30 results on '"Reuben M. Buckley"'
Search Results
2. Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture
- Author
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Jennifer R. S. Meadows, Jeffrey M. Kidd, Guo-Dong Wang, Heidi G. Parker, Peter Z. Schall, Matteo Bianchi, Matthew J. Christmas, Katia Bougiouri, Reuben M. Buckley, Christophe Hitte, Anthony K. Nguyen, Chao Wang, Vidhya Jagannathan, Julia E. Niskanen, Laurent A. F. Frantz, Meharji Arumilli, Sruthi Hundi, Kerstin Lindblad-Toh, Catarina Ginja, Kadek Karang Agustina, Catherine André, Adam R. Boyko, Brian W. Davis, Michaela Drögemüller, Xin-Yao Feng, Konstantinos Gkagkavouzis, Giorgos Iliopoulos, Alexander C. Harris, Marjo K. Hytönen, Daniela C. Kalthoff, Yan-Hu Liu, Petros Lymberakis, Nikolaos Poulakakis, Ana Elisabete Pires, Fernando Racimo, Fabian Ramos-Almodovar, Peter Savolainen, Semina Venetsani, Imke Tammen, Alexandros Triantafyllidis, Bridgett vonHoldt, Robert K. Wayne, Greger Larson, Frank W. Nicholas, Hannes Lohi, Tosso Leeb, Ya-Ping Zhang, and Elaine A. Ostrander
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Canine ,Dog ,Genomics ,Variation ,Demographic history ,Mitochondrial DNA ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function. Results We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection. Conclusions We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available.
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- 2023
- Full Text
- View/download PDF
3. X‐linked myotubular myopathy associated with an MTM1 variant in a Maine coon cat
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Matthew A. Kopke, G. Diane Shelton, Leslie A. Lyons, Meredith J. Wall, Sarah Pemberton, Kristene R. Gedye, Rebecca Owen, Ling T. Guo, Reuben M. Buckley, Juan A. Valencia, Lives Consortium, and Boyd R. Jones
- Subjects
CNM ,congenital ,feline ,immunohistochemistry ,skeletal muscle ,XLMTM ,Veterinary medicine ,SF600-1100 - Abstract
Abstract Objective Describe the clinical course and diagnostic and genetic findings in a cat with X‐linked myotubular myopathy. Case Summary A 7‐month‐old male Maine coon was evaluated for progressively worsening gait abnormalities and generalized weakness. Neurolocalization was to the neuromuscular system. Genetic testing for spinal muscular atrophy (LIX1) was negative. Given the progressive nature and suspected poor long‐term prognosis, the owners elected euthanasia. Histopathology of skeletal muscle obtained post‐mortem disclosed numerous rounded atrophic or hypotrophic fibers with internal nuclei or central basophilic staining. Using oxidative reactions mediated by cytochrome C oxidase and succinic dehydrogenase, scattered myofibers were observed to have central dark staining structures and a “ring‐like” appearance. Given the cat's age and clinical history, a congenital myopathy was considered most likely, with the central nuclei and “ring‐like” changes consistent with either centronuclear or myotubular myopathy. Whole genome sequencing identified an underlying missense variant in myotubularin 1 (MTM1), a known candidate gene for X‐linked myotubular myopathy. New or Unique Information Provided This case is the first report of X‐linked myotubular myopathy in a cat with an MTM1 missense mutation. Maine coon cat breeders may consider screening for this variant to prevent production of affected cats and to eradicate the variant from the breeding population.
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- 2022
- Full Text
- View/download PDF
4. A domestic cat whole exome sequencing resource for trait discovery
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Alana R. Rodney, Reuben M. Buckley, Robert S. Fulton, Catrina Fronick, Todd Richmond, Christopher R. Helps, Peter Pantke, Dianne J. Trent, Karen M. Vernau, John S. Munday, Andrew C. Lewin, Rondo Middleton, Leslie A. Lyons, and Wesley C. Warren
- Subjects
Medicine ,Science - Abstract
Abstract Over 94 million domestic cats are susceptible to cancers and other common and rare diseases. Whole exome sequencing (WES) is a proven strategy to study these disease-causing variants. Presented is a 35.7 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. Whole exome sequencing was conducted on 41 cats with known and unknown genetic diseases and traits, of which ten cats had matching whole genome sequence (WGS) data available, used to validate WES performance. At 80 × mean exome depth of coverage, 96.4% of on-target base coverage had a sequencing depth > 20-fold, while over 98% of single nucleotide variants (SNVs) identified by WGS were also identified by WES. Platform-specific SNVs were restricted to sex chromosomes and a small number of olfactory receptor genes. Within the 41 cats, we identified 31 previously known causal variants and discovered new gene candidate variants, including novel missense variance for polycystic kidney disease and atrichia in the Peterbald cat. These results show the utility of WES to identify novel gene candidate alleles for diseases and traits for the first time in a feline model.
