franches-Montagnes (FM) horses were scored for the occurrence of white facial and leg markings using a standardized scoring system. A genome-wide association study (GWAS) was performed for several white patterning traits in 1,077 FM horses. Seven quantitative trait loci (QTL) affecting the white marking score with p-values p≤10(-4) were identified. Three loci, MC1R and the known white spotting genes, KIT and MITF, were identified as the major loci underlying the extent of white patterning in this breed. Together, the seven loci explain 54% of the genetic variance in total white marking score, while MITF and KIT alone account for 26%. Although MITF and KIT are the major loci controlling white patterning, their influence varies according to the basic coat color of the horse and the specific body location of the white patterning. Fine mapping across the MITF and KIT loci was used to characterize haplotypes present. Phylogenetic relationships among haplotypes were calculated to assess their selective and evolutionary influences on the extent of white patterning. This novel approach shows that KIT and MITF act in an additive manner and that accumulating mutations at these loci progressively increase the extent of white markings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075071PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787084PMC
May 2014

Empirical assessment of competitive hybridization and noise in ultra high density canine tiling arrays.

BMC Bioinformatics 2013 Jul 22;14:231. Epub 2013 Jul 22.

Faculty of Veterinary Science, The University of Sydney, Sydney, NSW 2006, Australia.

Background: In addition to probe sequence characteristics, noise in hybridization array data is thought to be influenced by competitive hybridization between probes tiled at high densities. Empirical evaluation of competitive hybridization and an estimation of what other non-sequence related features might affect noisy data is currently lacking.

Results: A high density array was designed to a 1.5 megabase region of the canine genome to explore the potential for probe competition to introduce noise. Multivariate assessment of the influence of probe, segment and design characteristics on hybridization intensity demonstrate that whilst increased density significantly depresses fluorescence intensities, this effect is largely consistent when an ultra high density offset is applied. Signal variation not attributable to sequence composition resulted from the reduction in competition when large inter-probe spacing was introduced due to long repetitive elements and when a lower density offset was applied. Tiling of probes immediately adjacent to various classes of repeat elements did not generate noise. Comparison of identical probe sets hybridized with DNA extracted from blood or saliva establishes salivary DNA as a source of noise.

Conclusions: This analysis demonstrates the occurrence of competitive hybridization between oligonucleotide probes in high density tiling arrays. It supports that probe competition does not generate random noise when it is maintained across a region. To prevent the introduction of noise from this source, the degree of competition should be regulated by minimizing variation in density across the target region. This finding can make an important contribution to optimizing coverage whilst minimizing sources of noise in the design of high density tiling arrays.
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http://dx.doi.org/10.1186/1471-2105-14-231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733988PMC
July 2013