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Canine Genetics
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Canine Genetics

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Animal Genetics and Genomics".

Deadline for manuscript submissions: closed (1 July 2019) | Viewed by 132487

Special Issue Editor

Dr. Elaine Ostrander

E-Mail Website
Guest Editor
National Human Genome Research Institute, the National Institutes of Health, Bethesda, MD 20814, USA
Interests: dog breeds; canine genetics; prostate cancer; domestic dog
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues

The domestic dog is unique among mammals, as it divided into an extraordinary number of breeds (over 400), with each characterized by specific attributes of behavior and morphology. However, the recent timeframe for the development of most breeds and their associated breeding programs means that dogs develop most of the same diseases as humans, often with the same symptoms, pathology, and response to treatment. Since the 1990s, we as a community have worked to develop the dog as a genetic system on par with other commonly used mammalian model systems (e.g., mice). This was facilitated first by the creation of maps which permitted navigation of the dog genome, followed by whole-genome sequencing of the boxer in 2005. Since then, we have developed a plethora of tools and resources for advancing dog genomics, as evidenced by the enormous strides in mapping genes and identifying variants responsible for diseases and breed traits important to both human and animal health. Key to fully exploiting the dog system is a need to understand critical issues in dog history, such as domestication, timing, and mechanisms of individual breed formation, and to perform additional whole-genome sequencing. Equally important are the needed advances in bioinformatics that will allow us to accurately identify actionable genetic variants among the many candidates presented from association and sequencing studies. For this Special Issue, we will present state-of-the-art work in canine genetics and genomics, assembling the most recent advances in our field in one place.

Dr. Elaine Ostrander
Guest Editor

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Keywords

  • Canis
  • dog
  • wolf
  • genomics
  • sequencing
  • breed
  • domestication
  • mapping
  • variants
  • genetics

Published Papers (18 papers)

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16 pages, 4304 KiB  
Article
Identification of Two Independent COL5A1 Variants in Dogs with Ehlers–Danlos Syndrome
by Anina Bauer, John F. Bateman, Shireen R. Lamandé, Eric Hanssen, Shannon G.M. Kirejczyk, Mark Yee, Ali Ramiche, Vidyha Jagannathan, Monika Welle, Tosso Leeb and Fiona L. Bateman
Genes 2019, 10(10), 731; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10100731 - 21 Sep 2019
Cited by 14 | Viewed by 7049
Abstract
The Ehlers–Danlos syndromes (EDS) are a heterogeneous group of heritable disorders affecting connective tissues. The mutations causing the various forms of EDS in humans are well characterized, but the genetic mutations causing EDS-like clinical pathology in dogs are not known, thus hampering accurate [...] Read more.
The Ehlers–Danlos syndromes (EDS) are a heterogeneous group of heritable disorders affecting connective tissues. The mutations causing the various forms of EDS in humans are well characterized, but the genetic mutations causing EDS-like clinical pathology in dogs are not known, thus hampering accurate clinical diagnosis. Clinical analysis of two independent cases of skin hyperextensibility and fragility, one with pronounced joint hypermobility was suggestive of EDS. Whole-genome sequencing revealed de novo mutations of COL5A1 in both cases, confirming the diagnosis of the classical form of EDS. The heterozygous COL5A1 p.Gly1013ValfsTer260 mutation characterized in case 1 introduced a premature termination codon and would be expected to result in α1(V) mRNA nonsense-mediated mRNA decay and collagen V haploinsufficiency. While mRNA was not available from this dog, ultrastructural analysis of the dermis demonstrated variability in collagen fibril diameter and the presence of collagen aggregates, termed ‘collagen cauliflowers’, consistent with COL5A1 mutations underlying classical EDS. In the second case, DNA sequencing demonstrated a p.Gly1571Arg missense variant in the COL5A1 gene. While samples were not available for further analysis, such a glycine substitution would be expected to destabilize the strict molecular structure of the collagen V triple helix and thus affect protein stability and/or integration of the mutant collagen into the collagen V/collagen I heterotypic dermal fibrils. This is the first report of genetic variants in the COL5A1 gene causing the clinical presentation of EDS in dogs. These data provided further evidence of the important role of collagen V in dermal collagen fibrillogenesis. Importantly, from the clinical perspective, we showed the utility of DNA sequencing, combined with the established clinical criteria, in the accurate diagnosis of EDS in dogs. Full article
(This article belongs to the Special Issue Canine Genetics)
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12 pages, 1007 KiB  
Article
Novel Locus Associated with Symmetrical Lupoid Onychodystrophy in the Bearded Collie
by Liza C. Gershony, Janelle M. Belanger, Marjo K. Hytönen, Hannes Lohi and Anita M. Oberbauer
Genes 2019, 10(9), 635; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10090635 - 22 Aug 2019
Cited by 2 | Viewed by 4145
Abstract
Symmetrical lupoid onychodystrophy (SLO) is characterized by inflammation of the nail bed and nail sloughing that causes affected dogs considerable pain. Disease etiology remains unclear, although an autoimmune component is suspected. A genome-wide association study on Bearded Collies revealed regions of association on [...] Read more.