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- 2021
- Full Text
- View/download PDF
5. Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon in CLN6
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Martin L. Katz, Reuben M. Buckley, Vanessa Biegen, Dennis P. O’Brien, Gayle C. Johnson, Wesley C. Warren, and Leslie A. Lyons
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feline ,whole exome sequencing ,lysosomal storage disease ,batten disease ,mutation ,hereditary ,Genetics ,QH426-470 - Abstract
A neutered male domestic medium-haired cat presented at a veterinary neurology clinic at 20 months of age due to progressive neurological signs that included visual impairment, focal myoclonus, and frequent severe generalized seizures that were refractory to treatment with phenobarbital. Magnetic resonance imaging revealed diffuse global brain atrophy. Due to the severity and frequency of its seizures, the cat was euthanized at 22 months of age. Microscopic examination of the cerebellum, cerebral cortex and brainstem revealed pronounced intracellular accumulations of autofluorescent storage material and inflammation in all 3 brain regions. Ultrastructural examination of the storage material indicated that it consisted almost completely of tightly-packed membrane-like material. The clinical signs and neuropathology strongly suggested that the cat suffered from a form of neuronal ceroid lipofuscinosis (NCL). Whole exome sequence analysis was performed on genomic DNA from the affected cat. Comparison of the sequence data to whole exome sequence data from 39 unaffected cats and whole genome sequence data from an additional 195 unaffected cats revealed a homozygous variant in CLN6 that was unique to the affected cat. This variant was predicted to cause a stop gain in the transcript due to a guanine to adenine transition (ENSFCAT00000025909:c.668G > A; XM_003987007.5:c.668G > A) and was the sole loss of function variant detected. CLN6 variants in other species, including humans, dogs, and sheep, are associated with the CLN6 form of NCL. Based on the affected cat’s clinical signs, neuropathology and molecular genetic analysis, we conclude that the cat’s disorder resulted from the loss of function of CLN6. This study is only the second to identify the molecular genetic basis of a feline NCL. Other cats exhibiting similar signs can now be screened for the CLN6 variant. This could lead to establishment of a feline model of CLN6 disease that could be used in therapeutic intervention studies.
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- 2020
- Full Text
- View/download PDF
6. Dog10K_Boxer_Tasha_1.0: A Long-Read Assembly of the Dog Reference Genome
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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
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Canis lupus familiaris ,high quality ,contiguity ,Pacific biosciences ,annotation ,resource ,Genetics ,QH426-470 - 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 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.
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- 2021
- Full Text
- View/download PDF
7. A Deletion in GDF7 is Associated with a Heritable Forebrain Commissural Malformation Concurrent with Ventriculomegaly and Interhemispheric Cysts in Cats
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Yoshihiko Yu, Erica K. Creighton, Reuben M. Buckley, Leslie A. Lyons, and Lives Consortium
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feline ,Felis catus ,brain malformation ,BMP12 ,neurodevelopment ,genetics ,Genetics ,QH426-470 - Abstract
An inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation, concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test and a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion in growth differentiation factor 7 (GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats, by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. In mice, GDF7 mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasized the importance of GDF7 in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.
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- 2020
- Full Text
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8. Werewolf, There Wolf: Variants in Hairless Associated with Hypotrichia and Roaning in the Lykoi Cat Breed
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Reuben M. Buckley, Barbara Gandolfi, Erica K. Creighton, Connor A. Pyne, Delia M. Bouhan, Michelle L. LeRoy, David A. Senter, Johnny R. Gobble, Marie Abitbol, Leslie A. Lyons, and Lives Consortium
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atrichia ,domestic cat ,Felis catus ,fur ,HR ,naked ,Genetics ,QH426-470 - Abstract
A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR lysine demethylase and nuclear receptor corepressor) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.
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- 2020
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9. The dogs of Chernobyl: Demographic insights into populations inhabiting the nuclear exclusion zone
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Gabriella J. Spatola, Reuben M. Buckley, Megan Dillon, Emily V. Dutrow, Jennifer A. Betz, Małgorzata Pilot, Heidi G. Parker, Wiesław Bogdanowicz, Rachel Thomas, Ihor Chyzhevskyi, Gennadi Milinevsky, Norman Kleiman, Matthew Breen, Elaine A. Ostrander, and Timothy A. Mousseau
- Subjects
Multidisciplinary - Abstract
The 1986 Chernobyl nuclear disaster initiated a series of catastrophic events resulting in long-term and widespread environmental contamination. We characterize the genetic structure of 302 dogs representing three free-roaming dog populations living within the power plant itself, as well as those 15 to 45 kilometers from the disaster site. Genome-wide profiles from Chernobyl, purebred and free-breeding dogs, worldwide reveal that the individuals from the power plant and Chernobyl City are genetically distinct, with the former displaying increased intrapopulation genetic similarity and differentiation. Analysis of shared ancestral genome segments highlights differences in the extent and timing of western breed introgression. Kinship analysis reveals 15 families, with the largest spanning all collection sites within the radioactive exclusion zone, reflecting migration of dogs between the power plant and Chernobyl City. This study presents the first characterization of a domestic species in Chernobyl, establishing their importance for genetic studies into the effects of exposure to long-term, low-dose ionizing radiation.
