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4 pages, 208 KiB

Open AccessEditorial

Special Issue: “Canine Genetics 2”

by Tosso Leeb

Genes 2023, 14(10), 1930; https://doi.org/10.3390/genes14101930 - 12 Oct 2023

Viewed by 1402

Abstract

Wolves were the first animal species to become domesticated by humans, approximately 30,000–50,000 years ago. Human-directed dog breeding over thousands of generations has generated more than 350 recognized breeds displaying surprisingly different phenotypes with respect to morphology, behavior and disease predispositions. The domestication [...] Read more.

Wolves were the first animal species to become domesticated by humans, approximately 30,000–50,000 years ago. Human-directed dog breeding over thousands of generations has generated more than 350 recognized breeds displaying surprisingly different phenotypes with respect to morphology, behavior and disease predispositions. The domestication of wolves and the subsequent breeding of dogs can be viewed as one of humankind’s oldest and largest genetic experiments and provides us with unique opportunities for research. Dogs have not only become human’s best friend but were also described as geneticists’ best friend in a past issue of Science. In recognition of the importance of canine genetics, this Special Issue, entitled “Canine Genetics 2”, was compiled. It represents a sequel to the former Special Issue “Canine Genetics”, which was published in 2019. During the last 15 years, the canine community has heavily relied on a reference genome derived from the female Boxer Tasha. “Canine Genetics 2” includes an article describing a greatly improved version of this important community resource. This Special Issue further contains several reports related to monogenic or complex inherited diseases in dogs. Finally, important aspects of wild canid research, genetic diversity in different populations and canine morphology were investigated. Full article

(This article belongs to the Special Issue Canine Genetics 2)

Research

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25 pages, 3429 KiB

Open AccessArticle

Genomic and Transcriptomic Characterization of Atypical Recurrent Flank Alopecia in the Cesky Fousek

by Silvie Neradilová, Alexandria M. Schauer, Jessica J. Hayward, Magdalena A. T. Brunner, Magdalena Bohutínská, Vidhya Jagannathan, Laurie B. Connell, Adam R. Boyko, Monika M. Welle and Barbora Černá Bolfíková

Genes 2022, 13(4), 650; https://doi.org/10.3390/genes13040650 - 7 Apr 2022

Cited by 3 | Viewed by 3571

Abstract

Non-inflammatory alopecia is a frequent skin problem in dogs, causing damaged coat integrity and compromised appearance of affected individuals. In this study, we examined the Cesky Fousek breed, which displays atypical recurrent flank alopecia (aRFA) at a high frequency. This type of alopecia [...] Read more.

Non-inflammatory alopecia is a frequent skin problem in dogs, causing damaged coat integrity and compromised appearance of affected individuals. In this study, we examined the Cesky Fousek breed, which displays atypical recurrent flank alopecia (aRFA) at a high frequency. This type of alopecia can be quite severe and is characterized by seasonal episodes of well demarcated alopecic areas without hyperpigmentation. The genetic component responsible for aRFA remains unknown. Thus, here we aimed to identify variants involved in aRFA using a combination of histological, genomic, and transcriptomic data. We showed that aRFA is histologically similar to recurrent flank alopecia, characterized by a lack of anagen hair follicles and the presence of severely shortened telogen or kenogen hair follicles. We performed a genome-wide association study (GWAS) using 216 dogs phenotyped for aRFA and identified associations on chromosomes 19, 8, 30, 36, and 21, highlighting 144 candidate genes, which suggests a polygenic basis for aRFA. By comparing the skin cell transcription pattern of six aRFA and five control dogs, we identified 236 strongly differentially expressed genes (DEGs). We showed that the GWAS genes associated with aRFA are often predicted to interact with DEGs, suggesting their joint contribution to the development of the disease. Together, these genes affect four major metabolic pathways connected to aRFA: collagen formation, muscle structure/contraction, lipid metabolism, and the immune system. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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8 pages, 657 KiB

Open AccessArticle

FYCO1 Frameshift Deletion in Wirehaired Pointing Griffon Dogs with Juvenile Cataract

by Gabriela Rudd Garces, Matthias Christen, Robert Loechel, Vidhya Jagannathan and Tosso Leeb

Genes 2022, 13(2), 334; https://doi.org/10.3390/genes13020334 - 11 Feb 2022

Cited by 3 | Viewed by 2542

Abstract

Different breed-specific inherited cataracts have been described in dogs. In this study, we investigated an inbred family of Wirehaired Pointing Griffon dogs in which three offspring were affected by juvenile cataract. The pedigree suggested monogenic autosomal recessive inheritance of the trait. Whole-genome sequencing [...] Read more.