Symmetrical lupoid onychodystrophy (SLO) is characterized by inflammation of the nail bed and nail sloughing that causes affected dogs considerable pain. Disease etiology remains unclear, although an autoimmune component is suspected. A genome-wide association study on Bearded Collies revealed regions of association on canine chromosomes (CFA) 12 and 17. The large region of association on CFA12 likely consists of two smaller linked regions, both of which are also linked to the dog leukocyte antigen (DLA) class II genes. Dogs homozygous for the alternate allele at the top CFA12 SNP also carried two DLA class II risk haplotypes for SLO, and this locus explained most of the increased risk for disease seen throughout the CFA12 region of association. A stronger peak was seen on CFA17 when analysis was done solely on dogs that carried DLA class II risk haplotypes for SLO. The majority of SLO dogs carried a homozygous alternate genotype on CFA12 and at least one CFA17 risk haplotype. Our findings offer progress toward uncovering the genetic basis of SLO. While the contribution of the CFA17 region remains unclear, both CFA12 and CFA17 regions are significantly associated with SLO disease expression in the Bearded Collie and contain potential candidate genes for this disease. Full article
(This article belongs to the Special Issue Canine Genetics)
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7 pages, 815 KiB  
Article
AKNA Frameshift Variant in Three Dogs with Recurrent Inflammatory Pulmonary Disease
by Petra Hug, Linda Anderegg, Alexandra Kehl, Vidhya Jagannathan and Tosso Leeb
Genes 2019, 10(8), 567; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10080567 - 26 Jul 2019
Cited by 5 | Viewed by 3249
Abstract
We investigated three related Rough Collies with recurrent inflammatory pulmonary disease. The clinical symptoms were similar to primary ciliary dyskinesia (PCD). However, the affected dogs did not carry any known pathogenic PCD variants. Pedigree analysis suggested a recessive mode of inheritance. Combined linkage [...] Read more.
We investigated three related Rough Collies with recurrent inflammatory pulmonary disease. The clinical symptoms were similar to primary ciliary dyskinesia (PCD). However, the affected dogs did not carry any known pathogenic PCD variants. Pedigree analysis suggested a recessive mode of inheritance. Combined linkage and homozygosity mapping in three cases and seven non-affected family members delineated 19 critical intervals on 10 chromosomes comprising a total of 99 Mb. The genome of one affected dog was sequenced and compared to 601 control genomes. We detected only a single private homozygous protein-changing variant in the critical intervals. The detected variant was a 4 bp deletion, c.2717_2720delACAG, in the AKNA gene encoding the AT-hook transcription factor. It causes a frame-shift introducing a premature stop codon and truncates 37% of the open reading frame, p.(Asp906Alafs*173). We genotyped 88 Rough Collies consisting of family members and unrelated individuals. All three available cases were homozygous for the mutant allele and all 85 non-affected dogs were either homozygous wildtype (n = 67) or heterozygous (n = 18). AKNA modulates inflammatory immune responses. Akna−/− knockout mice die shortly after birth due to systemic autoimmune inflammatory processes including lung inflammation that is accompanied by enhanced leukocyte infiltration and alveolar destruction. The perfect genotype-phenotype association and the comparative functional data strongly suggest that the detected AKNA:c.2717_2720delACAG variant caused the observed severe airway inflammation in the investigated dogs. Our findings enable genetic testing, which can be used to avoid the unintentional breeding of affected puppies. Full article
(This article belongs to the Special Issue Canine Genetics)
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11 pages, 1176 KiB  
Article
Activating Mutations in PTPN11 and KRAS in Canine Histiocytic Sarcomas
by Marilia Takada, Lauren A. Smyth, Tuddow Thaiwong, Marlee Richter, Sarah M. Corner, Peter Z. Schall, Matti Kiupel and Vilma Yuzbasiyan-Gurkan
Genes 2019, 10(7), 505; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10070505 - 04 Jul 2019
Cited by 15 | Viewed by 3888
Abstract
While the genetic contributions to the predisposition of Bernese mountain dogs (BMDs) to histiocytic sarcoma (HS) remains unclear, some insights into key genetic drivers have been gained. Our group recently reported a mutation in the PTPN11 gene (E76K). We have now identified a [...] Read more.
