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Advances in Canine Genetics
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Advances in 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 (20 November 2022) | Viewed by 53860

Special Issue Editor

Dr. Dayna Dreger

E-Mail Website
Guest Editor
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
Interests: domestic dog; selection; population genetics; breeds; morphology; behavior; canine genetics

Special Issue Information

Dear Colleagues,

The centuries through which humans have shared our homes and livelihoods with dogs are written in their genomes. Our technological and analytical innovations allow us to reveal those long-held secrets that have tied our species together over time. Through the combined efforts of the global canine genetics research community, the domestic dog has been propelled to the forefront of scientific advancements in the areas of health, morphology, population genetics, domestication, and behavior. The continually improving accessibility to cutting-edge genetic technologies has opened the door for amazing discoveries that benefit both dogs and humans.

This Special Issue on advances in canine genetics will explore the ways in which the domestic dog contributes to scientific discoveries. Broad topic areas include the genetic mapping of variants in disease and morphology, population genetics and demography of domestic and wild canids, the inheritance of complex phenotypes such as cancer and behavior, and bioinformatic applications and innovations.

Dr. Dayna Dreger
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • dog
  • genomics
  • genetics
  • mapping
  • variant
  • population
  • domestication
  • disease
  • behavior
  • morphology

Published Papers (19 papers)

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Research

13 pages, 2460 KiB  
Article
SGCD Missense Variant in a Lagotto Romagnolo Dog with Autosomal Recessively Inherited Limb-Girdle Muscular Dystrophy
by Barbara Brunetti, Barbara Bacci, Jessica Maria Abbate, Giorgia Tura, Orlando Paciello, Emanuela Vaccaro, Francesco Prisco, Gualtiero Gandini, Samuel Okonji, Andrea di Paola, Anna Letko, Cord Drögemüller, Vidhya Jagannathan, Maria Elena Turba, Tolulope Grace Ogundipe, Luca Lorenzini, Marco Rosati, Dimitra Psalla, Tosso Leeb and Michaela Drögemüller
Genes 2023, 14(8), 1641; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14081641 - 18 Aug 2023
Cited by 1 | Viewed by 1116
Abstract
An 8-month-old female Lagotto Romagnolo dog was presented for a 1-month history of an initial severe reluctance to move, rapidly progressing to a marked stiff gait and progressive muscular weakness and evolving to tetraparesis, which persuaded the owner to request euthanasia. A primary [...] Read more.
An 8-month-old female Lagotto Romagnolo dog was presented for a 1-month history of an initial severe reluctance to move, rapidly progressing to a marked stiff gait and progressive muscular weakness and evolving to tetraparesis, which persuaded the owner to request euthanasia. A primary muscle pathology was supported by necropsy and histopathological findings. Macroscopically, the muscles were moderately atrophic, except for the diaphragm and the neck muscles, which were markedly thickened. Histologically, all the skeletal muscles examined showed atrophy, hypertrophy, necrosis with calcification of the fibers, and mild fibrosis and inflammation. On immunohistochemistry, all three dystrophin domains and sarcoglycan proteins were absent. On Western blot analysis, no band was present for delta sarcoglycan. We sequenced the genome of the affected dog and compared the data to more than 900 control genomes of different dog breeds. Genetic analysis revealed a homozygous private protein-changing variant in the SGCD gene encoding delta- sarcoglycan in the affected dog. The variant was predicted to induce a SGCD:p.(Leu242Pro) change in the protein. In silico tools predicted the change to be deleterious. Other 770 Lagotto Romagnolo dogs were genotyped for the variant and all found to be homozygous wild type. Based on current knowledge of gene function in other mammalian species, including humans, hamsters, and dogs, we propose the SGCD missense variant as the causative variant of the observed form of muscular dystrophy in the index case. The absence of the variant allele in the Lagotto Romagnolo breeding population indicates a rare allele that has appeared recently. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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12 pages, 1017 KiB  
Article
Genomic Diversity and Runs of Homozygosity in Bernese Mountain Dogs
by Anna Letko, Benoît Hédan, Anna Snell, Alexander C. Harris, Vidhya Jagannathan, Göran Andersson, Bodil S. Holst, Elaine A. Ostrander, Pascale Quignon, Catherine André and Tosso Leeb
Genes 2023, 14(3), 650; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14030650 - 04 Mar 2023
Cited by 2 | Viewed by 3165
Abstract
Bernese mountain dogs are a large dog breed formed in the early 1900s in Switzerland. While originally farm dogs that were used for pulling carts, guarding, and driving cattle, today they are considered multi-purpose companion and family dogs. The breed is predisposed to [...] Read more.