Different breed-specific inherited cataracts have been described in dogs. In this study, we investigated an inbred family of Wirehaired Pointing Griffon dogs in which three offspring were affected by juvenile cataract. The pedigree suggested monogenic autosomal recessive inheritance of the trait. Whole-genome sequencing of an affected dog revealed 12 protein-changing variants that were not present in 566 control genomes, of which two were located in functional candidate genes, FYCO1 and CRYGB. Targeted genotyping of both variants in the investigated family excluded CRYGB and revealed perfect co-segregation of the FYCO1 variant with the juvenile cataract phenotype. This variant, FYCO1:c.2024delG, represents a 1 bp frameshift deletion predicted to truncate ~50% of the open reading frame p.(Ser675Thrfs*5). FYCO1 encodes the FYVE and coiled-coil domain autophagy adaptor 1, a known regulator of lens autophagy, which is required for the normal homeostasis in the eye. In humans, at least 37 pathogenic variants in FYCO1 have been shown to cause autosomal recessive cataract. Fcyo1^−/− knockout mice also develop cataracts. Together with the current knowledge on FYCO1 variants and their functional impact in humans and mice, our data strongly suggest FYCO1:c.2024delG as a candidate causative variant for the observed juvenile cataract in Wirehaired Pointing Griffon dogs. To the best of our knowledge, this study represents the first report of a FYCO1-related cataract in domestic animals. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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8 pages, 748 KiB

Open AccessArticle

The Effects of FGF4 Retrogenes on Canine Morphology

by Danika Bannasch, Kevin Batcher, Fabienne Leuthard, Michael Bannasch, Petra Hug, Denis J. Marcellin-Little, Peter J. Dickinson, Michaela Drögemüller, Cord Drögemüller and Tosso Leeb

Genes 2022, 13(2), 325; https://doi.org/10.3390/genes13020325 - 10 Feb 2022

Cited by 10 | Viewed by 4718

Abstract

Two FGF4 retrogenes (FGF4L1 on chromosome 18 and FGF4L2 on chromosome 12) have been identified to cause dwarfism across many dog breeds. Some breeds are nearly homozygous for both retrogenes (e.g., Dachshunds) and others are homozygous for just one (e.g., Beagles and [...] Read more.

Two FGF4 retrogenes (FGF4L1 on chromosome 18 and FGF4L2 on chromosome 12) have been identified to cause dwarfism across many dog breeds. Some breeds are nearly homozygous for both retrogenes (e.g., Dachshunds) and others are homozygous for just one (e.g., Beagles and Scottish Terriers). Since most breeds do not segregate both of these retrogenes, it is challenging to evaluate their individual effects on long bone length and body size. We identified two dog breeds selected for hunting ability, the Alpine Dachsbracke and the Schweizer Niederlaufhund, that segregate both of these retrogenes. Using individual measurements of height at the shoulder, back length, head width, thorax depth and width, and thoracic limb measurements, we evaluated the combined effects of FGF4 retrogenes within these breeds. We applied multivariable linear regression analysis to determine the effects of retrogene copy numbers on the measurements. Copy numbers of both retrogenes had significant effects reducing height at the shoulders and antebrachial length, with FGF4L1 having a much greater effect than FGF4L2. FGF4L1 alone influenced the degree of carpal valgus and FGF4L2 alone increased head width. Neither retrogene had an effect on thorax width or depth. Selectively breeding dogs with FGF4L1 and without FGF4L2 would likely lead to a reduction in the FGF4L2-related risk of intervertebral disc herniation while maintaining the reduction in leg length resulting from FGF4L1. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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12 pages, 2341 KiB

Open AccessArticle

Genetic Rescue of the Highly Inbred Norwegian Lundehund

by Claudia Melis, Cino Pertoldi, William Basil Ludington, Carol Beuchat, Gunnar Qvigstad and Astrid Vik Stronen

Genes 2022, 13(1), 163; https://doi.org/10.3390/genes13010163 - 17 Jan 2022

Cited by 4 | Viewed by 11999

Abstract

Augmenting the genetic diversity of small, inbred populations by the introduction of new individuals is often termed “genetic rescue”. An example is the Norwegian Lundehund, a small spitz dog with inbreeding-related health problems that is being crossed with three Nordic breeds, including the [...] Read more.

Augmenting the genetic diversity of small, inbred populations by the introduction of new individuals is often termed “genetic rescue”. An example is the Norwegian Lundehund, a small spitz dog with inbreeding-related health problems that is being crossed with three Nordic breeds, including the Norwegian Buhund. Conservation breeding decisions for the (typically) small number of outcrossed individuals are vital for managing the rescue process, and we genotyped the Lundehund (n = 12), the Buhund (n = 12), their crosses (F1, n = 7) and first-generation backcrosses to the Lundehund (F2, n = 12) with >170,000 single nucleotide polymorphism loci to compare their levels of genetic diversity. We predicted that genome-wide diversity in F2 dogs would be higher than in the Lundehund but lower than in the F1 and the Buhund, and the heterozygosity values showed the expected patterns. We also found that runs of homozygosity, extended chromosomal regions of homozygous genotypes inherited from a common ancestor, were reduced in F2 individuals compared with Lundehund individuals. Our analyses demonstrate the benefits of outcrossing but indicate that some of the acquired genetic diversity is lost following immediate backcrossing. Additional breeding among F2 crosses could therefore merit from further consideration in genetic rescue management. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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10 pages, 1260 KiB

Open AccessArticle

Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus

by Anna Letko, Katie M. Minor, Elaine M. Norton, Voichita D. Marinescu, Michaela Drögemüller, Emma Ivansson, Kate Megquier, Hyun Ji Noh, Mike Starkey, Steven G. Friedenberg, Kerstin Lindblad-Toh, James R. Mickelson and Cord Drögemüller

Genes 2021, 12(12), 1964; https://doi.org/10.3390/genes12121964 - 9 Dec 2021

Cited by 11 | Viewed by 5404

Abstract

Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large- to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing [...] Read more.

Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large- to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density imputed SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h²_SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10⁻⁴) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h²_SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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11 pages, 2324 KiB

Open AccessFeature PaperArticle

Heritability and Genomic Architecture of Episodic Exercise-Induced Collapse in Border Collies

by Elaine M. Norton, Katie M. Minor, Susan M. Taylor, Molly E. McCue and James R. Mickelson

Genes 2021, 12(12), 1927; https://doi.org/10.3390/genes12121927 - 29 Nov 2021

Cited by 3 | Viewed by 5124

Abstract

An episodic nervous system disorder triggered by strenuous exercise, termed border collie collapse (BCC), exists in border collies and related breeds. The genetic basis of BCC is unknown but is believed to be a complex genetic disorder. Our goal was to estimate the [...] Read more.

An episodic nervous system disorder triggered by strenuous exercise, termed border collie collapse (BCC), exists in border collies and related breeds. The genetic basis of BCC is unknown but is believed to be a complex genetic disorder. Our goal was to estimate the heritability (h²_SNP) of BCC, define its underlying genetic architecture, and identify associated genomic loci using dense whole-genome single-nucleotide polymorphism (SNP) genotyping data. Genotype data were obtained for ~440,000 SNPs from 343 border collies (168 BCC cases and 175 controls). h²_SNP was calculated to be 49–61% depending on the estimated BCC prevalence. A total of 2407 SNPs across the genome accounted for nearly all the h2_SNP of BCC, with an estimated 2003 SNPs of small effect, 349 SNPs of moderate effect, and 56 SNPs of large effect. Genome-wide association analyses identified significantly associated loci on chromosomes 1, 6, 11, 20, and 28, which accounted for ~5% of the total BCC h²_SNP. We conclude that BCC is a moderately- to highly-heritable complex polygenetic disease resulting from contributions from hundreds to thousands of genetic variants with variable effect sizes. Understanding how much the BCC phenotype is determined by genetics and whether major gene mutations are likely to exist inform veterinarians and working/stock dog communities of the true nature of this condition. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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10 pages, 1774 KiB

Open AccessArticle

LAMA2 Nonsense Variant in an Italian Greyhound with Congenital Muscular Dystrophy

by Matthias Christen, Victoria Indzhova, Ling T. Guo, Vidhya Jagannathan, Tosso Leeb, G. Diane Shelton and Josep Brocal

Genes 2021, 12(11), 1823; https://doi.org/10.3390/genes12111823 - 19 Nov 2021

Cited by 2 | Viewed by 2787

Abstract

A 4-month-old, male Italian Greyhound with clinical signs of a neuromuscular disease was investigated. The affected dog presented with an abnormal short-strided gait, generalized muscle atrophy, and poor growth since 2-months of age. Serum biochemistry revealed a marked elevation in creatine kinase activity. [...] Read more.

A 4-month-old, male Italian Greyhound with clinical signs of a neuromuscular disease was investigated. The affected dog presented with an abnormal short-strided gait, generalized muscle atrophy, and poor growth since 2-months of age. Serum biochemistry revealed a marked elevation in creatine kinase activity. Electrodiagnostic testing supported a myopathy. Histopathology of muscle biopsies confirmed a dystrophic phenotype with excessive variability in myofiber size, degenerating fibers, and endomysial fibrosis. A heritable form of congenital muscular dystrophy (CMD) was suspected, and a genetic analysis initiated. We sequenced the genome of the affected dog and compared the data to that of 795 control genomes. This search revealed a private homozygous nonsense variant in LAMA2, XM_022419950.1:c.3285G>A, predicted to truncate 65% of the open reading frame of the wild type laminin α2 protein, XP_022275658.1:p.(Trp1095*). Immunofluorescent staining performed on muscle cryosections from the affected dog confirmed the complete absence of laminin α2 in skeletal muscle. LAMA2 loss of function variants were shown to cause severe laminin α2-related CMD in humans, mouse models, and in one previously described dog. Our data together with current knowledge on other species suggest the LAMA2 nonsense variant as cause for the CMD phenotype in the investigated dog. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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19 pages, 1195 KiB

Open AccessArticle

A Missense Variant in the Bardet-Biedl Syndrome 2 Gene (BBS2) Leads to a Novel Syndromic Retinal Degeneration in the Shetland Sheepdog

by Rebekkah J. Hitti-Malin, Louise M. Burmeister, Frode Lingaas, Maria Kaukonen, Inka Pettinen, Hannes Lohi, David Sargan and Cathryn S. Mellersh

Genes 2021, 12(11), 1771; https://doi.org/10.3390/genes12111771 - 8 Nov 2021

Cited by 4 | Viewed by 5796

Abstract

Canine progressive retinal atrophy (PRA) describes a group of hereditary diseases characterized by photoreceptor cell death in the retina, leading to visual impairment. Despite the identification of multiple PRA-causing variants, extensive heterogeneity of PRA is observed across and within dog breeds, with many [...] Read more.