While the genetic contributions to the predisposition of Bernese mountain dogs (BMDs) to histiocytic sarcoma (HS) remains unclear, some insights into key genetic drivers have been gained. Our group recently reported a mutation in the PTPN11 gene (E76K). We have now identified a second missense mutation in PTPN11 (G503V), and a mutation in KRAS (Q61H) present in HS cell lines. These mutations are associated with malignancies in humans, and known to be gain-of-function mutations that result in activation of the mitogen-activated protein kinase (MAPK) pathway. The goal of the present study was to evaluate the prevalence of these mutations in a large sample of HS cases from BMDs and golden retrievers, and in lymphoma cases, from a cohort of BMDs. Mutations in PTPN11 were present in HS in 41/96 (43%) BMDs, and in 3/13 (23%) golden retrievers. PTPN11 mutations E76K and G503V did not coexist in the same neoplasm. The KRAS mutation was much less frequent, with a prevalence of 3.1% (3/96). We did not identify either PTPN11 nor KRAS mutations in any of the lymphoma samples. These results point out the potential relevance of PTPN11 and KRAS mutations as activators of the oncogenic MAPK pathway for canine HS, particularly in BMDs. Full article
(This article belongs to the Special Issue Canine Genetics)
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14 pages, 2616 KiB  
Article
Genome-Wide Analysis of Long Non-Coding RNA Profiles in Canine Oral Melanomas
by Christophe Hitte, Céline Le Béguec, Edouard Cadieu, Valentin Wucher, Aline Primot, Anaïs Prouteau, Nadine Botherel, Benoît Hédan, Kerstin Lindblad-Toh, Catherine André and Thomas Derrien
Genes 2019, 10(6), 477; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10060477 - 23 Jun 2019
Cited by 15 | Viewed by 4426
Abstract
Mucosal melanomas (MM) are rare aggressive cancers in humans, and one of the most common forms of oral cancers in dogs. Similar biological and histological features are shared between MM in both species, making dogs a powerful model for comparative oncology studies of [...] Read more.
Mucosal melanomas (MM) are rare aggressive cancers in humans, and one of the most common forms of oral cancers in dogs. Similar biological and histological features are shared between MM in both species, making dogs a powerful model for comparative oncology studies of melanomas. Although exome sequencing recently identified recurrent coding mutations in canine MM, little is known about changes in non-coding gene expression, and more particularly, in canine long non-coding RNAs (lncRNAs), which are commonly dysregulated in human cancers. Here, we sampled a large cohort (n = 52) of canine normal/tumor oral MM from three predisposed breeds (poodles, Labrador retrievers, and golden retrievers), and used deep transcriptome sequencing to identify more than 400 differentially expressed (DE) lncRNAs. We further prioritized candidate lncRNAs by comparative genomic analysis to pinpoint 26 dog–human conserved DE lncRNAs, including SOX21-AS, ZEB2-AS, and CASC15 lncRNAs. Using unsupervised co-expression network analysis with coding genes, we inferred the potential functions of the DE lncRNAs, suggesting associations with cancer-related genes, cell cycle, and carbohydrate metabolism Gene Ontology (GO) terms. Finally, we exploited our multi-breed design to identify DE lncRNAs within breeds. This study provides a unique transcriptomic resource for studying oral melanoma in dogs, and highlights lncRNAs that may potentially be diagnostic or therapeutic targets for human and veterinary medicine. Full article
(This article belongs to the Special Issue Canine Genetics)
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11 pages, 1214 KiB  
Article
A SIX6 Nonsense Variant in Golden Retrievers with Congenital Eye Malformations
by Petra Hug, Linda Anderegg, Nicole Dürig, Vincent Lepori, Vidhya Jagannathan, Bernhard Spiess, Marianne Richter and Tosso Leeb
Genes 2019, 10(6), 454; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10060454 - 14 Jun 2019
Cited by 5 | Viewed by 4207
Abstract
Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies [...] Read more.