Bernese mountain dogs are a large dog breed formed in the early 1900s in Switzerland. While originally farm dogs that were used for pulling carts, guarding, and driving cattle, today they are considered multi-purpose companion and family dogs. The breed is predisposed to several complex diseases, such as histiocytic sarcoma, degenerative myelopathy, or hip dysplasia. Using whole-genome sequencing (WGS) data, we assessed the genomic architecture of 33 unrelated dogs from four countries: France, Sweden, Switzerland, and the United States. Analysis of runs of homozygosity (ROH) identified 12,643 ROH with an average length of 2.29 Mb and an average inbreeding coefficient of 0.395. Multidimensional scaling analysis of the genetic relatedness revealed limited clustering of European versus USA dogs, suggesting exchanges of breeding stock between continents. Furthermore, only two mtDNA haplotypes were detected in the 33 studied dogs, both of which are widespread throughout multiple dog breeds. WGS-based ROH analyses revealed several fixed or nearly fixed regions harboring discreet morphological trait-associated as well as disease-associated genetic variants. Several genes involved in the regulation of immune cells were found in the ROH shared by all dogs, which is notable in the context of the breed’s strong predisposition to hematopoietic cancers. High levels of inbreeding and relatedness, strongly exaggerated in the last 30 years, have likely led to the high prevalence of specific genetic disorders in this breed. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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20 pages, 3357 KiB  
Article
Cellular Transcriptomics of Carboplatin Resistance in a Metastatic Canine Osteosarcoma Cell Line
by McKaela A. Hodge, Tasha Miller, Marcus A. Weinman, Brandan Wustefeld-Janssens, Shay Bracha and Brian W. Davis
Genes 2023, 14(3), 558; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14030558 - 23 Feb 2023
Viewed by 1711
Abstract
Osteosarcoma prognosis has remained unchanged for the past three decades. In both humans and canines, treatment is limited to excision, radiation, and chemotherapy. Chemoresistance is the primary cause of treatment failure, and the trajectory of tumor evolution while under selective pressure from treatment [...] Read more.
Osteosarcoma prognosis has remained unchanged for the past three decades. In both humans and canines, treatment is limited to excision, radiation, and chemotherapy. Chemoresistance is the primary cause of treatment failure, and the trajectory of tumor evolution while under selective pressure from treatment is thought to be the major contributing factor in both species. We sought to understand the nature of platinum-based chemotherapy resistance by investigating cells that were subjected to repeated treatment and recovery cycles with increased carboplatin concentrations. Three HMPOS-derived cell lines, two resistant and one naïve, underwent single-cell RNA sequencing to examine transcriptomic perturbation and identify pathways leading to resistance and phenotypic changes. We identified the mechanisms of acquired chemoresistance and inferred the induced cellular trajectory that evolved with repeated exposure. The gene expression patterns indicated that acquired chemoresistance was strongly associated with a process similar to epithelial–mesenchymal transition (EMT), a phenomenon associated with the acquisition of migratory and invasive properties associated with metastatic disease. We conclude that the observed trajectory of tumor adaptability is directly correlated with chemoresistance and the phase of the EMT-like phenotype is directly affected by the level of chemoresistance. We infer that the EMT-like phenotype is a critical component of tumor evolution under treatment pressure and is vital to understanding the mechanisms of chemoresistance and to improving osteosarcoma prognosis. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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27 pages, 4859 KiB  
Article
History of Polish Canidae (Carnivora, Mammalia) and Their Biochronological Implications on the Eurasian Background
by Adrian Marciszak, Aleksandra Kropczyk, Wiktoria Gornig, Małgorzata Kot, Adam Nadachowski and Grzegorz Lipecki
Genes 2023, 14(3), 539; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14030539 - 21 Feb 2023
Cited by 4 | Viewed by 2836
Abstract
The remains of 12 canid species that date back ca. 4.9 myr have been found at 116 paleontological localities. Among these localities, eight are dated to the Pliocene age, 12 are dated to the Early Pleistocene age, 12 are from the Middle Pleistocene [...] Read more.
The remains of 12 canid species that date back ca. 4.9 myr have been found at 116 paleontological localities. Among these localities, eight are dated to the Pliocene age, 12 are dated to the Early Pleistocene age, 12 are from the Middle Pleistocene age, while the most numerous group includes 84 sites from the Late Pleistocene–Holocene age. Some, especially older forms such as Eucyon odessanus and Nyctereutes donnezani, have only been found at single sites, while the remains of species from the genus Lycaon, Canis and Vulpes have been recorded at numerous sites from the last 2 myr. Ancient canids such as Eucyon and Nyctereutes had already vanished from Poland in the Earliest Pleistocene, between 2.5 and 2.2 myr ago. Poland’s extant canid fauna is characterised by the presence of two new species, which spread into the territory due to a human introduction (Nyctereutes procyonoides) or natural expansion (Canis aureus). Research indicates a strong competition between dogs, especially between Lycaon, Canis and Cuon, with a strong lycaon-limiting effect on the wolf between 2.5 and 0.4 myr ago. After the extinction of Lycaon lycaonoides, Canis lupus evolved rapidly, increasing in number and size, and taking over the niche occupied by Lycaon. In order to reduce competition, the body size of Cuon alpinus gradually reduced, and it became an animal adapted to the forest, highland and mountain environments. Generally, the history of canids in Poland is similar to that known of Eurasia with some noteworthy events, such as the early occurrence of Canis cf. etruscus from Węże 2 (2.9–2.6 myr ago), Lycaon falconeri from Rębielice Królewskie 1A or one of the latest occurrences of L. lycaonoides from Draby 3 (430–370 kyr). Predominantly lowland or upland in the southern part and devoid of significant ecological barriers, Poland is also an important migration corridor in the East–West system. This 500–600 km wide corridor was the Asian gateway to Europe, from where species of an eastern origin penetrated the continent’s interior. In colder periods, it was in turn a region through which boreal species or those associated with the mammoth steppe retreated. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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16 pages, 6249 KiB  
Article
Loss of Mitochondrial Genetic Diversity despite Population Growth: The Legacy of Past Wolf Population Declines
by Isabel Salado, Michaela Preick, Natividad Lupiáñez-Corpas, Alberto Fernández-Gil, Carles Vilà, Michael Hofreiter and Jennifer A. Leonard
Genes 2023, 14(1), 75; https://0-doi-org.brum.beds.ac.uk/10.3390/genes14010075 - 26 Dec 2022
Cited by 3 | Viewed by 5049
Abstract
Gray wolves (Canis lupus) in the Iberian Peninsula declined substantially in both range and population size in the last few centuries due to human persecution and habitat fragmentation. However, unlike many other western European populations, gray wolves never went extinct in [...] Read more.
