Whole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology

Plassais, Jocelyn; Kim, Jaemin; Davis, Brian W.; Karyadi, Danielle M.; Hogan, Andrew N.; Harris, Alex C.; Decker, Brennan; Parker, Heidi G.; Ostrander, Elaine A.

doi:10.1038/s41467-019-09373-w

Cited by 274 publications

(434 citation statements)

References 76 publications

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“…This is the first report of the tan point ( ASIP ), and long hair ( FGF5 ) variants in wild canine populations. A recent paper verified the CFA10 ear shape locus, and demonstrated that, while definitively a contributing locus, it does not perfectly account for ear phenotype (28). Thus, the higher frequency of ear shape and hair length variant alleles in wild populations is perhaps not surprising, as these phenotypes are known to be driven by more than one locus (20,27,54).…”

Section: Discussionmentioning

confidence: 99%

True Colors: commercially-acquired morphological genotypes reveal hidden allele variation among dog breeds, informing both trait ancestry and breed potential

Dreger

Hooser

Hughes

et al. 2019

Preprint

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Direct-to-consumer canine genetic testing is becoming increasingly popular among dog owners. The data collected therein provides intriguing insight into the current status of morphological variation present within purebred populations. Mars WISDOM PANELTM data from 11,790 anonymized dogs, representing 212 breeds and 4 wild canine species, were evaluated at genes associated with 7 coat color traits and 5 physical characteristics. Frequencies for all tested alleles at these 12 genes were determined by breed and by phylogenetic grouping. A sub-set of the data, consisting of 30 breeds, was divided into separate same-breed populations based on country of collection, body size, coat variation, or lineages selected for working or conformation traits. Significantly different (p ≤ 0.00167) allele frequencies were observed between populations for at least one of the tested genes in 26 of the 30 breeds. Next, standard breed descriptions from major American and international registries were used to determine colors and tail lengths (e.g. genetic bobtail) accepted within each breed. Alleles capable of producing traits incongruous with breed descriptions were observed in 143 breeds, such that random mating within breeds has probabilities of between 4.9e−7 and 0.25 of creating undesirable phenotypes. Finally, the presence of rare alleles within breeds, such as those for the recessive black coloration and natural bobtail, was combined with previously published identity-by-decent haplotype sharing levels to propose pathways by which the alleles may have spread throughout dog breeds. Taken together, this work demonstrates that: 1) the occurrence of low frequency alleles within breeds can reveal the influence of regional or functional selection practices; 2) it is possible to trace the mode by which characteristics have spread across breeds during historical breed formation; and 3) the necessity of addressing conflicting ideals in breed descriptions relative to actual genetic potential is crucial.Author SummaryFrom the sleek Doberman Pinscher to the coifed Poodle, the sunny Golden Retriever to the aristocratic Pekingese, the world of purebred dogs offers options that appeal to nearly all aesthetics. Pure dog breeds, of which there are over 400 worldwide, are created through selective breeding over multiple generations, toward an ideal goal of temperament, behavior, and physical appearance. Written descriptions of these breed-specific ideals are produced and maintained by dedicated breed enthusiasts, and provide guidelines that direct breeders in their selection choices. However, the genetic mechanisms that produce the spectrum of canine colors and patterns, sculpt the small triangular ears of a Siberian Husky or the long soft ears of a Basset Hound, are complicated and intertwined. This means that some breeds can carry rare, hidden traits for many generations, hampering selection efforts toward uniformity. We have determined the genotypes of >11,000 dogs, representing >200 breeds, at 12 genes that impact coat color and physical characteristics. In doing so, we can now present realistic trait frequencies within each breed, report occurrences of gene variants that can produce undesirable traits, and draw conclusions about the historic spread of characteristics across modern related breeds and those with distant shared ancestry.