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- 2023
10. Divergent genome evolution caused by regional variation in DNA gain and loss between human and mouse.
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Reuben M. Buckley, R. Daniel Kortschak, and David L. Adelson
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- 2018
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11. Standardization of a SNP panel for parentage verification and identification in the domestic cat (Felis silvestris catus)
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H Anderson, C Bauguil, Maria Longeri, L H P van der Goor, Reuben M. Buckley, M. de Groot, G. Sofronidis, H Bauer, J Qiu, Robert A. Grahn, Peter Dovč, L Kock, R Brugidou, Leslie A. Lyons, S Mouysset-Geniez, O Forman, and Rebecca R. Bellone
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0301 basic medicine ,breeds ,Genetic Markers ,Genotyping Techniques ,Animal Genetics ,Population ,Biology ,Breeding ,Polymorphism, Single Nucleotide ,genetic testing ,03 medical and health sciences ,single nucleotide polymorphism ,Genetics ,Animals ,education ,Genotyping ,Oligonucleotide Array Sequence Analysis ,education.field_of_study ,Genetic diversity ,Full Paper ,Felis ,0402 animal and dairy science ,04 agricultural and veterinary sciences ,General Medicine ,Full Papers ,biology.organism_classification ,040201 dairy & animal science ,SNP genotyping ,030104 developmental biology ,Genetics, Population ,Evolutionary biology ,Genetic marker ,Cats ,Microsatellite ,Animal Science and Zoology ,DNA profile - Abstract
Summary The domestic cat (Felis silvestris catus) is a valued companion animal throughout the world. Over 60 different cat breeds are accepted for competition by the cat fancy registries in different countries. Genetic markers, including short tandem repeats and SNPs, are available to evaluate and manage levels of inbreeding and genetic diversity, population and breed structure relationships, and individual identification for forensic and registration purposes. The International Society of Animal Genetics (ISAG) hosts the Applied Genetics in Companion Animals Workshop, which supports the standardization of genetic marker panels and genotyping for the identification of cats via comparison testing. SNP panels have been in development for many species, including the domestic cat. An ISAG approved core panel of SNPs for use in cat identification and parentage analyses is presented. SNPs (n = 121) were evaluated by different university‐based and commercial laboratories using 20 DNA samples as part of the ISAG comparison testing procedures. Different SNP genotyping technologies were examined, including DNA arrays, genotyping‐by‐sequencing and mass spectroscopy, to select a robust and efficient panel of 101 SNPs as the ISAG core panel for cats. The SNPs are distributed across all chromosomes including two on the X chromosome and an XY pseudo‐autosomal sexing marker (zinc‐finger XY; ZFXY). A population study demonstrated that the markers have an average polymorphic information content of 0.354 and a power of exclusion greater than 0.9999. The SNP panel should keep testing affordable while also allowing for the development of additional panels to monitor health, phenotypic traits, hybrid cats and highly inbred cats.
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- 2021
12. Direct-to-Consumer Genetic Testing for Domestic Cats
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Leslie A. Lyons and Reuben M. Buckley
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medicine.medical_specialty ,CATS ,medicine.diagnostic_test ,040301 veterinary sciences ,business.industry ,Genetic counseling ,0402 animal and dairy science ,04 agricultural and veterinary sciences ,Cat Diseases ,Precision medicine ,040201 dairy & animal science ,0403 veterinary science ,Direct-To-Consumer Screening and Testing ,Family medicine ,Health care ,Cats ,medicine ,Animals ,Genomic medicine ,Genetic Testing ,Personalized medicine ,Small Animals ,business ,Genetic testing - Abstract
The era of precision/genomic medicine has arrived, including its application within veterinary medicine for the health care of companion animals. The plummeting costs of assaying large groups of genetic tests into one panel has led many laboratories offering direct-to-consumer (DTC) genetic testing for animals, including cats. However, proper education of the consumer and the veterinarian is lacking, causing a significant lack of genetic counseling pertaining to the results of the genetic tests. This article addresses the current state of DTC testing in domestic cats and the implications for veterinary care.
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- 2020
13. Precision/Genomic Medicine for Domestic Cats
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Reuben M. Buckley and Leslie A. Lyons
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Whole genome sequencing ,040301 veterinary sciences ,business.industry ,0402 animal and dairy science ,04 agricultural and veterinary sciences ,Computational biology ,Dna variants ,Cat Diseases ,Precision medicine ,Health outcomes ,040201 dairy & animal science ,0403 veterinary science ,Health problems ,Health care ,Cats ,Animals ,Genomic medicine ,Medicine ,Genetic Testing ,Precision Medicine ,Small Animals ,business - Abstract
The era of Precision / Genomic Medicine has arrived and can improve the veterinary healthcare of companion animals. The goal of Precision / Genomic Medicine is to use an individual's DNA signature / profile to tailor their treatments of their specific health problems. Whole genome sequencing is now a cost-effective diagnostic tool, leading to the discovery of DNA variants associated with health outcomes. These DNA variants become genetic tests and can readily be applied to future cases of individuals with similar symptoms. This article addresses the current state of Precision Medicine in domestic cats and the implications for veterinary care.
- Published
- 2020
14. Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon in CLN6
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Dennis P. O'Brien, Leslie A. Lyons, Martin L. Katz, Vanessa Biegen, Wesley C. Warren, Reuben M. Buckley, and Gayle C. Johnson
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Pathology ,medicine.medical_specialty ,Batten disease ,Neuropathology ,Biology ,QH426-470 ,medicine.disease_cause ,whole exome sequencing ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Lysosomal storage disease ,Genetics ,feline ,Molecular Biology ,Exome ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,0303 health sciences ,Mutation ,CATS ,batten disease ,medicine.disease ,lysosomal storage disease ,Neuronal ceroid lipofuscinosis ,mutation ,hereditary ,030217 neurology & neurosurgery - Abstract
A neutered male domestic medium-haired cat presented at a veterinary neurology clinic at 20 months of age due to progressive neurological signs that included visual impairment, focal myoclonus, and frequent severe generalized seizures that were refractory to treatment with phenobarbital. Magnetic resonance imaging revealed diffuse global brain atrophy. Due to the severity and frequency of its seizures, the cat was euthanized at 22 months of age. Microscopic examination of the cerebellum, cerebral cortex and brainstem revealed pronounced intracellular accumulations of autofluorescent storage material and inflammation in all 3 brain regions. Ultrastructural examination of the storage material indicated that it consisted almost completely of tightly-packed membrane-like material. The clinical signs and neuropathology strongly suggested that the cat suffered from a form of neuronal ceroid lipofuscinosis (NCL). Whole exome sequence analysis was performed on genomic DNA from the affected cat. Comparison of the sequence data to whole exome sequence data from 39 unaffected cats and whole genome sequence data from an additional 195 unaffected cats revealed a homozygous variant in CLN6 that was unique to the affected cat. This variant was predicted to cause a stop gain in the transcript due to a guanine to adenine transition (ENSFCAT00000025909:c.668G > A; XM_003987007.5:c.668G > A) and was the sole loss of function variant detected. CLN6 variants in other species, including humans, dogs, and sheep, are associated with the CLN6 form of NCL. Based on the affected cat’s clinical signs, neuropathology and molecular genetic analysis, we conclude that the cat’s disorder resulted from the loss of function of CLN6. This study is only the second to identify the molecular genetic basis of a feline NCL. Other cats exhibiting similar signs can now be screened for the CLN6 variant. This could lead to establishment of a feline model of CLN6 disease that could be used in therapeutic intervention studies.