Gray wolves (Canis lupus) in the Iberian Peninsula declined substantially in both range and population size in the last few centuries due to human persecution and habitat fragmentation. However, unlike many other western European populations, gray wolves never went extinct in Iberia. Since the minimum number was recorded around 1970, their numbers have significantly increased and then stabilized in recent decades. We analyzed mitochondrial genomes from 54 historical specimens of Iberian wolves from across their historical range using ancient DNA methods. We compared historical and current mitochondrial diversity in Iberian wolves at the 5′ end of the control region (n = 17 and 27) and the whole mitochondrial genome excluding the control region (n = 19 and 29). Despite an increase in population size since the 1970s, genetic diversity declined. We identified 10 whole mitochondrial DNA haplotypes in 19 historical specimens, whereas only six of them were observed in 29 modern Iberian wolves. Moreover, a haplotype that was restricted to the southern part of the distribution has gone extinct. Our results illustrate a lag between demographic and genetic diversity changes, and show that after severe population declines, genetic diversity can continue to be lost in stable or even expanding populations. This suggests that such populations may be of conservation concern even after their demographic trajectory has been reversed. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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12 pages, 2444 KiB  
Article
PCYT1A Missense Variant in Vizslas with Disproportionate Dwarfism
by Odette Ludwig-Peisker, Emily Ansel, Daniela Schweizer, Vidhya Jagannathan, Robert Loechel and Tosso Leeb
Genes 2022, 13(12), 2354; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13122354 - 13 Dec 2022
Viewed by 2492
Abstract
Disproportionate dwarfism phenotypes represent a heterogeneous subset of skeletal dysplasias and have been described in many species including humans and dogs. In this study, we investigated Vizsla dogs that were affected by disproportionate dwarfism that we propose to designate as skeletal dysplasia 3 [...] Read more.
Disproportionate dwarfism phenotypes represent a heterogeneous subset of skeletal dysplasias and have been described in many species including humans and dogs. In this study, we investigated Vizsla dogs that were affected by disproportionate dwarfism that we propose to designate as skeletal dysplasia 3 (SD3). The most striking skeletal changes comprised a marked shortening and deformation of the humerus and femur. An extended pedigree with six affected dogs suggested autosomal recessive inheritance. Combined linkage and homozygosity mapping localized a potential genetic defect to a ~4 Mb interval on chromosome 33. We sequenced the genome of an affected dog, and comparison with 926 control genomes revealed a single, private protein-changing variant in the critical interval, PCYT1A:XM_038583131.1:c.673T>C, predicted to cause an exchange of a highly conserved amino acid, XP_038439059.1:p.(Y225H). We observed perfect co-segregation of the genotypes with the phenotype in the studied family. When genotyping additional Vizslas, we encountered a single dog with disproportionate dwarfism that did not carry the mutant PCYT1A allele, which we hypothesize was due to heterogeneity. In the remaining 130 dogs, we observed perfect genotype–phenotype association, and none of the unaffected dogs were homozygous for the mutant PCYT1A allele. PCYT1A loss-of-function variants cause spondylometaphyseal dysplasia with cone–rod dystrophy (SMD-CRD) in humans. The skeletal changes in Vizslas were comparable to human patients. So far, no ocular phenotype has been recognized in dwarf Vizslas. We propose the PCYT1A missense variant as a candidate causative variant for SD3. Our data facilitate genetic testing of Vizslas to prevent the unintentional breeding of further affected puppies. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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15 pages, 1717 KiB  
Article
Genetic Variants at the Nebulette Locus Are Associated with Myxomatous Mitral Valve Disease Severity in Cavalier King Charles Spaniels
by Sophie E. Mead, Niek J. Beijerink, Mitchell O’Brien and Claire M. Wade
Genes 2022, 13(12), 2292; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13122292 - 05 Dec 2022
Viewed by 3021
Abstract
The most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually [...] Read more.