Causative genetic variants for more than 30 heritable eye disorders in dogs have been reported. For other clinically described eye disorders, the genetic cause is still unclear. We investigated four Golden Retriever litters segregating for highly variable congenital eye malformations. Several affected puppies had unilateral or bilateral retina dysplasia and/or optic nerve hypoplasia. The four litters shared the same father or grandfather suggesting a heritable condition with an autosomal dominant mode of inheritance. The genome of one affected dog was sequenced and compared to 601 control genomes. A heterozygous private nonsense variant, c.487C>T, was found in the SIX6 gene. This variant is predicted to truncate about a third of the open reading frame, p.(Gln163*). We genotyped all available family members and 464 unrelated Golden Retrievers. All three available cases were heterozygous. Five additional close relatives including the common sire were also heterozygous, but did not show any obvious eye phenotypes. The variant was absent from the 464 unrelated Golden Retrievers and 17 non-affected siblings of the cases. The SIX6 protein is a homeobox transcription factor with a known role in eye development. In humans and other species, SIX6 loss of function variants were reported to cause congenital eye malformations. This strongly suggests that the c.487C>T variant detected contributed to the observed eye malformations. We hypothesize that the residual amount of functional SIX6 protein likely to be expressed in heterozygous dogs is sufficient to explain the observed incomplete penetrance and the varying severity of the eye defects in the affected dogs. Full article
(This article belongs to the Special Issue Canine Genetics)
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14 pages, 955 KiB  
Article
Homozygosity for Mobile Element Insertions Associated with WBSCR17 Could Predict Success in Assistance Dog Training Programs
by Dhriti Tandon, Kyra Ressler, Daniel Petticord, Andrea Papa, Juliana Jiranek, Riley Wilkinson, Rebecca Y. Kartzinel, Elaine A. Ostrander, Nathaniel Burney, Carol Borden, Monique A. R. Udell and Bridgett M. VonHoldt
Genes 2019, 10(6), 439; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10060439 - 09 Jun 2019
Cited by 8 | Viewed by 5224
Abstract
Assistance dog training programs can see as many as 60% of their trainees dismissed. Many training programs utilize behavioral assays prior to admittance to identify likely successful candidates, yet such assays can be insconsistent. Recently, four canine retrotransposon mobile element insertions (MEIs) in [...] Read more.
Assistance dog training programs can see as many as 60% of their trainees dismissed. Many training programs utilize behavioral assays prior to admittance to identify likely successful candidates, yet such assays can be insconsistent. Recently, four canine retrotransposon mobile element insertions (MEIs) in or near genes WBSCR17 (Cfa6.6 and Cfa6.7), GTF2I (Cfa6.66) and POM121 (Cfa6.83) were identified in domestic dogs and gray wolves. Variations in these MEIs were significantly associated with a heightened propensity to initiate prolonged social contact or hypersociability. Using our dataset of 837 dogs, 228 of which had paired survey-based behavioral data, we discovered that one of the insertions in WBSCR17 is the most important predictor of dog sociable behaviors related to human proximity, measured by the Canine Behavioral Assessment Research Questionnaire (C-BARQ©). We found a positive correlation between insertions at Cfa6.6 and dog separation distress in the form of restlessness when about to be left alone by the owner. Lastly, assistance dogs showed significant heterozygosity deficiency at locus Cfa6.6 and higher frequency of insertions at Cfa6.6 and Cfa6.7. We suggest that training programs could utilize this genetic survey to screen for MEIs at WBSCR17 to identify dogs with sociable traits compatible with successful assistance dog performance. Full article
(This article belongs to the Special Issue Canine Genetics)
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17 pages, 1943 KiB  
Article
Phenotypic Effects of FGF4 Retrogenes on Intervertebral Disc Disease in Dogs
by Kevin Batcher, Peter Dickinson, Michelle Giuffrida, Beverly Sturges, Karen Vernau, Marguerite Knipe, Sheida Hadji Rasouliha, Cord Drögemüller, Tosso Leeb, Kimberly Maciejczyk, Christopher A. Jenkins, Cathryn Mellersh and Danika Bannasch
Genes 2019, 10(6), 435; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10060435 - 07 Jun 2019
Cited by 31 | Viewed by 12478
Abstract
Two FGF4 retrogenes on chromosomes 12 (12-FGF4RG) and 18 (18-FGF4RG) contribute to short-limbed phenotypes in dogs. 12-FGF4RG has also been associated with intervertebral disc disease (IVDD). Both of these retrogenes were found to be widespread among dog [...] Read more.
