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Pigment Intensity in Dogs is Associated with a Copy Number Variant Upstream of KITLG.

ABSTRACT: Dogs exhibit a wide variety of coat color types, and many genes have been identified that control pigment production, appearance, and distribution. Some breeds, such as the Nova Scotia Duck Tolling Retriever (NSDTR), exhibit variation in pheomelanin pigment intensity that is not explained by known genetic variants. A genome-wide association study comparing light red to dark red in the NSDTR identified a significantly associated region on canine chromosome 15 (CFA 15:23 Mb-38 Mb). Coverage analysis of whole genome sequence data from eight dogs identified a 6 kb copy number variant (CNV) 152 kb upstream of KITLG. Genotyping with digital droplet PCR (ddPCR) confirmed a significant association between an increased copy number with the dark-red coat color in NSDTR (p = 6.1 × 10^-7). The copy number of the CNV was also significantly associated with coat color variation in both eumelanin and pheomelanin-based Poodles (p = 1.5 × 10^-8, 4.0 × 10^-9) and across other breeds. Moreover, the copy number correlated with pigment intensity along the hair shaft in both pheomelanin and eumelanin coats. KITLG plays an important role in melanogenesis, and variants upstream of KITLG have been associated with coat color variation in mice as well as hair color in humans consistent with its role in the domestic dog.

SUBMITTER: Weich K

PROVIDER: S-EPMC7017362 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Correction: Weich, K., et al. Pigment Intensity in Dogs Is Associated with a Copy Number Variant Upstream of KITLG. Genes 2020, 11, 75.

Project description:The authors wish to make the following corrections to this paper [...].

| S-EPMC8000075 | biostudies-literature

A copy number variant at the KITLG locus likely confers risk for canine squamous cell carcinoma of the digit.

Project description:The domestic dog is a robust model for studying the genetics of complex disease susceptibility. The strategies used to develop and propagate modern breeds have resulted in an elevated risk for specific diseases in particular breeds. One example is that of Standard Poodles (STPOs), who have increased risk for squamous cell carcinoma of the digit (SCCD), a locally aggressive cancer that causes lytic bone lesions, sometimes with multiple toe recurrence. However, only STPOs of dark coat color are at high risk; light colored STPOs are almost entirely unaffected, suggesting that interactions between multiple pathways are necessary for oncogenesis. We performed a genome-wide association study (GWAS) on STPOs, comparing 31 SCCD cases to 34 unrelated black STPO controls. The peak SNP on canine chromosome 15 was statistically significant at the genome-wide level (P(raw) = 1.60 × 10(-7); P(genome) = 0.0066). Additional mapping resolved the region to the KIT Ligand (KITLG) locus. Comparison of STPO cases to other at-risk breeds narrowed the locus to a 144.9-Kb region. Haplotype mapping among 84 STPO cases identified a minimal region of 28.3 Kb. A copy number variant (CNV) containing predicted enhancer elements was found to be strongly associated with SCCD in STPOs (P = 1.72 × 10(-8)). Light colored STPOs carry the CNV risk alleles at the same frequency as black STPOs, but are not susceptible to SCCD. A GWAS comparing 24 black and 24 light colored STPOs highlighted only the MC1R locus as significantly different between the two datasets, suggesting that a compensatory mutation within the MC1R locus likely protects light colored STPOs from disease. Our findings highlight a role for KITLG in SCCD susceptibility, as well as demonstrate that interactions between the KITLG and MC1R loci are potentially required for SCCD oncogenesis. These findings highlight how studies of breed-limited diseases are useful for disentangling multigene disorders.

| S-EPMC3610924 | biostudies-literature

Genome-wide copy number variant discovery in dogs using the CanineHD genotyping array.

Project description:BACKGROUND: Substantial contribution to phenotypic diversity is accounted for by copy number variants (CNV). In human, as well as other species, the effect of CNVs range from benign to directly disease-causing which motivates the continued investigations of CNVs. Previous canine genome-wide screenings for CNVs have been performed using high-resolution comparative genomic hybridisation arrays which have contributed with a detailed catalogue of CNVs. Here, we present the first CNV investigation in dogs based on the recently reported CanineHD 170 K genotyping array. The hitherto largest dataset in canine CNV discovery was assessed, 351 dogs from 30 different breeds, enabling identification of novel CNVs and a thorough characterisation of breed-specific CNVs. RESULTS: A stringent procedure identified 72 CNV regions with the smallest size of 38 kb and of the 72 CNV regions, 38 overlapped 148 annotated genes. A total of 29 novel CNV regions were found containing 44 genes. Furthermore, 15 breed specific CNV regions were identified of which 14 were novel and some of them overlapped putative disease susceptibility genes. In addition, the human ortholog of 23 canine copy number variable genes identified herein has been previously suggested to be dosage-sensitive in human. CONCLUSIONS: The present study evaluated the performance of the CanineHD in detecting CNVs and extends the current catalogue of canine CNV regions with several dozens of novel CNV regions. These novel CNV regions, which harbour candidate genes that possibly contribute to phenotypic variation in dogs or to disease-susceptibility, are a rich resource for future investigations.

| S-EPMC4234435 | biostudies-literature

Genome-wide copy number variant discovery in dogs using the CanineHD genotyping array

Project description:This study used the CanineHD genotyping array to investigate copy number variants in the dog genome in a total of 351 samples from 30 different breeds.