- Published
- 2020
15. Genetic Origins of the Two Canis lupus familiaris (Dog) Freight Dog Populations
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Muhammad Basil Ali, Dayna L Dreger, Reuben M Buckley, Shahid Mansoor, Qaiser M Khan, and Elaine A Ostrander
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Dogs ,Genome ,Wolves ,Haplotypes ,Genetics ,Animals ,Genomics ,Original Articles ,Molecular Biology ,Genetics (clinical) ,Biotechnology - Abstract
Despite periodic drops in popularity, Arctic sled dogs continue to play a vital role in northern societies, providing both freight transit and recreational race activities. In this study, we selected the Mackenzie River Husky, a freight dog of complex history, and the Chinook, an American Kennel Club recognized freight dog breed whose heritage reportedly overlaps that of the MKRH, for detailed population analysis. We tested each to determine their component breeds and used admixture analysis to ascertain their population structure. We utilized haplotype analysis to identify genomic regions shared between each population and their founding breeds. Our data show that the Alaskan Malamutes and modern Greenland sled dog contributed to both populations, but there are also unexpected contributions from the German Shepherd dog and Collie. We used haplotype analysis to identify genomic regions nearing fixation in population type and identify provocative genes in each region. Finally, in response to recent reports regarding the importance of dietary lipid genes in Arctic dogs, we analyzed 8 such genes in a targeted analysis observing signatures of selection in both populations at the MLXIPL gene loci. These data highlight the genetic routes that breeds of similar function have taken toward their occupation as successful sled dogs.
- Published
- 2021
16. Best practices for analyzing imputed genotypes from low-pass sequencing in dogs
- Author
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Reuben M. Buckley, Ya-Ping Zhang, Guo-Dong Wang, Alex C. Harris, D. Thad Whitaker, and Elaine A. Ostrander
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Whole genome sequencing ,Genotype ,Whole Genome Sequencing ,Low Confidence ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,SNP genotyping ,Set (abstract data type) ,Dogs ,Case-Control Studies ,Quality Score ,Statistics ,Genetics ,Animals ,Imputation (statistics) ,Imputation (genetics) ,Genetic association ,Genome-Wide Association Study - Abstract
Although DNA array-based approaches for genome wide association studies (GWAS) permit the collection of thousands of low-cost genotypes, it is often at the expense of resolution and completeness, as SNP chip technologies are ultimately limited by SNPs chosen during array development. An alternative low-cost approach is low-pass whole genome sequencing (WGS) followed by imputation. Rather than relying on high levels of genotype confidence at a set of select loci, low-pass WGS and imputation relies on the combined information from millions of randomly sampled low confidence genotypes. To investigate low-pass WGS and imputation in the dog, we assessed accuracy and performance by downsampling 97 high-coverage (>15x) WGS datasets from 51 different breeds to approximately 1x coverage, simulating low-pass WGS. Using a reference panel of 676 dogs from 91 breeds, genotypes were imputed from the downsampled data and compared to a truth set of genotypes generated from high coverage WGS. Using our truth set, we optimized a variant quality filtering strategy that retained approximately 80% of 14M imputed sites and lowered the imputation error rate from 3.0% to 1.5%. Seven million sites remained with a MAF > 5% and an average imputation quality score of 0.95. Finally, we simulated the impact of imputation errors on outcomes for case-control GWAS, where small effect sizes were most impacted and medium to large effect sizes were minorly impacted. These analyses provide best practice guidelines for study design and data post-processing of low-pass WGS imputed genotypes in dogs.
- Published
- 2021
17. A domestic cat whole exome sequencing resource for trait discovery
- Author
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Catrina Fronick, Todd Richmond, Dianne J. Trent, John S. Munday, Alana R. Rodney, Robert S. Fulton, Christopher R Helps, Andrew C. Lewin, Leslie A. Lyons, Karen M. Vernau, Rondo P. Middleton, Reuben M. Buckley, Wesley C. Warren, and Peter Pantke
- Subjects
Male ,Bioinformatics ,Science ,Sequence assembly ,Computational biology ,Biology ,Cat Diseases ,Genome ,Polymorphism, Single Nucleotide ,Deep sequencing ,Article ,Exome Sequencing ,Genetics ,Animals ,2.1 Biological and endogenous factors ,Genetic Predisposition to Disease ,Exome ,Allele ,Polymorphism ,Aetiology ,Gene ,Exome sequencing ,Whole genome sequencing ,Multidisciplinary ,Human Genome ,Single Nucleotide ,Good Health and Well Being ,Sequence annotation ,Cats ,HIV/AIDS ,Medicine ,Female ,Biotechnology - Abstract
Over 94 million domestic cats are susceptible to cancers and other common and rare diseases. Whole exome sequencing (WES) is a proven strategy to study these disease-causing variants. Presented is a 35.7 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. Whole exome sequencing was conducted on 41 cats with known and unknown genetic diseases and traits, of which ten cats had matching whole genome sequence (WGS) data available, used to validate WES performance. At 80 × mean exome depth of coverage, 96.4% of on-target base coverage had a sequencing depth > 20-fold, while over 98% of single nucleotide variants (SNVs) identified by WGS were also identified by WES. Platform-specific SNVs were restricted to sex chromosomes and a small number of olfactory receptor genes. Within the 41 cats, we identified 31 previously known causal variants and discovered new gene candidate variants, including novel missense variance for polycystic kidney disease and atrichia in the Peterbald cat. These results show the utility of WES to identify novel gene candidate alleles for diseases and traits for the first time in a feline model.