Two FGF4 retrogenes on chromosomes 12 (12-FGF4RG) and 18 (18-FGF4RG) contribute to short-limbed phenotypes in dogs. 12-FGF4RG has also been associated with intervertebral disc disease (IVDD). Both of these retrogenes were found to be widespread among dog breeds with allele frequencies ranging from 0.02 to 1; however, their additive contribution to disease is unknown. Surgical cases of IVDD (n = 569) were evaluated for age of onset, disc calcification, and genotypes for the FGF4 retrogenes. Multivariable linear regression analysis identified the presence of one or two copies of 12-FGF4RG associated with significantly younger age at first surgery in a dominant manner. 18-FGF4RG had only a minor effect in dogs with one copy. Multivariable logistic regression showed that 12-FGF4RG had an additive effect on radiographic disc calcification, while 18-FGF4RG had no effect. Multivariable logistic regression using mixed breed cases and controls identified only 12-FGF4RG as highly associated with disc herniation in a dominant manner (Odds Ratio, OR, 18.42, 95% Confidence Interval (CI) 7.44 to 50.26; p < 0.001). The relative risk for disc surgery associated with 12-FGF4RG varied from 5.5 to 15.1 within segregating breeds and mixed breeds. The FGF4 retrogene on CFA12 acts in a dominant manner to decrease the age of onset and increase the overall risk of disc disease in dogs. Other modifiers of risk may be present within certain breeds, including the FGF4 retrogene on CFA18. Full article
(This article belongs to the Special Issue Canine Genetics)
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28 pages, 5528 KiB  
Article
BarkBase: Epigenomic Annotation of Canine Genomes
by Kate Megquier, Diane P. Genereux, Jessica Hekman, Ross Swofford, Jason Turner-Maier, Jeremy Johnson, Jacob Alonso, Xue Li, Kathleen Morrill, Lynne J. Anguish, Michele Koltookian, Brittney Logan, Claire R. Sharp, Lluis Ferrer, Kerstin Lindblad-Toh, Vicki N. Meyers-Wallen, Andrew Hoffman and Elinor K. Karlsson
Genes 2019, 10(6), 433; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10060433 - 07 Jun 2019
Cited by 21 | Viewed by 8542
Abstract
Dogs are an unparalleled natural model for investigating the genetics of health and disease, particularly for complex diseases like cancer. Comprehensive genomic annotation of regulatory elements active in healthy canine tissues is crucial both for identifying candidate causal variants and for designing functional [...] Read more.
Dogs are an unparalleled natural model for investigating the genetics of health and disease, particularly for complex diseases like cancer. Comprehensive genomic annotation of regulatory elements active in healthy canine tissues is crucial both for identifying candidate causal variants and for designing functional studies needed to translate genetic associations into disease insight. Currently, canine geneticists rely primarily on annotations of the human or mouse genome that have been remapped to dog, an approach that misses dog-specific features. Here, we describe BarkBase, a canine epigenomic resource available at barkbase.org. BarkBase hosts data for 27 adult tissue types, with biological replicates, and for one sample of up to five tissues sampled at each of four carefully staged embryonic time points. RNA sequencing is complemented with whole genome sequencing and with assay for transposase-accessible chromatin using sequencing (ATAC-seq), which identifies open chromatin regions. By including replicates, we can more confidently discern tissue-specific transcripts and assess differential gene expression between tissues and timepoints. By offering data in easy-to-use file formats, through a visual browser modeled on similar genomic resources for human, BarkBase introduces a powerful new resource to support comparative studies in dogs and humans. Full article
(This article belongs to the Special Issue Canine Genetics)
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27 pages, 5778 KiB  
Article
The Red Fox Y-Chromosome in Comparative Context
by Halie M. Rando, William H. Wadlington, Jennifer L. Johnson, Jeremy T. Stutchman, Lyudmila N. Trut, Marta Farré and Anna V. Kukekova
Genes 2019, 10(6), 409; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10060409 - 28 May 2019
Cited by 6 | Viewed by 4557
Abstract
While the number of mammalian genome assemblies has proliferated, Y-chromosome assemblies have lagged behind. This discrepancy is caused by biological features of the Y-chromosome, such as its high repeat content, that present challenges to assembly with short-read, next-generation sequencing technologies. Partial Y-chromosome assemblies [...] Read more.