The most common cardiovascular disease in domestic dogs is myxomatous mitral valve disease (MMVD), accounting for 75% of all cardiac disease. An increase in age is generally associated with increased incidence of the disease, but Cavalier King Charles Spaniels (CKCS) exhibit an unusually high prevalence of early-onset MMVD, and thus, potentially greater cardiac morbidity and mortality compared to other breeds. Previous research has suggested that selected candidate risk alleles for MMVD are fixed in CKCSs, including six locations within the Nebulette (NEBL) gene on CFA2. The current study analysed genotypes of 180 Australian CKCSs at the identified risk loci. Of these, 178 were phenotyped for severity of disease by echocardiographic measurements of left atrium to aortic root ratio (LA:Ao) and weight normalised left ventricular end diastolic diameter (LVIDdN). Genotyping array markers correctly predicted the genotype at the risk-variant loci in the CKCS population, and the NEBL1, NEBL2 and NEBL3 variants were observed to be in perfect linkage disequilibrium in this cohort. The CKCS cohort included 6/178 dogs being heterozygous for the protective/wild-type alleles at the NEBL locus. The mean LA:Ao and LVIDdN scores of these dogs heterozygous at NEBL1-3 variants were significantly smaller, and with significantly lower variance compared to age-matched CKCSs that were homozygous for risk alleles. The lower cardiac measurements in the heterozygous dogs indicate a significantly reduced risk of severe MMVD disease. Our analysis suggests that despite relative fixation of the NEBL risk alleles, healthy reference alleles at NEBL1-3 exist in low frequency in the CKCS breed and can be used to reduce MMVD severity and mortality. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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18 pages, 3183 KiB  
Article
Balancing at the Borderline of a Breed: A Case Study of the Hungarian Short-Haired Vizsla Dog Breed, Definition of the Breed Profile Using Simple SNP-Based Methods
by László Varga, Erika Meleg Edviné, Péter Hudák, István Anton, Nóra Pálinkás-Bodzsár and Attila Zsolnai
Genes 2022, 13(11), 2022; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13112022 - 03 Nov 2022
Cited by 2 | Viewed by 2678
Abstract
The aim of this study was to determine the breed boundary of the Hungarian Short-haired Vizsla (HSV) dog breed. Seventy registered purebred HSV dogs were genotyped on approximately 145,000 SNPs. Principal Component Analysis (PCA) and Admixture analysis certified that they belong to the [...] Read more.
The aim of this study was to determine the breed boundary of the Hungarian Short-haired Vizsla (HSV) dog breed. Seventy registered purebred HSV dogs were genotyped on approximately 145,000 SNPs. Principal Component Analysis (PCA) and Admixture analysis certified that they belong to the same population. The outer point of the breed demarcation was a single Hungarian Wire-haired Vizsla (HWV) individual, which was the closest animal genetically to the HSV population in the PCA analysis. Three programs were used for the breed assignment calculations, including the widely used GeneClass2.0 software and two additional approaches developed here: the ‘PCA-distance’ and ‘IBS-central’ methods. Both new methods calculate a single number that represents how closely a dog fits into the actual reference population. The former approach calculates this number based on the PCA distances from the median of HSV animals. The latter calculates it from identity by state (IBS) data, measuring the distance from a central animal that is the best representative of the breed. Having no mixed-breed dogs with known HSV genome proportion, admixture animals were simulated by using data of HSV and HWV individuals to calibrate the inclusion/exclusion probabilities for the assignment. The numbers generated from these relatively simple calculations can be used by breeders and clubs to keep their populations under genetic supervision. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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9 pages, 607 KiB  
Article
ACADM Frameshift Variant in Cavalier King Charles Spaniels with Medium-Chain Acyl-CoA Dehydrogenase Deficiency
by Matthias Christen, Jos Bongers, Déborah Mathis, Vidhya Jagannathan, Rodrigo Gutierrez Quintana and Tosso Leeb
Genes 2022, 13(10), 1847; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101847 - 13 Oct 2022
Cited by 4 | Viewed by 2728
Abstract
A 3-year-old, male neutered Cavalier King Charles Spaniel (CKCS) presented with complex focal seizures and prolonged lethargy. The aim of the study was to investigate the clinical signs, metabolic changes and underlying genetic defect. Blood and urine organic acid analysis revealed increased medium-chain [...] Read more.