Canine progressive retinal atrophy (PRA) describes a group of hereditary diseases characterized by photoreceptor cell death in the retina, leading to visual impairment. Despite the identification of multiple PRA-causing variants, extensive heterogeneity of PRA is observed across and within dog breeds, with many still genetically unsolved. This study sought to elucidate the causal variant for a distinct form of PRA in the Shetland sheepdog, using a whole-genome sequencing approach. Filtering variants from a single PRA-affected Shetland sheepdog genome compared to 176 genomes of other breeds identified a single nucleotide variant in exon 11 of the Bardet–Biedl syndrome-2 gene (BBS2) (c.1222G>C; p.Ala408Pro). Genotyping 1386 canids of 155 dog breeds, 15 cross breeds and 8 wolves indicated the c.1222G>C variant was only segregated within Shetland sheepdogs. Out of 505 Shetland sheepdogs, seven were homozygous for the variant. Clinical history and photographs for three homozygotes indicated the presence of a novel phenotype. In addition to PRA, additional clinical features in homozygous dogs support the discovery of a novel syndromic PRA in the breed. The development and utilization of a diagnostic DNA test aim to prevent the mutation from becoming more prevalent in the breed. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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9 pages, 1357 KiB

Open AccessArticle

MIA3 Splice Defect in Cane Corso Dogs with Dental-Skeletal-Retinal Anomaly (DSRA)

by Matthias Christen, Henriëtte Booij-Vrieling, Jelena Oksa-Minalto, Cynthia de Vries, Alexandra Kehl, Vidhya Jagannathan and Tosso Leeb

Genes 2021, 12(10), 1497; https://doi.org/10.3390/genes12101497 - 25 Sep 2021

Cited by 8 | Viewed by 6428

Abstract

We investigated a hereditary syndrome in Cane Corso dogs. Affected dogs developed dental-skeletal-retinal anomaly (DSRA), clinically characterized by brittle, discolored, translucent teeth, disproportionate growth and progressive retinal degeneration resulting in vision loss. Combined linkage and homozygosity mapping delineated a 5.8 Mb critical interval. [...] Read more.

We investigated a hereditary syndrome in Cane Corso dogs. Affected dogs developed dental-skeletal-retinal anomaly (DSRA), clinically characterized by brittle, discolored, translucent teeth, disproportionate growth and progressive retinal degeneration resulting in vision loss. Combined linkage and homozygosity mapping delineated a 5.8 Mb critical interval. The comparison of whole genome sequence data of an affected dog to 789 control genomes revealed a private homozygous splice region variant in the critical interval. It affected the MIA3 gene encoding the MIA SH3 domain ER export factor 3, which has an essential role in the export of collagen and other secreted proteins. The identified variant, XM_005640835.3:c.3822+3_3822+4del, leads to skipping of two exons from the wild type transcript, XM_005640835.3:r.3712_3822del. Genotypes at the variant were consistent with monogenic autosomal recessive mode of inheritance in a complete family and showed perfect genotype-phenotype association in 18 affected and 22 unaffected Cane Corso dogs. MIA3 variants had previously been shown to cause related phenotypes in humans and mice. Our data in dogs together with the existing functional knowledge of MIA3 variants in other mammalian species suggest the MIA3 splice defect and a near complete loss of gene function as causative molecular pathomechanism for the DSRA phenotype in the investigated dogs. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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11 pages, 2358 KiB

Open AccessArticle

A Single Base Insertion in F9 Causing Hemophilia B in a Family of Newfoundland–Parti Standard Poodle Hybrid Dogs

by Henrike Kuder, Liubov Sandzhieva-Vuzzo, Alexandra Kehl, Jonathan M. Rappaport, Elisabeth Müller and Urs Giger

Genes 2021, 12(10), 1491; https://doi.org/10.3390/genes12101491 - 24 Sep 2021

Cited by 2 | Viewed by 5617

Abstract

Hemophilia B is an x-linked recessive hereditary coagulopathy that has been reported in various species. We describe a male Newfoundland–Parti Standard Poodle hybrid puppy and its family with hemophilia B from clinical manifestations to the molecular genetic defect. The index case presented for [...] Read more.

Hemophilia B is an x-linked recessive hereditary coagulopathy that has been reported in various species. We describe a male Newfoundland–Parti Standard Poodle hybrid puppy and its family with hemophilia B from clinical manifestations to the molecular genetic defect. The index case presented for dyspnea was found to have a mediastinal hematoma, while surgical removal and transfusion support brought some relief, progressive hematoma formations led to humane euthanasia. Sequencing the F9 exons revealed a single nucleotide insertion resulting in a frameshift in the last exon (NM_001003323.2:c.821_822insA), predicted to result in a premature stop codon (NP_001003323.1:p.Asn274LysfsTer23) with a loss of 178 of 459 amino acids. The unexpected high residual plasma factor IX activity (3% to 11% of control) was likely erroneous, but no further studies were performed. Both the purebred Newfoundland dam and her sister were heterozygous for the insertion. Five additional male offspring developed severe hemorrhage and were hemizygous for the F9 variant and/or had a prolonged aPTT. In contrast, other male littermates had normal aPTTs and no evidence of bleeding. While they are related to a common Newfoundland granddam, the prevalence of the pathogenic variant in the Newfoundland breed is currently unknown. These clinical to molecular genetic studies illustrate that precision medicine is achievable in clinical companion animal practice. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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11 pages, 3056 KiB