While the number of mammalian genome assemblies has proliferated, Y-chromosome assemblies have lagged behind. This discrepancy is caused by biological features of the Y-chromosome, such as its high repeat content, that present challenges to assembly with short-read, next-generation sequencing technologies. Partial Y-chromosome assemblies have been developed for the cat (Felis catus), dog (Canis lupus familiaris), and grey wolf (Canis lupus lupus), providing the opportunity to examine the red fox (Vulpes vulpes) Y-chromosome in the context of closely related species. Here we present a data-driven approach to identifying Y-chromosome sequence among the scaffolds that comprise the short-read assembled red fox genome. First, scaffolds containing genes found on the Y-chromosomes of cats, dogs, and wolves were identified. Next, analysis of the resequenced genomes of 15 male and 15 female foxes revealed scaffolds containing male-specific k-mers and patterns of inter-sex copy number variation consistent with the heterogametic chromosome. Analyzing variation across these two metrics revealed 171 scaffolds containing 3.37 Mbp of putative Y-chromosome sequence. The gene content of these scaffolds is consistent overall with that of the Y-chromosome in other carnivore species, though the red fox Y-chromosome carries more copies of BCORY2 and UBE1Y than has been reported in related species and fewer copies of SRY than in other canids. The assignment of these scaffolds to the Y-chromosome serves to further characterize the content of the red fox draft genome while providing resources for future analyses of canid Y-chromosome evolution. Full article
(This article belongs to the Special Issue Canine Genetics)
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9 pages, 1408 KiB  
Article
Identification of a Missense Variant in MFSD12 Involved in Dilution of Phaeomelanin Leading to White or Cream Coat Color in Dogs
by Benoit Hédan, Edouard Cadieu, Nadine Botherel, Caroline Dufaure de Citres, Anna Letko, Maud Rimbault, Cord Drögemüller, Vidhya Jagannathan, Thomas Derrien, Sheila Schmutz, Tosso Leeb and Catherine André
Genes 2019, 10(5), 386; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10050386 - 21 May 2019
Cited by 18 | Viewed by 11487
Abstract
White coat color in mammals has been selected several times during the domestication process. Numerous dog breeds are fixed for one form of white coat color that involves darkly pigmented skin. The genetic basis of this color, due to the absence of pigment [...] Read more.
White coat color in mammals has been selected several times during the domestication process. Numerous dog breeds are fixed for one form of white coat color that involves darkly pigmented skin. The genetic basis of this color, due to the absence of pigment in the hairs, was suggested to correspond to extreme dilution of the phaeomelanin, by both the expression of only phaeomelanin (locus E) and its extreme dilution (locus I). To go further, we performed genome-wide association studies (GWAS) using a multiple breed approach. The first GWAS, using 34 white dogs and 128 non-white dogs, including White Shepherds, Poodles, Cotons de Tulear and Bichons allowed us to identify two significantly associated loci on the locus E and a novel locus on chromosome 20. A second GWAS using 15 other breeds presenting extreme phaeomelanin dilution confirmed the position of locus I on the chromosome 20 (position 55 Mb pcorrected = 6 × 10−13). Using whole-genome sequencing, we identified a missense variant in the first exon of MFSD12, a gene recently identified to be involved in human, mouse and horse pigmentation. We confirmed the role of this variant in phaeomelanin dilution of numerous canine breeds, and the conserved role of MFSD12 in mammalian pigmentation. Full article
(This article belongs to the Special Issue Canine Genetics)
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17 pages, 2565 KiB  
Article
Whole Genome Sequencing of Giant Schnauzer Dogs with Progressive Retinal Atrophy Establishes NECAP1 as a Novel Candidate Gene for Retinal Degeneration
by Rebekkah J. Hitti, James A. C. Oliver, Ellen C. Schofield, Anina Bauer, Maria Kaukonen, Oliver P. Forman, Tosso Leeb, Hannes Lohi, Louise M. Burmeister, David Sargan and Cathryn S. Mellersh
Genes 2019, 10(5), 385; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10050385 - 21 May 2019
Cited by 6 | Viewed by 8273
Abstract
Canine progressive retinal atrophies (PRA) are genetically heterogeneous diseases characterized by retinal degeneration and subsequent blindness. PRAs are untreatable and affect multiple dog breeds, significantly impacting welfare. Three out of seven Giant Schnauzer (GS) littermates presented with PRA around four years of age. [...] Read more.
Canine progressive retinal atrophies (PRA) are genetically heterogeneous diseases characterized by retinal degeneration and subsequent blindness. PRAs are untreatable and affect multiple dog breeds, significantly impacting welfare. Three out of seven Giant Schnauzer (GS) littermates presented with PRA around four years of age. We sought to identify the causal variant to improve our understanding of the aetiology of this form of PRA and to enable development of a DNA test. Whole genome sequencing of two PRA-affected full-siblings and both unaffected parents was performed. Variants were filtered based on those segregating appropriately for an autosomal recessive disorder and predicted to be deleterious. Successive filtering against 568 canine genomes identified a single nucleotide variant in the gene encoding NECAP endocytosis associated 1 (NECAP1): c.544G>A (p.Gly182Arg). Five thousand one hundred and thirty canids of 175 breeds, 10 cross-breeds and 3 wolves were genotyped for c.544G>A. Only the three PRA-affected GS were homozygous (allele frequency in GS, excluding proband family = 0.015). In addition, we identified heterozygotes belonging to Spitz and Dachshund varieties, demonstrating c.544G>A segregates in other breeds of German origin. This study, in parallel with the known retinal expression and role of NECAP1 in clathrin mediated endocytosis (CME) in synapses, presents NECAP1 as a novel candidate gene for retinal degeneration in dogs and other species. Full article
(This article belongs to the Special Issue Canine Genetics)
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10 pages, 2114 KiB  
Article
A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia
by Anna Letko, Elisabeth Dietschi, Marco Nieburg, Vidhya Jagannathan, Corinne Gurtner, Anna Oevermann and Cord Drögemüller
Genes 2019, 10(5), 362; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10050362 - 10 May 2019
Cited by 7 | Viewed by 3650
Abstract
Spinocerebellar ataxias is an umbrella term for clinically- and neuropathologically-heterogeneous early-onset hereditary neurodegenerative diseases affecting several dog breeds. The purpose of this study is to identify the causative genetic variant associated with ataxia, tremor, and loss of balance in Alpine Dachsbracke dogs. We [...] Read more.