- Published
- 2021
18. Dog10K_Boxer_Tasha_1.0: A Long-Read Assembly of the Dog Reference Genome
- Author
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Xiangquan Zhang, Christophe Hitte, Elaine A. Ostrander, Patrick Masterson, Terence Murphy, Yan-Hu Liu, Jeffrey M. Kidd, S. Emery, Brian W. Davis, Tosso Leeb, Ya-Ping Zhang, Reuben M. Buckley, Guo-Dong Wang, Vidhya Jagannathan, University of Bern, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Michigan [Ann Arbor], University of Michigan System, National Center for Biotechnology Information (NCBI), Texas A&M University [College Station], National Human Genome Research Institute (NHGRI), Kunming Institute of Zoology, Chinese Academy of Sciences [Beijing] (CAS), 2019YFA0707101, The National Key R&D Program of China, R01GM140135, National Institutes of Health, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Kunming Institute of Zoology (KIZ)
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clone (Java method) ,0301 basic medicine ,Canis lupus familiaris ,contiguity ,0206 medical engineering ,Sequence assembly ,610 Medicine & health ,02 engineering and technology ,Computational biology ,QH426-470 ,Biology ,resource ,Article ,Contig Mapping ,03 medical and health sciences ,Annotation ,high quality ,Dogs ,0302 clinical medicine ,Pacific biosciences ,Genetics ,Animals ,Canine genetics ,Gene ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Genome ,630 Agriculture ,Shotgun sequencing ,Molecular Sequence Annotation ,Gene Annotation ,[SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics ,030104 developmental biology ,annotation ,590 Animals (Zoology) ,570 Life sciences ,biology ,020602 bioinformatics ,030217 neurology & neurosurgery ,Reference genome - 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 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.
- Published
- 2021
- Full Text
- View/download PDF
19. A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism
- Author
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William J. Murphy, Tina Graves, Chad Tomlinson, LaDeana W. Hillier, Reuben M. Buckley, Kei Kuroki, Gang Li, Brian W. Davis, Leslie A. Lyons, Fabiana H.G. Farias, Wesley A. Brashear, Wesley C. Warren, Patrick Minx, Milinn Kremitzki, Rondo P. Middleton, and Barsh, Gregory S
- Subjects
Male ,Cancer Research ,F-Box-WD Repeat-Containing Protein 7 ,Sequence assembly ,Dwarfism ,QH426-470 ,Genome ,0302 clinical medicine ,Gene duplication ,2.1 Biological and endogenous factors ,Aetiology ,Genetics (clinical) ,Phylogeny ,Genetics ,Mammals ,0303 health sciences ,Mammalian Genomics ,Bacterial Genomics ,Pets and Companion Animals ,Microbial Genetics ,Eukaryota ,Chromosome Mapping ,Single Nucleotide ,Genomics ,Veterinary Diseases ,Perspective ,Vertebrates ,HIV/AIDS ,Biotechnology ,Microbial Genomics ,Biology ,Research and Analysis Methods ,Uridine Diphosphate Glucose Dehydrogenase ,Microbiology ,Polymorphism, Single Nucleotide ,Human Genomics ,03 medical and health sciences ,Rare Diseases ,medicine ,Animals ,Bacterial Genetics ,Humans ,Genetic Predisposition to Disease ,Allele ,Polymorphism ,Molecular Biology Techniques ,Gene ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Alleles ,030304 developmental biology ,Sequence (medicine) ,Whole genome sequencing ,Radiation Hybrid Mapping ,Whole Genome Sequencing ,Human Genome ,Gene Mapping ,Organisms ,Chromosome ,Biology and Life Sciences ,Computational Biology ,Bacteriology ,Molecular Sequence Annotation ,medicine.disease ,Genome Analysis ,Genome Annotation ,Animal Genomics ,Amniotes ,Cats ,Veterinary Science ,Zoology ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
The domestic cat (Felis catus) numbers over 94 million in the USA alone, occupies households as a companion animal, and, like humans, suffers from cancer and common and rare diseases. However, genome-wide sequence variant information is limited for this species. To empower trait analyses, a new cat genome reference assembly was developed from PacBio long sequence reads that significantly improve sequence representation and assembly contiguity. The whole genome sequences of 54 domestic cats were aligned to the reference to identify single nucleotide variants (SNVs) and structural variants (SVs). Across all cats, 16 SNVs predicted to have deleterious impacts and in a singleton state were identified as high priority candidates for causative mutations. One candidate was a stop gain in the tumor suppressor FBXW7. The SNV is found in cats segregating for feline mediastinal lymphoma and is a candidate for inherited cancer susceptibility. SV analysis revealed a complex deletion coupled with a nearby potential duplication event that was shared privately across three unrelated dwarfism cats and is found within a known dwarfism associated region on cat chromosome B1. This SV interrupted UDP-glucose 6-dehydrogenase (UGDH), a gene involved in the biosynthesis of glycosaminoglycans. Importantly, UGDH has not yet been associated with human dwarfism and should be screened in undiagnosed patients. The new high-quality cat genome reference and the compilation of sequence variation demonstrate the importance of these resources when searching for disease causative alleles in the domestic cat and for identification of feline biomedical models.Author summaryThe practice of genomic medicine is predicated on the availability of a high quality reference genome and an understanding of the impact of genome variation. Such resources have lead to countless discoveries in humans, however by working exclusively within the framework of human genetics, our potential for understanding diseases biology is limited, as similar analyses in other species have often lead to novel insights. The generation of Felis_catus_9.0, a new high quality reference genome for the domestic cat, helps facilitate the expansion of genomic medicine into the felis lineage. Using Felis_catus_9.0 we analyze the landscape of genomic variation from a collection of 54 cats within the context of human gene constraint. The distribution of variant impacts in cats is correlated with patterns of gene constraint in humans, indicating the utility of this reference for identifying novel mutations that cause phenotypes relevant to human and cat health. Moreover, structural variant analysis revealed a novel variant for feline dwarfism in UGDH, a gene that has not been associated with dwarfism in any other species, suggesting a role for UGDH in cases of undiagnosed dwarfism in humans.