Open AccessArticle

PRKG2 Splice Site Variant in Dogo Argentino Dogs with Disproportionate Dwarfism

by Gabriela Rudd Garces, Maria Elena Turba, Myriam Muracchini, Alessia Diana, Vidhya Jagannathan, Fabio Gentilini and Tosso Leeb

Genes 2021, 12(10), 1489; https://doi.org/10.3390/genes12101489 - 24 Sep 2021

Cited by 6 | Viewed by 4586

Abstract

Dwarfism phenotypes occur in many species and may be caused by genetic or environmental factors. In this study, we investigated a family of nine Dogo Argentino dogs, in which two dogs were affected by disproportionate dwarfism. Radiographs of an affected dog revealed a [...] Read more.

Dwarfism phenotypes occur in many species and may be caused by genetic or environmental factors. In this study, we investigated a family of nine Dogo Argentino dogs, in which two dogs were affected by disproportionate dwarfism. Radiographs of an affected dog revealed a decreased level of endochondral ossification in its growth plates, and a premature closure of the distal ulnar physes. The pedigree of the dogs presented evidence of monogenic autosomal recessive inheritance; combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 34 genome segments, totaling 125 Mb. The genome of an affected dog was sequenced and compared to 795 control genomes. The prioritization of private variants revealed a clear top candidate variant for the observed dwarfism. This variant, PRKG2:XM_022413533.1:c.1634+1G>T, affects the splice donor site and is therefore predicted to disrupt the function of the PKRG2 gene encoding protein, kinase cGMP-dependent type 2, a known regulator of chondrocyte differentiation. The genotypes of the PRKG2 variant were perfectly associated with the phenotype in the studied family of dogs. PRKG2 loss-of-function variants were previously reported to cause disproportionate dwarfism in humans, cattle, mice, and rats. Together with the comparative data from other species, our data strongly suggest PRKG2:c.1634+1G>T to be a candidate causative variant for the observed dwarfism phenotype in Dogo Argentino dogs. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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8 pages, 1307 KiB

Open AccessArticle

MYO5A Frameshift Variant in a Miniature Dachshund with Coat Color Dilution and Neurological Defects Resembling Human Griscelli Syndrome Type 1

by Matthias Christen, Madeleine de le Roi, Vidhya Jagannathan, Kathrin Becker and Tosso Leeb

Genes 2021, 12(10), 1479; https://doi.org/10.3390/genes12101479 - 23 Sep 2021

Cited by 11 | Viewed by 5529

Abstract

A 1-month-old, female, smooth-haired miniature Dachshund with dilute color and neurological defects was investigated. The aim of this study was to characterize the clinical signs, histopathological changes and underlying genetic defect. The puppy had visible coat color dilution and was unable to hold [...] Read more.

A 1-month-old, female, smooth-haired miniature Dachshund with dilute color and neurological defects was investigated. The aim of this study was to characterize the clinical signs, histopathological changes and underlying genetic defect. The puppy had visible coat color dilution and was unable to hold its head on its own or to remain in a stable prone position for an extended period. Histopathological examination revealed an accumulation of clumped melanin and deposition of accumulated keratin within the hair follicles, accompanied by dermal pigmentary incontinence. These dermatological changes were compatible with the histopathology described in dogs with an MLPH-related dilute coat color. We sequenced the genome of the affected dog and compared the data to 795 control genomes. MYO5A, coding for myosin VA, was investigated as the top functional candidate gene. This search revealed a private homozygous frameshift variant in MYO5A, XM_022412522.1:c.4973_4974insA, predicted to truncate 269 amino acids (13.8%) of the wild type myosin VA protein, XP_022268230.1:p.(Asn1658Lysfs*28). The genotypes of the index family showed the expected co-segregation with the phenotype and the mutant allele was absent from 142 additionally genotyped, unrelated Dachshund dogs. MYO5A loss of function variants cause Griscelli type 1 syndrome in humans, lavender foal in horses and the phenotype of the dilute mouse mutant. Based on the available data, together with current knowledge on other species, we propose the identified MYO5A frameshift insertion as a candidate causative variant for the observed dermatological and neurological signs in the investigated dog. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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22 pages, 2172 KiB

Open AccessArticle

Genetic Diversity and Relatedness among Captive African Painted Dogs in North America

by Cassandra M. Miller-Butterworth, Karen Vacco, Amy L. Russell and Joseph C. Gaspard III

Genes 2021, 12(10), 1463; https://doi.org/10.3390/genes12101463 - 22 Sep 2021

Cited by 7 | Viewed by 3622

Abstract

African painted dogs (Lycaon pictus, APD) are highly endangered, with fewer than 7000 remaining in nature. Captive breeding programs can preserve a genetically diverse population and provide a source of individuals for reintroductions. However, most programs are initiated from few founders and [...] Read more.