2014-03-28 | GSE55134 | GEO

Genome-wide copy number variant discovery in dogs using the CanineHD genotyping array

Project description:This study used the CanineHD genotyping array to investigate copy number variants in the dog genome in a total of 351 samples from 30 different breeds. In total, 359 samples from 30 different breeds were genotyped on the CanineHD array. Signal intensities from the array were used to assess copy number variants and a supplied clusterfile from Illumina was used as reference file (downloadable at http://supportres.illumina.com/documents/downloads/productfiles/caninehd/caninehd_a.egt). Eight samples did not fulfill the quality criteria for CNV calling and therefore CNV calling was performed on 351 samples.

2014-03-28 | E-GEOD-55134 | biostudies-arrayexpress

The genomic architecture of segmental duplications and associated copy number variants in dogs.

Project description:Structural variation is an important and abundant source of genetic and phenotypic variation. Here we describe the first systematic and genome-wide analysis of segmental duplications and associated copy number variants (CNVs) in the modern domesticated dog, Canis familiaris, which exhibits considerable morphological, physiological, and behavioral variation. Through computational analyses of the publicly available canine reference sequence, we estimate that segmental duplications comprise approximately 4.21% of the canine genome. Segmental duplications overlap 841 genes and are significantly enriched for specific biological functions such as immunity and defense and KRAB box transcription factors. We designed high-density tiling arrays spanning all predicted segmental duplications and performed aCGH in a panel of 17 breeds and a gray wolf. In total, we identified 3583 CNVs, approximately 68% of which were found in two or more samples that map to 678 unique regions. CNVs span 429 genes that are involved in a wide variety of biological processes such as olfaction, immunity, and gene regulation. Our results provide insight into mechanisms of canine genome evolution and generate a valuable resource for future evolutionary and phenotypic studies.

| S-EPMC2661811 | biostudies-literature

Identification of Copy Number Variants in Dogs

Project description:Custom exome aCGH analysis of copy number across the genomes of 16 canine breeds

2012-03-08 | GSE36333 | GEO

De novo copy number variations in cloned dogs

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-12-17 | GSE49357 | GEO

Copy number variation upstream of PMP22 in Charcot-Marie-Tooth disease.

Project description:In several individuals with a Charcot-Marie-Tooth (CMT) phenotype, we found a copy number variation (CNV) on chromosome 17p12 in the direct vicinity of the peripheral myelin protein 22 (PMP22) gene. The exact borders and size of this CNV were determined by Southern blot analysis, MLPA, vectorette PCR, and microarray hybridization analyses. All patients from six apparently unrelated families carried an identical 186-kb duplication different from the commonly reported 1.5-Mb duplication associated with CMT1A. This ancestral mutation that was not reported in the human structural variation database was only detected in affected individuals and family members. It was absent in 2124 control chromosomes and 40 patients with a chronic inflammatory demyelinating polyneuropathy (CIDP) and therefore should be regarded as causative for the disease. This variant escapes most routine diagnostic screens for CMT1A, because copy numbers of PMP22 probes were all normal. No indications were found for the involvement of the genes that are located within this duplication. A possible association of this duplication with a mutation in the PMP22 coding regions was also excluded. We suggest that this CNV proximal of the PMP22 gene leads to CMT through an unknown mechanism affecting PMP22 expression.

| S-EPMC2987248 | biostudies-literature

Case Report: Novel Copy Number Variant 16p11.2 Duplication Associated With Prune Belly Syndrome.

Project description:Prune belly syndrome (PBS) is a rare congenital disease that predominantly occurs in males and is identified by its classic triad of abdominal wall musculature deficiencies, cryptorchidism, and urinary tract abnormalities. However, numerous anomalies involving the kidneys, heart, lungs, and muscles have also been reported. A multitude of chromosomal abnormalities have been implicated in its pathogenesis. PBS can occur in association with trisomy 18 and 21. Gene duplications and deletions have also been reported; however, a definite cause of PBS is still unknown. We report the first PBS patient with a copy number variant in 16p11.2.

| S-EPMC8496350 | biostudies-literature

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