- Published
- 2020
20. Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy
- Author
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Julia H. Wildschutte, Marta G. Castelhano, Max F. Rothschild, Maria Kaukonen, Georgios Kellaris, Joshua A. Stern, Stéphane Bézieau, Laurence Legeai-Mallet, Shrinivas P. Mane, Dominique Debray, Hannes Lohi, Ottmar Distl, Laurence M. Occelli, Kinga M. Bujakowska, Marjo K. Hytönen, Oliver P. Forman, Elizabeth A. Wilcox, Richard Malik, Tosso Leeb, Ronald H.L. Li, Elizabeth L. Cadena, William F. Swanson, Teri L. Lear, Yoshihiko Yu, Robert J. Harvey, Dominique Caldari, Erica E. Davis, Bianca Haase, Eric A. Pierce, Reuben M. Buckley, Stephen P. Daiger, L. Martin, D. Aberdein, Clare Rusbridge, Simon M. Petersen-Jones, Edward I. Ginns, Daniel C. Koboldt, Benjamin Cogné, Lokuliyanage Dona Samudita Senaratne, Michael B. Gorin, Niels C Pedersen, Margret L. Casal, Xenia Latypova, Adam R. Boyko, Isabel Hernandez, Tomoki Kosho, Sara J. Bowne, Nicholas H. Dodman, Tomas F. Bergström, Nicholas Katsanis, Rebecca R. Bellone, Guylène Le Meur, Bertrand Isidor, Daisuke Hasegawa, Christopher B. Kaelin, Mathilde Nizon, Karen A. Terio, Paulo C. Alves, Leslie A. Lyons, Christopher R Helps, Eirik Frengen, Emilie Leclerc, William J. Murphy, Beth Shapiro, Mark A. Magnuson, Lorraine Fievet, Maria Longeri, Rory J. Todhunter, Jeffrey A. Brockman, Lori S. Sullivan, Dorian J. Garrick, Jens Häggström, Jonathan E. Fogle, N. Matthew Ellinwood, Wesley C. Warren, John S. Munday, Gregory S. Barsh, Université Paris Cité (UPC), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
- Subjects
Male ,Heterozygote ,Rhodopsin ,[SDV]Life Sciences [q-bio] ,Kinesins ,Biology ,Retina ,03 medical and health sciences ,Young Adult ,KIFAP3 ,Intraflagellar transport ,Report ,Retinitis pigmentosa ,Genetics ,medicine ,Animals ,Humans ,KIF3A ,Photoreceptor Cells ,Amino Acid Sequence ,Cilia ,Genetics (clinical) ,Exome sequencing ,Zebrafish ,030304 developmental biology ,Genes, Dominant ,0303 health sciences ,Cilium ,030305 genetics & heredity ,Middle Aged ,medicine.disease ,Ciliopathies ,Pedigree ,Ciliopathy ,Phenotype ,Child, Preschool ,Larva ,Mutation ,Cats ,Kinesin ,Female ,sense organs ,Genome-Wide Association Study - Abstract
Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.
- Published
- 2020
21. A domestic cat whole exome sequencing resource for trait discovery
- Author
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Catrina Fronick, Dianne J. Trent, Reuben M. Buckley, Robert S. Fulton, Peter Pantke, Todd Richmond, Leslie A. Lyons, Alana R. Rodney, Christopher R Helps, and Wesley C. Warren
- Subjects
Whole genome sequencing ,Genetics ,biology ,Felis ,Sequence assembly ,Single-nucleotide polymorphism ,Allele ,biology.organism_classification ,Genome ,Exome ,Exome sequencing - Abstract
Over 94 million domestic cats are considered pets, who, as our companions, are also susceptible to cancers, common and rare diseases. Whole exome sequencing (WES) is a cost-effective strategy to study their putative disease-causing variants. Presented is ~35.8 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. WES was conducted on 41 cats from various breeds with known and unknown diseases and traits, including 10 cats with prior whole genome sequence (WGS) data available, to test WES capture probe performance. A WES and WGS comparison was completed to understand variant discovery capability of each platform. At ~80x exome coverage, the percent of on-target base coverage >20x was 96.4% with an average of 10.4% off-target. For variant discovery, greater than 98% of WGS SNPs were also discovered by WES. Platform specific variants were mainly restricted to a small number of sex chromosome and olfactory receptor genes. Within the 41 cats with ~31 diseases and normal traits, 45 previously known disease or trait causal variants were observed, such as Persian progressive retinal degeneration and hydrocephalus. Novel candidate variants for polycystic kidney disease and atrichia in the Peterbald breed were also identified as well as a new cat patient with a known variant for cystinuria. These results show the discovery potential of deep exome sequencing to validate existing disease gene models and identify novel gene candidate alleles for many common and rare diseases in cats.