A 3-year-old, male neutered Cavalier King Charles Spaniel (CKCS) presented with complex focal seizures and prolonged lethargy. The aim of the study was to investigate the clinical signs, metabolic changes and underlying genetic defect. Blood and urine organic acid analysis revealed increased medium-chain fatty acids and together with the clinical findings suggested a diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. We sequenced the genome of the affected dog and compared the data to 923 control genomes of different dog breeds. The ACADM gene encoding MCAD was considered the top functional candidate gene. The genetic analysis revealed a single homozygous private protein-changing variant in ACADM in the affected dog. This variant, XM_038541645.1:c.444_445delinsGTTAATTCTCAATATTGTCTAAGAATTATG, introduces a premature stop codon and is predicted to result in truncation of ~63% of the wild type MCAD open reading frame, XP_038397573.1:p.(Thr150Ilefs*6). Targeted genotyping of the variant in 162 additional CKCS revealed a variant allele frequency of 23.5% and twelve additional homozygous mutant dogs. The acylcarnitine C8/C12 ratio was elevated ~43.3 fold in homozygous mutant dogs as compared to homozygous wild type dogs. Based on available clinical and biochemical data together with current knowledge in humans, we propose the ACADM frameshift variant as causative variant for the MCAD deficiency with likely contribution to the neurological phenotype in the index case. Testing the CKCS breeding population for the identified ACADM variant is recommended to prevent the unintentional breeding of dogs with MCAD deficiency. Further prospective studies are warranted to assess the clinical consequences of this enzyme defect. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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11 pages, 1388 KiB  
Article
Genome Wide Association Study with Imputed Whole Genome Sequence Data Identifies a 431 kb Risk Haplotype on CFA18 for Congenital Laryngeal Paralysis in Alaskan Sled Dogs
by Krishnamoorthy Srikanth, Dirsko J. F. von Pfeil, Bryden J. Stanley, Caroline Griffitts and Heather J. Huson
Genes 2022, 13(10), 1808; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101808 - 06 Oct 2022
Cited by 2 | Viewed by 3212
Abstract
Congenital laryngeal paralysis (CLP) is an inherited disorder that affects the ability of the dog to exercise and precludes it from functioning as a working sled dog. Though CLP is known to occur in Alaskan sled dogs (ASDs) since 1986, the genetic mutation [...] Read more.
Congenital laryngeal paralysis (CLP) is an inherited disorder that affects the ability of the dog to exercise and precludes it from functioning as a working sled dog. Though CLP is known to occur in Alaskan sled dogs (ASDs) since 1986, the genetic mutation underlying the disease has not been reported. Using a genome-wide association study (GWAS), we identified a 708 kb region on CFA 18 harboring 226 SNPs to be significantly associated with CLP. The significant SNPs explained 47.06% of the heritability of CLP. We narrowed the region to 431 kb through autozygosity mapping and found 18 of the 20 cases to be homozygous for the risk haplotype. Whole genome sequencing of two cases and a control ASD, and comparison with the genome of 657 dogs from various breeds, confirmed the homozygous status of the risk haplotype to be unique to the CLP cases. Most of the dogs that were homozygous for the risk allele had blue eyes. Gene annotation and a gene-based association study showed that the risk haplotype encompasses genes implicated in developmental and neurodegenerative disorders. Pathway analysis showed enrichment of glycoproteins and glycosaminoglycans biosynthesis, which play a key role in repairing damaged nerves. In conclusion, our results suggest an important role for the identified candidate region in CLP. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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14 pages, 1629 KiB  
Article
Cerebellar Abiotrophy in Australian Working Kelpies Is Associated with Two Major Risk Loci
by Claire M. Wade, Annie Y. H. Pan, Rosanne M. Taylor and Peter Williamson
Genes 2022, 13(10), 1709; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101709 - 23 Sep 2022
Cited by 4 | Viewed by 2419
Abstract
An autosomal recessive form of inherited cerebellar abiotrophy (CA) that is characterized by a degeneration of Purkinje and granule cells in the cerebellar cortex occurs in the Australian working kelpie dog breed. The clinical signs of CA include ataxia, head tremor, motor in-coordination, [...] Read more.
An autosomal recessive form of inherited cerebellar abiotrophy (CA) that is characterized by a degeneration of Purkinje and granule cells in the cerebellar cortex occurs in the Australian working kelpie dog breed. The clinical signs of CA include ataxia, head tremor, motor in-coordination, wide-based stance, and high-stepping gait. Investigation of clinical and pathological features indicated two closely related diseases with differences in age of onset. A genome-wide association study on 45 CA affected and 290 normal healthy Kelpies identified two significantly associated loci, one on CFA9 and a second on CFA20. Dogs homozygous for the risk haplotype on CFA20 (23 dogs) show clinical signs before ten weeks of age. Missense variants in the sixth exon of disruptor of telomeric silencing 1-like (DOT1Lp.R200Q) and in the only exon of Leucine Rich Repeat And Ig Domain Containing 3 (LINGO3p.R359C), both on CFA20, segregate with the associated risk marker which has incomplete penetrance (42%). Affected dogs homozygous for the risk haplotype on CFA9 have later onset ataxia. A missense variant in exon 5 of Vacuole Membrane Protein 1 (VMP1 p.P160Q) on CFA9 segregates as a fully penetrant Mendelian recessive with later-onset CA. Across mammals, the variety of causative loci so far identified as influencing cerebellar disorders reinforces the complexity of the pathways that contribute to cerebellar development and function, and to the pathophysiological mechanisms that may lead to cerebellar ataxia. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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16 pages, 2695 KiB  
Article
Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs
by Katheryn Meek, Ya-Ting Yang, Marilia Takada, Maciej Parys, Marlee Richter, Alexander I. Engleberg, Tuddow Thaiwong, Rachel L. Griffin, Peter Z. Schall, Alana J. Kramer and Vilma Yuzbasiyan-Gurkan
Genes 2022, 13(10), 1693; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13101693 - 21 Sep 2022
Cited by 1 | Viewed by 2214
Abstract
Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. [...] Read more.
Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have identified several loci to be associated with predisposition to HS in BMDs, including near the MTAP/CDKN2A region, but no causative coding variant has been identified. Here we report the presence of a coding polymorphism in the gene encoding FANCG, near the MTAP/CDKN2A locus. This variant is in a conserved region of the protein and appears to be specific to BMDs. Canine fibroblasts derived from dogs homozygous for this variant are hypersensitive to cisplatin. We show this canine FANCG variant and a previously defined hypomorphic FANCG allele in humans impart similar defects in DNA repair. However, our data also indicate that this variant is neither necessary nor sufficient for the development of HS. Furthermore, BMDs homozygous for this FANCG allele display none of the characteristic phenotypes associated with Fanconi anemia (FA) such as anemia, short stature, infertility, or an earlier age of onset for HS. This is similar to findings in FA deficient mice, which do not develop overt FA without secondary genetic mutations that exacerbate the FA deficit. In sum, our data suggest that dogs with deficits in the FA pathway are, like mice, innately resistant to the development of FA. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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14 pages, 2067 KiB  
Article
Coyotes in New York City Carry Variable Genomic Dog Ancestry and Influence Their Interactions with Humans
by Anthony Caragiulo, Stephen J. Gaughran, Neil Duncan, Christopher Nagy, Mark Weckel and Bridgett M. vonHoldt
Genes 2022, 13(9), 1661; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13091661 - 16 Sep 2022
Cited by 3 | Viewed by 3674
Abstract
Coyotes are ubiquitous on the North American landscape as a result of their recent expansion across the continent. They have been documented in the heart of some of the most urbanized cities, such as Chicago, Los Angeles, and New York City. Here, we [...] Read more.
Coyotes are ubiquitous on the North American landscape as a result of their recent expansion across the continent. They have been documented in the heart of some of the most urbanized cities, such as Chicago, Los Angeles, and New York City. Here, we explored the genomic composition of 16 coyotes in the New York metropolitan area to investigate genomic demography and admixture for urban-dwelling canids in Queens County, New York. We identified moderate-to-high estimates of relatedness among coyotes living in Queens (r = 0.0–0.5) and adjacent neighborhoods, suggestive of a relatively small population. Although we found low background levels of domestic-dog ancestry across most coyotes in our sample (5%), we identified a male suspected to be a first-generation coyote–dog hybrid with 46% dog ancestry, as well as his two putative backcrossed offspring that carried approximately 25% dog ancestry. The male coyote–dog hybrid and one backcrossed offspring each carried two transposable element insertions that are associated with human-directed hypersociability in dogs and gray wolves. An additional, unrelated coyote with little dog ancestry also carried two of these insertions. These genetic patterns suggest that gene flow from domestic dogs may become an increasingly important consideration as coyotes continue to inhabit metropolitan regions. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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20 pages, 3139 KiB  
Article
EHBP1L1 Frameshift Deletion in English Springer Spaniel Dogs with Dyserythropoietic Anemia and Myopathy Syndrome (DAMS) or Neonatal Losses
by Sarah Østergård Jensen, Matthias Christen, Veronica Rondahl, Christopher T. Holland, Vidhya Jagannathan, Tosso Leeb and Urs Giger
Genes 2022, 13(9), 1533; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13091533 - 26 Aug 2022
Cited by 1 | Viewed by 3957
Abstract
Hereditary myopathies are well documented in dogs, whereas hereditary dyserythropoietic anemias are rarely seen. The aim of this study was to further characterize the clinical and clinicopathological features of and to identify the causative genetic variant for a dyserythropoietic anemia and myopathy syndrome [...] Read more.
Hereditary myopathies are well documented in dogs, whereas hereditary dyserythropoietic anemias are rarely seen. The aim of this study was to further characterize the clinical and clinicopathological features of and to identify the causative genetic variant for a dyserythropoietic anemia and myopathy syndrome (DAMS) in English springer spaniel dogs (ESSPs). Twenty-six ESSPs, including five dogs with DAMS and two puppies that died perinatally, were studied. Progressive weakness, muscle atrophy—particularly of the temporal and pelvic muscles—trismus, dysphagia, and regurgitation due to megaesophagus were observed at all ages. Affected dogs had a non-regenerative, microcytic hypochromic anemia with metarubricytosis, target cells, and acanthocytes. Marked erythroid hyperplasia and dyserythropoiesis with non-orderly maturation of erythrocytes and inappropriate microcytic metarubricytosis were present. Muscle biopsies showed centralized nuclei, central pallor, lipocyte infiltrates, and fibrosis, which was consistent with centronuclear myopathy. The genome sequencing of two affected dogs was compared to 782 genomes of different canine breeds. A homozygous frameshift single-base deletion in EHBP1L1 was identified; this gene was not previously associated with DAMS. Pedigree analysis confirmed that the affected ESSPs were related. Variant genotyping showed appropriate complete segregation in the family, which was consistent with an autosomal recessive mode of inheritance. This study expands the known genotype–phenotype correlation of EHBP1L1 and the list of potential causative genes in dyserythropoietic anemias and myopathies in humans. EHBP1L1 deficiency was previously reported as perinatally lethal in humans and knockout mice. Our findings enable the genetic testing of ESSP dogs for early diagnosis and disease prevention through targeted breeding strategies. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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20 pages, 2229 KiB  
Article
Genomic Assessment of Cancer Susceptibility in the Threatened Catalina Island Fox (Urocyon littoralis catalinae)
by Sarah A. Hendricks, Julie L. King, Calvin L. Duncan, Winston Vickers, Paul A. Hohenlohe and Brian W. Davis
Genes 2022, 13(8), 1496; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13081496 - 22 Aug 2022
Cited by 2 | Viewed by 2385
Abstract
Small effective population sizes raise the probability of extinction by increasing the frequency of potentially deleterious alleles and reducing fitness. However, the extent to which cancers play a role in the fitness reduction of genetically depauperate wildlife populations is unknown. Santa Catalina island [...] Read more.