Spinocerebellar ataxias is an umbrella term for clinically- and neuropathologically-heterogeneous early-onset hereditary neurodegenerative diseases affecting several dog breeds. The purpose of this study is to identify the causative genetic variant associated with ataxia, tremor, and loss of balance in Alpine Dachsbracke dogs. We investigated two related litters in which four cases were reported. Neuropathology of two dogs revealed spongy degeneration associated with axonal degeneration. Combined genetic linkage and autozygosity analyses in four cases and eight related controls showed one critical disease-associated interval on chromosomes 27. Private whole-genome sequence variants of one ataxia case against 600 unrelated controls revealed one protein-changing variant within the critical interval in the SCN8A gene (c.4898G>T; p.Gly1633Val). Perfect segregation with the phenotype was confirmed by genotyping >200 Alpine Dachsbracke dogs. SCN8A encodes a voltage-gated sodium channel and the missense variant was predicted deleterious by three different in silico prediction tools. Pathogenic variants in SCN8A were previously reported in humans with ataxia, pancerebellar atrophy, and cognitive disability. Furthermore, cerebellar ataxia syndrome in the ‘jolting’ mutant mice is caused by a missense variant in Scn8a. Therefore, we considered the SCN8A:c.4898G>T variant to be the most likely cause for recessively inherited spinocerebellar ataxia in Alpine Dachsbracke dogs. Full article
(This article belongs to the Special Issue Canine Genetics)
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12 pages, 1736 KiB  
Article
Genomic Characterization of External Morphology Traits in Kelpies Does Not Support Common Ancestry with the Australian Dingo
by Tracy Chew, Cali E. Willet, Bianca Haase and Claire M. Wade
Genes 2019, 10(5), 337; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10050337 - 03 May 2019
Cited by 11 | Viewed by 17443
Abstract
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 (Canis dingo), a canid species present on the Australian [...] Read more.
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 (Canis 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. Full article
(This article belongs to the Special Issue Canine Genetics)
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11 pages, 788 KiB  
Article
Hair of the Dog: Identification of a Cis-Regulatory Module Predicted to Influence Canine Coat Composition
by D. Thad Whitaker and Elaine A. Ostrander
Genes 2019, 10(5), 323; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10050323 - 26 Apr 2019
Cited by 14 | Viewed by 6012
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Canine Genetics)
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11 pages, 2224 KiB  
Article
Novel Y Chromosome Retrocopies in Canids Revealed through a Genome-Wide Association Study for Sex
by Kate L. Tsai, Jacquelyn M. Evans, Rooksana E. Noorai, Alison N. Starr-Moss and Leigh Anne Clark
Genes 2019, 10(4), 320; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10040320 - 25 Apr 2019
Cited by 15 | Viewed by 4701
Abstract
The lack of an annotated reference sequence for the canine Y chromosome has limited evolutionary studies, as well as our understanding of the role of Y-linked sequences in phenotypes with a sex bias. In genome-wide association studies (GWASs), we observed spurious associations with [...] Read more.