- Published
- 2020
22. Werewolf, there wolf: variants in Hairless associated with hypotrichia and roaning in the lykoi cat breed
- Author
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David A. Senter, Conner A. Pyne, Delia M. Bouhan, Johnny R. Gobble, Leslie A. Lyons, Reuben M. Buckley, Michelle L. LeRoy, Marie Abitbol, Barbara Gandolfi, and Erica K. Creighton
- Subjects
Genetics ,0303 health sciences ,Coat ,CATS ,Biology ,Compound heterozygosity ,Hair follicle ,Stop codon ,Breed ,Hairless ,03 medical and health sciences ,Exon ,0302 clinical medicine ,medicine.anatomical_structure ,medicine ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi, was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR: lysine demethylase and nuclear receptor corepressor) as candidate causal variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.
- Published
- 2020
- Full Text
- View/download PDF
23. Assisted reproduction mediated resurrection of a feline model for Chediak-Higashi syndrome caused by a large duplication in LYST
- Author
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Reuben M. Buckley, Mark D Kittleson, Robert A. Grahn, Jason R. Herrick, H. L. Bateman, William F. Swanson, J. Newsom, Leslie A. Lyons, D. J. Prieur, and Barbara Gandolfi
- Subjects
0301 basic medicine ,Male ,Gene duplication ,Genotype ,Vesicular Transport Proteins ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Biology ,medicine.disease_cause ,Article ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Genetic ,hemic and lymphatic diseases ,Lysosomal trafficking regulator ,Genetics ,medicine ,2.1 Biological and endogenous factors ,Animals ,Aetiology ,Allele ,Polymorphism ,lcsh:Science ,Genotyping ,Alleles ,Animal breeding ,Mutation ,Polymorphism, Genetic ,Multidisciplinary ,Animal ,Chédiak–Higashi syndrome ,lcsh:R ,Exons ,Fibroblasts ,medicine.disease ,Pedigree ,Disease Models, Animal ,030104 developmental biology ,Disease Models ,Cats ,lcsh:Q ,Female ,Tandem exon duplication ,Chediak-Higashi Syndrome ,Medical genomics - Abstract
Chediak-Higashi Syndrome (CHS) is a well-characterized, autosomal recessively inherited lysosomal disease caused by mutations in lysosomal trafficking regulator (LYST). The feline model for CHS was originally maintained for ~20 years. However, the colonies were disbanded and the CHS cat model was lost to the research community before the causative mutation was identified. To resurrect the cat model, semen was collected and cryopreserved from a lone, fertile, CHS carrier male. Using cryopreserved semen, laparoscopic oviductal artificial insemination was performed on three queens, two queens produced 11 viable kittens. To identify the causative mutation, a fibroblast cell line, derived from an affected cat from the original colony, was whole genome sequenced. Visual inspection of the sequence data identified a candidate causal variant as a ~20 kb tandem duplication within LYST, spanning exons 30 through to 38 (NM_001290242.1:c.8347-2422_9548 + 1749dup). PCR genotyping of the produced offspring demonstrated three individuals inherited the mutant allele from the CHS carrier male. This study demonstrated the successful use of cryopreservation and assisted reproduction to maintain and resurrect biomedical models and has defined the variant causing Chediak-Higashi syndrome in the domestic cat.
- Published
- 2020
24. Similar Evolutionary Trajectories for Retrotransposon Accumulation in Mammals
- Author
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Reuben M. Buckley, David L. Adelson, Joy M. Raison, and R. Daniel Kortschak
- Subjects
0301 basic medicine ,Genome evolution ,Retroelements ,Interspersed repeat ,genetic processes ,Genomics ,Retrotransposon ,Biology ,genome evolution ,Genome ,Evolution, Molecular ,03 medical and health sciences ,0302 clinical medicine ,Species Specificity ,Genetics ,Animals ,Regulatory Elements, Transcriptional ,Gene ,Ecology, Evolution, Behavior and Systematics ,Synteny ,Comparative genomics ,Mammals ,genome architecture ,fungi ,food and beverages ,transposable element ,Chromatin ,Long interspersed nuclear element ,030104 developmental biology ,Evolutionary biology ,health occupations ,030217 neurology & neurosurgery ,Research Article - Abstract
The factors guiding retrotransposon insertion site preference are not well understood. Different types of retrotransposons share common replication machinery and yet occupy distinct genomic domains. Autonomous long interspersed elements accumulate in gene-poor domains and their non-autonomous short interspersed elements accumulate in gene-rich domains. To determine genomic factors that contribute to this discrepancy we analysed the distribution of retrotransposons within the framework of chromosomal domains and regulatory elements. Using comparative genomics, we identified large-scale conserved patterns of retrotransposon accumulation across several mammalian genomes. Importantly, retrotransposons that were active after our sample-species diverged accumulated in orthologous regions. This suggested a similar evolutionary interaction between retrotransposon activity and conserved genome architecture across our species. In addition, we found that retrotransposons accumulated at regulatory element boundaries in open chromatin, where accumulation of particular retrotransposon types depended on insertion size and local regulatory element density. From our results, we propose a model where density and distribution of genes and regulatory elements canalise retrotransposon accumulation. Through conservation of synteny, gene regulation and nuclear organisation, mammalian genomes with dissimilar retrotransposons follow similar evolutionary trajectories.