Small effective population sizes raise the probability of extinction by increasing the frequency of potentially deleterious alleles and reducing fitness. However, the extent to which cancers play a role in the fitness reduction of genetically depauperate wildlife populations is unknown. Santa Catalina island foxes (Urocyon littoralis catalinae) sampled in 2007–2008 have a high prevalence of ceruminous gland tumors, which was not detected in the population prior to a recent bottleneck caused by a canine distemper epidemic. The disease appears to be associated with inflammation from chronic ear mite (Otodectes) infections and secondary elevated levels of Staphyloccus pseudointermedius bacterial infections. However, no other environmental factors to date have been found to be associated with elevated cancer risk in this population. Here, we used whole genome sequencing of the case and control individuals from two islands to identify candidate loci associated with cancer based on genetic divergence, nucleotide diversity, allele frequency spectrum, and runs of homozygosity. We identified several candidate loci based on genomic signatures and putative gene functions, suggesting that cancer susceptibility in this population may be polygenic. Due to the efforts of a recovery program and weak fitness effects of late-onset disease, the population size has increased, which may allow selection to be more effective in removing these presumably slightly deleterious alleles. Long-term monitoring of the disease alleles, as well as overall genetic diversity, will provide crucial information for the long-term persistence of this threatened population. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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7 pages, 1864 KiB  
Article
An EHPB1L1 Nonsense Mutation Associated with Congenital Dyserythropoietic Anemia and Polymyopathy in Labrador Retriever Littermates
by G. Diane Shelton, Katie M. Minor, Ling T. Guo, Alison Thomas-Hollands, Koranda A. Walsh, Steven G. Friedenberg, Jonah N. Cullen and James R. Mickelson
Genes 2022, 13(8), 1427; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13081427 - 11 Aug 2022
Cited by 4 | Viewed by 1593
Abstract
In this report, we describe a novel genetic basis for congenital dyserythropoietic anemia and polymyopathy in Labrador Retriever littermates characterized by incidental detection of marked microcytosis, inappropriate metarubricytosis, pelvic limb weakness and muscle atrophy. A similar syndrome has been described in English Springer [...] Read more.
In this report, we describe a novel genetic basis for congenital dyserythropoietic anemia and polymyopathy in Labrador Retriever littermates characterized by incidental detection of marked microcytosis, inappropriate metarubricytosis, pelvic limb weakness and muscle atrophy. A similar syndrome has been described in English Springer Spaniel littermates with an early onset of anemia, megaesophagus, generalized muscle atrophy and cardiomyopathy. Muscle histopathology in both breeds showed distinctive pathological changes consistent with congenital polymyopathy. Using whole genome sequencing and mapping to the CanFam4 (Canis lupus familiaris reference assembly 4), a nonsense variant in the EHBP1L1 gene was identified in a homozygous form in the Labrador Retriever littermates. The mutation produces a premature stop codon that deletes approximately 90% of the protein. This variant was not present in the English Springer Spaniels. Currently, EHPB1L1 is described as critical to actin cytoskeletal organization and apical-directed transport in polarized epithelial cells, and through connections with Rab8 and a BIN1-dynamin complex generates membrane vesicles in the endocytic recycling compartment. Furthermore, EHBP1L1 knockout mice die early and develop severe anemia. The connection of EHBP1L1 to BIN1 and DMN2 functions is particularly interesting due to BIN1 and DMN2 mutations being causative in forms of centronuclear myopathy. This report, along with an independent study conducted by another group, are the first reports of an association of EHBP1L1 mutations with congenital dyserythropoietic anemia and polymyopathy. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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10 pages, 762 KiB  
Article
Genome-Wide Association Analysis for Chronic Superficial Keratitis in the Australian Racing Greyhound
by Steven Karamatic, Rebecca Goode, Niruba Bageswaran, Cali E. Willet, Georgina Samaha, Ray Ferguson, Hamutal Mazrier and Claire M. Wade
Genes 2022, 13(8), 1328; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13081328 - 26 Jul 2022
Cited by 1 | Viewed by 2523
Abstract
Chronic superficial keratitis (CSK) is a progressive inflammatory condition of the eye (cornea) that can cause discomfort and blindness. Differential disease risk across dog breeds strongly suggests that CSK has a genetic basis. In addition to genetic risk, the occurrence of CSK is [...] Read more.