African painted dogs (Lycaon pictus, APD) are highly endangered, with fewer than 7000 remaining in nature. Captive breeding programs can preserve a genetically diverse population and provide a source of individuals for reintroductions. However, most programs are initiated from few founders and suffer from low genetic diversity and inbreeding. The aims of this study were to use molecular markers to assess genetic variation, inbreeding, and relatedness among APDs in the North American captive population, to use these data to realign studbook records, and to compare these data to wild populations and to the European captive population to facilitate the development of a global management plan. We sequenced mitochondrial and major histocompatibility (MHC) class II loci and genotyped 14 microsatellite loci from 109 APDs from 34 institutions in North America. We identified three likely studbook errors and resolved ten cases of uncertain paternity. Overall, microsatellite heterozygosity was higher than reported in Europe, but effective population size estimates were lower. Mitochondrial sequence variation was extremely limited, and there were fewer MHC haplotypes than in Europe or the wild. Although the population did not show evidence of significant inbreeding overall, several individuals shared high relatedness values, which should be incorporated into future breeding programs. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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15 pages, 2130 KiB

Open AccessArticle

Whole Genome Sequencing Reveals Multiple Linked Genetic Variants on Canine Chromosome 12 Associated with Risk for Symmetrical Lupoid Onychodystrophy (SLO) in the Bearded Collie

by Liza C. Gershony, Janelle M. Belanger, Marjo K. Hytönen, Hannes Lohi and Anita M. Oberbauer

Genes 2021, 12(8), 1265; https://doi.org/10.3390/genes12081265 - 19 Aug 2021

Cited by 4 | Viewed by 4827

Abstract

In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association [...] Read more.

In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association study of the Bearded Collie revealed two regions of association that conferred risk for disease: one on canine chromosome (CFA) 12 that encompasses the DLA genes, and one on CFA17. Case-control association was employed on whole genome sequencing data to uncover putative causative variants in SLO within the CFA12 and CFA17 associated regions. Genotype imputation was then employed to refine variants of interest. Although no SLO-associated protein-coding variants were identified on CFA17, multiple variants, many with predicted damaging effects, were identified within potential candidate genes on CFA12. Furthermore, many potentially damaging alleles were fully correlated with the presence of DLA class II risk haplotypes for SLO, suggesting that the variants may reflect DLA class II haplotype association with disease or vice versa. Strong linkage disequilibrium in the region precluded the ability to isolate and assess the individual or combined effect of variants on disease development. Nonetheless, all were predictive of risk for SLO and, with judicious assessment, their application in selective breeding may prove useful to reduce the incidence of SLO in the breed. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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8 pages, 2222 KiB

Open AccessArticle

Effects of Cocoa Genotypes on Coat Color, Platelets and Coagulation Parameters in French Bulldogs

by Anna Laukner, Laura Truchet, Georgi Manukjan, Harald Schulze, Ines Langbein-Detsch, Elisabeth Mueller, Tosso Leeb and Alexandra Kehl

Genes 2021, 12(7), 1092; https://doi.org/10.3390/genes12071092 - 19 Jul 2021

Cited by 1 | Viewed by 8428

Abstract

A nonsense variant in HPS3, c.2420G>A or p.Trp807*, was recently discovered as the cause for a brown coat color termed cocoa in French Bulldogs. Here, we studied the genotype–phenotype correlation regarding coat color in HPS3 mutant dogs that carried various combinations of [...] Read more.

A nonsense variant in HPS3, c.2420G>A or p.Trp807*, was recently discovered as the cause for a brown coat color termed cocoa in French Bulldogs. Here, we studied the genotype–phenotype correlation regarding coat color in HPS3 mutant dogs that carried various combinations of mutant alleles at other coat color genes. Different combinations of HPS3, MLPH and TYRP1 genotypes resulted in subtly different shades of brown coat colors. As HPS3 variants in humans cause the Hermansky–Pudlak syndrome type 3, which in addition to oculocutaneous albinism is characterized by a storage pool deficiency leading to bleeding tendency, we also investigated the phenotypic consequences of the HPS3 variant in French Bulldogs on hematological parameters. HPS3 mutant dogs had a significantly lowered platelet dense granules abundance. However, no increased bleeding tendencies in daily routine were reported by dog owners. We therefore conclude that in dogs, the phenotypic effect of the HPS3 variant is largely restricted to pigmentation. While an effect on platelet morphology is evident, we did not obtain any indications for major health problems associated with the cocoa coat color in French Bulldogs. Further studies will be necessary to definitely rule out very subtle effects on visual acuity or a clinically relevant bleeding disorder. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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17 pages, 1563 KiB

Open AccessArticle

Dog10K_Boxer_Tasha_1.0: A Long-Read Assembly of the Dog Reference Genome

by Vidhya Jagannathan, Christophe Hitte, Jeffrey M. Kidd, Patrick Masterson, Terence D. Murphy, Sarah Emery, Brian Davis, Reuben M. Buckley, Yan-Hu Liu, Xiang-Quan Zhang, Tosso Leeb, Ya-Ping Zhang, Elaine A. Ostrander and Guo-Dong Wang

Genes 2021, 12(6), 847; https://doi.org/10.3390/genes12060847 - 30 May 2021

Cited by 28 | Viewed by 6479

Abstract

The domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named “Tasha” initially [...] Read more.

The domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named “Tasha” initially published in 2005. Derived from a Sanger whole genome shotgun sequencing approach coupled with limited clone-based sequencing, the initial assembly and subsequent updates have served as the predominant resource for canine genetics for 15 years. While the initial assembly produced a good-quality draft, as with all assemblies produced at the time, it contained gaps, assembly errors and missing sequences, particularly in GC-rich regions, which are found at many promoters and in the first exons of protein-coding genes. Here, we present Dog10K_Boxer_Tasha_1.0, an improved chromosome-level highly contiguous genome assembly of Tasha created with long-read technologies that increases sequence contiguity >100-fold, closes >23,000 gaps of the CanFam3.1 reference assembly and improves gene annotation by identifying >1200 new protein-coding transcripts. The assembly and annotation are available at NCBI under the accession GCF_000002285.5. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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13 pages, 1118 KiB

Open AccessArticle

A Missense Mutation in the KLF7 Gene Is a Potential Candidate Variant for Congenital Deafness in Australian Stumpy Tail Cattle Dogs

by Fangzheng Xu, Shuwen Shan, Susan Sommerlad, Jennifer M. Seddon and Bertram Brenig

Genes 2021, 12(4), 467; https://doi.org/10.3390/genes12040467 - 24 Mar 2021

Cited by 4 | Viewed by 4146

Abstract

Congenital deafness is prevalent among modern dog breeds, including Australian Stumpy Tail Cattle Dogs (ASCD). However, in ASCD, no causative gene has been identified so far. Therefore, we performed a genome-wide association study (GWAS) and whole genome sequencing (WGS) of affected and normal [...] Read more.

Congenital deafness is prevalent among modern dog breeds, including Australian Stumpy Tail Cattle Dogs (ASCD). However, in ASCD, no causative gene has been identified so far. Therefore, we performed a genome-wide association study (GWAS) and whole genome sequencing (WGS) of affected and normal individuals. For GWAS, 3 bilateral deaf ASCDs, 43 herding dogs, and one unaffected ASCD were used, resulting in 13 significantly associated loci on 6 chromosomes, i.e., CFA3, 8, 17, 23, 28, and 37. CFA37 harbored a region with the most significant association (−log₁₀(9.54 × 10⁻²¹) = 20.02) as well as 7 of the 13 associated loci. For whole genome sequencing, the same three affected ASCDs and one unaffected ASCD were used. The WGS data were compared with 722 canine controls and filtered for protein coding and non-synonymous variants, resulting in four missense variants present only in the affected dogs. Using effect prediction tools, two variants remained with predicted deleterious effects within the Heart development protein with EGF like domains 1 (HEG1) gene (NC_006615.3: g.28028412G>C; XP_022269716.1: p.His531Asp) and Kruppel-like factor 7 (KLF7) gene (NC_006619.3: g.15562684G>A; XP_022270984.1: p.Leu173Phe). Due to its function as a regulator in heart and vessel formation and cardiovascular development, HEG1 was excluded as a candidate gene. On the other hand, KLF7 plays a crucial role in the nervous system, is expressed in the otic placode, and is reported to be involved in inner ear development. 55 additional ASCD samples (28 deaf and 27 normal hearing dogs) were genotyped for the KLF7 variant, and the variant remained significantly associated with deafness in ASCD (p = 0.014). Furthermore, 24 dogs with heterozygous or homozygous mutations were detected, including 18 deaf dogs. The penetrance was calculated to be 0.75, which is in agreement with previous reports. In conclusion, KLF7 is a promising candidate gene causative for ASCD deafness. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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17 pages, 2795 KiB

Open AccessArticle

Genomic Regions Associated with Variation in Pigmentation Loss in Saddle Tan Beagles

by Mia E. Nord and Per Jensen

Genes 2021, 12(2), 316; https://doi.org/10.3390/genes12020316 - 23 Feb 2021

Cited by 2 | Viewed by 3283

Abstract

Loss of pigmentation is a hallmark of domestication, and dogs offer a unique model for understanding the genetics of fur coloration. The aim of this study was to use dense genetic mapping to map loci underlying variations in color and whiteness in a [...] Read more.

Loss of pigmentation is a hallmark of domestication, and dogs offer a unique model for understanding the genetics of fur coloration. The aim of this study was to use dense genetic mapping to map loci underlying variations in color and whiteness in a population of laboratory beagles. A total of 190 beagles with well-defined pedigrees were phenotyped for the amount of white color in six different body parts, including the saddle. All individuals were genotyped on 85,172 informative and valid SNP-markers and the genome-wide associations for the amount of white in each body part were determined. There was a large variation in the amount of white on different parts of the body, and the whiteness was highly correlated within individuals, except for saddle color which was only moderately correlated with overall whiteness. The GWAS showed significant associations with two loci, one on chromosome 5, containing the MC1R gene, and one on chromosome 20, containing the MITF gene. Our results suggest that the variation in loss of pigmentation is largely a function of regulatory variation related to these genes. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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19 pages, 1605 KiB

Open AccessArticle

Ancient DNA from the Asiatic Wild Dog (Cuon alpinus) from Europe

by Ulrike H. Taron, Johanna L. A. Paijmans, Axel Barlow, Michaela Preick, Arati Iyengar, Virgil Drăgușin, Ștefan Vasile, Adrian Marciszak, Martina Roblíčková and Michael Hofreiter

Genes 2021, 12(2), 144; https://doi.org/10.3390/genes12020144 - 22 Jan 2021

Cited by 5 | Viewed by 5389

Abstract

The Asiatic wild dog (Cuon alpinus), restricted today largely to South and Southeast Asia, was widespread throughout Eurasia and even reached North America during the Pleistocene. Like many other species, it suffered from a huge range loss towards the end of [...] Read more.