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Section: Discussionmentioning

confidence: 99%

True Colors: commercially-acquired morphological genotypes reveal hidden allele variation among dog breeds, informing both trait ancestry and breed potential

Dreger

Hooser

Hughes

et al. 2019

Preprint

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“…To predict the functional effects of the called variants, SnpEff [26] software together with NCBI annotation release 105 for the CanFam 3.1 genome reference assembly was used. For variant filtering we used 654 control genomes, which were either publicly available [27,28] or produced during other projects of our group [24] (Table S4).…”

Section: Variant Callingmentioning

confidence: 99%

A Missense Variant Affecting the C-Terminal Tail of UNC93B1 in Dogs with Exfoliative Cutaneous Lupus Erythematosus (ECLE)

Leeb

Leuthard

Jagannathan

et al. 2020

Genes

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Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form of chronic CLE that is inherited as a monogenic autosomal recessive trait. A genome-wide association study (GWAS) with 14 cases and 29 controls confirmed a previously published result that the causative variant maps to chromosome 18. Autozygosity mapping refined the ECLE locus to a 493 kb critical interval. Filtering of whole genome sequence data from two cases against 654 controls revealed a single private protein-changing variant in this critical interval, UNC93B1:c.1438C>A or p.Pro480Thr. The homozygous mutant genotype was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls. UNC93B1 is a transmembrane protein located in the endoplasmic reticulum and endolysosomes, which is required for correct trafficking of several Toll-like receptors (TLRs). The p.Pro480Thr variant is predicted to affect the C-terminal tail of the UNC93B1 that has recently been shown to restrict TLR7 mediated autoimmunity via an interaction with syndecan binding protein (SDCBP). The functional knowledge on UNC93B1 strongly suggests that p.Pro480Thr is causing ECLE in dogs. These dogs therefore represent an interesting spontaneous model for human lupus erythematosus. Our results warrant further investigations of whether genetic variants affecting the C-terminus of UNC93B1 might be involved in specific subsets of CLE or SLE cases in humans and other species.

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“…To predict the functional effects of the called variants, SnpEff [11] software together with NCBI annotation release 105 for the CanFam 3.1 genome reference assembly was used. We used a vcf-file containing 648 dog and 8 wolf genomes, which were either publicly available [12,13] or produced during other projects of our group [10]. We excluded 10 genome sequences from other Belgian Shepherd dogs from filtering to minimize the risk of having any unrecognized carriers in the control cohort.…”

Section: Variant Calling and Filteringmentioning

confidence: 99%

YARS2 Missense Variant in Belgian Shepherd Dogs with Cardiomyopathy and Juvenile Mortality

Gurtner

Hug

Kleiter

et al. 2020

Genes

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Dog puppy loss by the age of six to eight weeks after normal development is relatively uncommon. Necropsy findings in two spontaneously deceased Belgian Shepherd puppies indicated an abnormal accumulation of material in several organs. A third deceased puppy exhibited mild signs of an inflammation in the central nervous system and an enteritis. The puppies were closely related, raising the suspicion of a genetic cause. Pedigree analysis suggested a monogenic autosomal recessive inheritance. Combined linkage and homozygosity mapping assigned the most likely position of a potential genetic defect to 13 genome segments totaling 82 Mb. The genome of an affected puppy was sequenced and compared to 645 control genomes. Three private protein changing variants were found in the linked and homozygous regions. Targeted genotyping in 96 Belgian Shepherd dogs excluded two of these variants. The remaining variant, YARS2:1054G>A or p.Glu352Lys, was perfectly associated with the phenotype in a cohort of 474 Belgian Shepherd dogs. YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase 2 and the predicted amino acid change replaces a negatively charged and evolutionary conserved glutamate at the surface of the tRNA binding domain of YARS2 with a positively charged lysine. Human patients with loss-of-function variants in YARS2 suffer from myopathy, lactic acidosis, and sideroblastic anemia 2, a disease with clinical similarities to the phenotype of the studied dogs. The carrier frequency was 27.2% in the tested Belgian Shepherd dogs. Our data suggest YARS2:1054G>A as the candidate causative variant for the observed juvenile mortality.

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Whole genome sequencing of canids reveals genomic regions under selection and variants influencing morphology

Cited by 274 publications

References 76 publications

True Colors: commercially-acquired morphological genotypes reveal hidden allele variation among dog breeds, informing both trait ancestry and breed potential

True Colors: commercially-acquired morphological genotypes reveal hidden allele variation among dog breeds, informing both trait ancestry and breed potential

A Missense Variant Affecting the C-Terminal Tail of UNC93B1 in Dogs with Exfoliative Cutaneous Lupus Erythematosus (ECLE)

YARS2 Missense Variant in Belgian Shepherd Dogs with Cardiomyopathy and Juvenile Mortality

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