Chronic superficial keratitis (CSK) is a progressive inflammatory condition of the eye (cornea) that can cause discomfort and blindness. Differential disease risk across dog breeds strongly suggests that CSK has a genetic basis. In addition to genetic risk, the occurrence of CSK is exacerbated by exposure to ultraviolet light. Genome-wide association analysis considered 109 greyhounds, 70 with CSK and the remainder with normal phenotype at an age over four years. Three co-located variants on CFA18 near the 5′ region of the Epidermal Growth Factor Receptor (EGFR) gene were associated with genome-wide significance after multiple-test correction (BICF2P579527, CFA18: 6,068,508, praw = 1.77 × 10−7, pgenome = 0.017; BICF2P1310662, CFA18: 6,077,388, praw = 4.09 × 10−7, pgenome = 0.040; BICF2P160719, CFA18: 6,087,347, praw = 4.09 × 10−7, pgenome = 0.040) (canFam4)). Of the top 10 associated markers, eight were co-located with the significantly associated markers on CFA18. The associated haplotype on CFA18 is protective for the CSK condition. EGFR is known to play a role in corneal healing, where it initiates differentiation and proliferation of epithelial cells that in turn signal the involvement of stromal keratocytes to commence apoptosis. Further validation of the putative functional variants is required prior to their use in genetic testing for breeding programs. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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7 pages, 466 KiB  
Article
SLC25A12 Missense Variant in Nova Scotia Duck Tolling Retrievers Affected by Cerebellar Degeneration—Myositis Complex (CDMC)
by Matthias Christen, Stefan Rupp, Iris Van Soens, Sofie F. M. Bhatti, Kaspar Matiasek, Thilo von Klopmann, Vidhya Jagannathan, Indiana Madden, Kevin Batcher, Danika Bannasch and Tosso Leeb
Genes 2022, 13(7), 1223; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13071223 - 09 Jul 2022
Cited by 2 | Viewed by 2334
Abstract
We investigated two litters of distantly related Nova Scotia Duck Tolling Retrievers (NSDTR), of which four puppies were affected by cerebellar signs with or without neuromuscular weakness. The phenotype was termed cerebellar degeneration—myositis complex (CDMC). We suspected a heritable condition and initiated a [...] Read more.
We investigated two litters of distantly related Nova Scotia Duck Tolling Retrievers (NSDTR), of which four puppies were affected by cerebellar signs with or without neuromuscular weakness. The phenotype was termed cerebellar degeneration—myositis complex (CDMC). We suspected a heritable condition and initiated a genetic analysis. The genome of one affected dog was sequenced and compared to 565 control genomes. This search yielded a private protein-changing SLC25A12 variant in the affected dog, XM_038584842.1:c.1337C>T, predicted to result in the amino acid change XP_038440770.1:(p.Pro446Leu). The genotypes at the variant co-segregated with the phenotype as expected for a monogenic autosomal recessive mode of inheritance in both litters. Genotyping of 533 additional NSDTR revealed variant allele frequencies of 3.6% and 1.3% in a European and a North American cohort, respectively. The available clinical and biochemical data, together with current knowledge about SLC25A12 variants and their functional impact in humans, mice, and dogs, suggest the p.Pro446Leu variant is a candidate causative defect for the observed phenotype in the affected dogs. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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9 pages, 3964 KiB  
Article
A COL5A2 In-Frame Deletion in a Chihuahua with Ehlers-Danlos Syndrome
by Sarah Kiener, Lucie Chevallier, Vidhya Jagannathan, Amaury Briand, Noëlle Cochet-Faivre, Edouard Reyes-Gomez and Tosso Leeb
Genes 2022, 13(5), 934; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13050934 - 23 May 2022
Cited by 5 | Viewed by 3418
Abstract
Ehlers-Danlos syndrome (EDS) is a group of heterogeneous, rare diseases affecting the connective tissues. The main clinical signs of EDS are skin hyperextensibility, joint hypermobility, and skin fragility. Currently, the classification of EDS in humans distinguishes 13 clinical subtypes associated with variants in [...] Read more.
Ehlers-Danlos syndrome (EDS) is a group of heterogeneous, rare diseases affecting the connective tissues. The main clinical signs of EDS are skin hyperextensibility, joint hypermobility, and skin fragility. Currently, the classification of EDS in humans distinguishes 13 clinical subtypes associated with variants in 20 different genes, reflecting the heterogeneity of this set of diseases. At present, variants in three of these genes have also been identified in dogs affected by EDS. The purpose of this study was to characterize the clinical and histopathological phenotype of an EDS-affected Chihuahua and to identify the causative genetic variant for the disease. The clinical examination suggested a diagnosis of classical EDS. Skin histopathology revealed an abnormally thin dermis, which is compatible with classical EDS. Whole-genome sequencing identified a heterozygous de novo 27 bp deletion in the COL5A2 gene, COL5A2:c.3388_3414del. The in-frame deletion is predicted to remove 9 amino acids in the triple-helical region of COL5A2. The molecular analysis and identification of a likely pathogenic variant in COL5A2 confirmed the subtype as a form of classical EDS. This is the first report of a COL5A2-related EDS in a dog. Full article
(This article belongs to the Special Issue Advances in Canine Genetics)
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