The Asiatic wild dog (Cuon alpinus), restricted today largely to South and Southeast Asia, was widespread throughout Eurasia and even reached North America during the Pleistocene. Like many other species, it suffered from a huge range loss towards the end of the Pleistocene and went extinct in most of its former distribution. The fossil record of the dhole is scattered and the identification of fossils can be complicated by an overlap in size and a high morphological similarity between dholes and other canid species. We generated almost complete mitochondrial genomes for six putative dhole fossils from Europe. By using three lines of evidence, i.e., the number of reads mapping to various canid mitochondrial genomes, the evaluation and quantification of the mapping evenness along the reference genomes and phylogenetic analysis, we were able to identify two out of six samples as dhole, whereas four samples represent wolf fossils. This highlights the contribution genetic data can make when trying to identify the species affiliation of fossil specimens. The ancient dhole sequences are highly divergent when compared to modern dhole sequences, but the scarcity of dhole data for comparison impedes a more extensive analysis. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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8 pages, 514 KiB

Open AccessArticle

A SINE Insertion in F8 Gene Leads to Severe Form of Hemophilia A in a Family of Rhodesian Ridgebacks

by Alexandra Kehl, Anita Haug Haaland, Ines Langbein-Detsch and Elisabeth Mueller

Genes 2021, 12(2), 134; https://doi.org/10.3390/genes12020134 - 21 Jan 2021

Cited by 6 | Viewed by 2358

Abstract

Hemophilia A is the most common coagulation factor disorder in humans and dogs. The disease is characterized by the lack or diminished activity of Factor VIII (FVIII), caused by variants in the F8 gene and inherited as an X chromosomal trait. Two related [...] Read more.

Hemophilia A is the most common coagulation factor disorder in humans and dogs. The disease is characterized by the lack or diminished activity of Factor VIII (FVIII), caused by variants in the F8 gene and inherited as an X chromosomal trait. Two related male Rhodesian Ridgebacks were diagnosed with Hemophilia A due to reduced FVIII activity. The purpose of the study was to determine the genetic cause and give breeding advice for the remaining family members in order to eradicate the variant. By Sanger sequencing a short interspersed nuclear element (SINE) insertion in exon 14 of the F8 gene was found. Perfect correlation of this genetic variant with clinical signs of hemophilia A in the family tree, and the lack of this genetic variant in more than 500 unrelated dogs of the same and other breeds, confirms the hypothesis of this SINE being the underlying genetic cause of Hemophilia A in this family. The identification of clinically unaffected female carriers allows subsequent exclusion of these animals from breeding, to avoid future production of clinically affected male offspring and more subclinical female carriers. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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9 pages, 1309 KiB

Open AccessArticle

A COL7A1 Variant in a Litter of Neonatal Basset Hounds with Dystrophic Epidermolysis Bullosa

by Teresa Maria Garcia, Sarah Kiener, Vidhya Jagannathan, Duncan S. Russell and Tosso Leeb

Genes 2020, 11(12), 1458; https://doi.org/10.3390/genes11121458 - 4 Dec 2020

Cited by 6 | Viewed by 3082

Abstract

We investigated three neonatal Basset Hound littermates with lesions consistent with epidermolysis bullosa (EB), a group of genetic blistering diseases. A clinically normal bitch was bred to her grandfather by artificial insemination. Out of a litter of seven puppies, two affected puppies died [...] Read more.

We investigated three neonatal Basset Hound littermates with lesions consistent with epidermolysis bullosa (EB), a group of genetic blistering diseases. A clinically normal bitch was bred to her grandfather by artificial insemination. Out of a litter of seven puppies, two affected puppies died and one was euthanized, with these puppies being submitted for diagnostic necropsy. All had multiple bullae and ulcers involving the nasal planum and paw pads, as well as sloughing claws; one puppy also had oral and esophageal ulcers. The complete genome of one affected puppy was sequenced, and 37 known EB candidate genes were assessed. We found a candidate causative variant in COL7A1, which encodes the collagen VII alpha 1 chain. The variant is a complex rearrangement involving duplication of a 107 bp region harboring a frameshift deletion of 7 bp. The variant is predicted to truncate more than 75% of the open reading frame, p.(Val677Serfs*11). Targeted genotyping of this duplication confirmed that all three affected puppies were homozygous for the duplication, whereas 12 unaffected Basset Hounds did not carry the duplication. This variant was also not seen in the genomes of more than 600 dogs of other breeds. COL7A1 variants have been identified in humans and dogs with dystrophic epidermolysis bullosa (DEB). The identified COL7A1 variant therefore most likely represents the causative variant and allows the refinement of the preliminary EB diagnosis to DEB. Full article

(This article belongs to the Special Issue Canine Genetics 2)

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