The lack of an annotated reference sequence for the canine Y chromosome has limited evolutionary studies, as well as our understanding of the role of Y-linked sequences in phenotypes with a sex bias. In genome-wide association studies (GWASs), we observed spurious associations with autosomal SNPs when sex was unbalanced in case-control cohorts and hypothesized that a subset of SNPs mapped to autosomes are in fact sex-linked. Using the Illumina 230K CanineHD array in a GWAS for sex, we identified SNPs that amplify in both sexes but possess significant allele frequency differences between males and females. We found 48 SNPs mapping to 14 regions of eight autosomes and the X chromosome that are Y-linked, appearing heterozygous in males and monomorphic in females. Within these 14 regions are eight genes: three autosomal and five X-linked. We investigated the autosomal genes (MITF, PPP2CB, and WNK1) and determined that the SNPs are diverged nucleotides in retrocopies that have transposed to the Y chromosome. MITFY and WNK1Y are expressed and appeared recently in the Canidae lineage, whereas PPP2CBY represents a much older insertion with no evidence of expression in the dog. This work reveals novel canid Y chromosome sequences and provides evidence for gene transposition to the Y from autosomes and the X. Full article
(This article belongs to the Special Issue Canine Genetics)
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10 pages, 3066 KiB  
Article
A QIL1 Variant Associated with Ventricular Arrhythmias and Sudden Cardiac Death in the Juvenile Rhodesian Ridgeback Dog
by Kathryn M. Meurs, Steven G. Friedenberg, Natasha J. Olby, Julia Condit, Jess Weidman, Steve Rosenthal and G. Diane Shelton
Genes 2019, 10(2), 168; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10020168 - 21 Feb 2019
Cited by 11 | Viewed by 5430
Abstract
The QIl1 gene produces a component of the Mitochondrial Contact Site and Cristae Organizing System that forms and stabilizes mitochondrial cristae junctions and is important in cellular energy production. We previously reported a family of Rhodesian Ridgebacks with cardiac arrhythmias and sudden cardiac [...] Read more.
The QIl1 gene produces a component of the Mitochondrial Contact Site and Cristae Organizing System that forms and stabilizes mitochondrial cristae junctions and is important in cellular energy production. We previously reported a family of Rhodesian Ridgebacks with cardiac arrhythmias and sudden cardiac death. Here, we performed whole genome sequencing on a trio from the family. Variant calling was performed using a standardized bioinformatics approach. Variants were filtered against variants from 247 dogs of 43 different breeds. High impact variants were validated against additional affected and unaffected dogs. A single missense G/A variant in the QIL1 gene was associated with the cardiac arrhythmia (p < 0.0001). The variant was predicted to change the amino acid from conserved Glycine to Serine and to be deleterious. Ultrastructural analysis of the biceps femoris muscle from an affected dog revealed hyperplastic mitochondria, cristae rearrangement, electron dense inclusions and lipid bodies. We identified a variant in the Q1l1 gene resulting in a mitochondrial cardiomyopathy characterized by cristae abnormalities and cardiac arrhythmias in a canine model. This natural animal model of mitochondrial cardiomyopathy provides a large animal model with which to study the development and progression of disease as well as genotypic phenotypic relationships. Full article
(This article belongs to the Special Issue Canine Genetics)
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Review

Jump to: Research

20 pages, 2795 KiB  
Review
Canine Melanomas as Models for Human Melanomas: Clinical, Histological, and Genetic Comparison
by Anaïs Prouteau and Catherine André
Genes 2019, 10(7), 501; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10070501 - 30 Jun 2019
Cited by 82 | Viewed by 16365
Abstract
Despite recent genetic advances and numerous ongoing therapeutic trials, malignant melanoma remains fatal, and prognostic factors as well as more efficient treatments are needed. The development of such research strongly depends on the availability of appropriate models recapitulating all the features of human [...] Read more.
Despite recent genetic advances and numerous ongoing therapeutic trials, malignant melanoma remains fatal, and prognostic factors as well as more efficient treatments are needed. The development of such research strongly depends on the availability of appropriate models recapitulating all the features of human melanoma. The concept of comparative oncology, with the use of spontaneous canine models has recently acquired a unique value as a translational model. Canine malignant melanomas are naturally occurring cancers presenting striking homologies with human melanomas. As for many other cancers, dogs present surprising breed predispositions and higher frequency of certain subtypes per breed. Oral melanomas, which are much more frequent and highly severe in dogs and cutaneous melanomas with severe digital forms or uveal subtypes are subtypes presenting relevant homologies with their human counterparts, thus constituting close models for these human melanoma subtypes. This review addresses how canine and human melanoma subtypes compare based on their epidemiological, clinical, histological, and genetic characteristics, and how comparative oncology approaches can provide insights into rare and poorly characterized melanoma subtypes in humans that are frequent and breed-specific in dogs. We propose canine malignant melanomas as models for rare non-UV-induced human melanomas, especially mucosal melanomas. Naturally affected dogs offer the opportunity to decipher the genetics at both germline and somatic levels and to explore therapeutic options, with the dog entering preclinical trials as human patients, benefiting both dogs and humans. Full article
(This article belongs to the Special Issue Canine Genetics)
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