- Published
- 2017
25. Localization of a feline autosomal dominant dwarfism locus: a novel model of chondrodysplasia
- Author
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Joan R. Coates, Leslie A. Lyons, Robert A. Grahn, John R. Middleton, Barbara Gandolfi, N.A. Villani, Derek B. Fox, Michael J. Hamilton, S.T. Sellers, Lisa G. Britt, Reuben M. Buckley, Kari L. Chesney, and S. Pfleuger
- Subjects
musculoskeletal diseases ,Whole genome sequencing ,Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,0303 health sciences ,CATS ,endocrine system diseases ,040301 veterinary sciences ,Dwarfism ,Locus (genetics) ,04 agricultural and veterinary sciences ,Biology ,medicine.disease ,Phenotype ,0403 veterinary science ,Disproportionate dwarfism ,03 medical and health sciences ,medicine ,Gene ,030304 developmental biology ,Genetic association - Abstract
Despite the contribution of a few major genes for disproportionate dwarfism in humans, many dwarf patients are yet genetically undiagnosed. In domestic cats, disproportionate dwarfism has led to the development of a defined breed, the Munchkin or Minuet. This study examined the genetic aspects of feline dwarfism to consider cats as a new biomedical model. DNA from dwarf cats was genetically analyzed using parentage, linkage, and genome-wide association studies as well as whole genome sequencing. Each genetic approach localized the dwarfism phenotype to a region on cat chromosome B1. No coding variants suspected as causal for the feline dwarfism were identified but a critical region of ∼5.7 Mb from B1:170,278,183-175,975,857 was defined, which implicates a novel gene controlling disproportionate dwarfism. A yet unidentified but novel gene variant, likely structural or regulatory, produces disproportionate dwarfism in cats, which may define undiagnosed human patients.
- Published
- 2019
26. Retrotransposons: Genomic and Trans-Genomic Agents of Change
- Author
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Atma M. Ivancevic, Lu Zeng, Reuben M. Buckley, Zhipeng Qu, and David L. Adelson
- Subjects
Transposable element ,Innate immune system ,genetic processes ,fungi ,information science ,food and beverages ,Endogenous retrovirus ,Retrotransposon ,Exaptation ,Biology ,Genome ,Long terminal repeat ,Structural variation ,Evolutionary biology ,health occupations - Abstract
Genome structure in higher eukaryotes is highly dependent on the type and abundance of transposable elements, particularly retrotransposons , in their non-coding DNA. Retrotransposons are generally viewed as genomic parasites that must be suppressed in order to ensure genome integrity. This perception is based on the instances of retrotransposons having caused deleterious structural variation in genomes. Recent data are beginning to provide a more positive view of the impact of retrotransposons , particularly in mammals, where the evolution of the placenta has depended on the exaptation of a type of retrotransposon , endogenous retroviruses. Finally, exosome trafficking of retrotransposons between cells has been shown to induce the innate immune system gene expression, possibly indicative of a role for retrotransposons in the regulation of the innate immune system. It may be time for us to review the status of retrotransposons and reclassify them as symbionts rather than parasites.
- Published
- 2015
27. Bovine NK-lysin : Copy number variation and functional diversification
- Author
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John Huddleston, Junfeng Chen, Loren C. Skow, Evan E. Eichler, Mi Ok Lee, Reuben M. Buckley, Maika Malig, Leif Andersson, Sara D. Lawhon, and James E. Womack
- Subjects
gene family expansion ,Proteolipids ,Molecular Sequence Data ,Antimicrobial peptides ,Gene Dosage ,Lysin ,segmental duplication ,Biology ,Gene dosage ,NK-lysin ,antimicrobial peptides ,Microscopy, Electron, Transmission ,Sequence Homology, Nucleic Acid ,Gene Order ,Escherichia coli ,Genetics ,Animals ,Gene family ,Amino Acid Sequence ,Genetik ,Gene ,Peptide sequence ,Phylogeny ,Multidisciplinary ,Innate immune system ,Base Sequence ,Sequence Homology, Amino Acid ,copy number polymorphism ,Gene Expression Profiling ,Chromosomes, Mammalian ,Molecular biology ,Gene expression profiling ,PNAS Plus ,Organ Specificity ,Multigene Family ,Cattle ,Peptides - Abstract
NK-lysin is an antimicrobial peptide and effector protein in the host innate immune system. It is coded by a single gene in humans and most other mammalian species. In this study, we provide evidence for the existence of four NK-lysin genes in a repetitive region on cattle chromosome 11. The NK2A, NK2B, and NK2C genes are tandemly arrayed as three copies in similar to 30-35-kb segments, located 41.8 kb upstream of NK1. All four genes are functional, albeit with differential tissue expression. NK1, NK2A, and NK2B exhibited the highest expression in intestine Peyer's patch, whereas NK2C was expressed almost exclusively in lung. The four peptide products were synthesized ex vivo, and their antimicrobial effects against both Gram-positive and Gram-negative bacteria were confirmed with a bacteria-killing assay. Transmission electron microcopy indicated that bovine NK-lysins exhibited their antimicrobial activities by lytic action in the cell membranes. In summary, the single NK-lysin gene in other mammals has expanded to a four-member gene family by tandem duplications in cattle; all four genes are transcribed, and the synthetic peptides corresponding to the core regions are biologically active and likely contribute to innate immunity in ruminants.
- Published
- 2015
28. Mammalian genome evolution as a result of epigenetic regulation of transposable elements
- Author
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David L. Adelson and Reuben M. Buckley
- Subjects
Transposable element ,Genome evolution ,Small RNA ,QH301-705.5 ,genome evolution ,Biology ,Genome ,General Biochemistry, Genetics and Molecular Biology ,Epigenesis, Genetic ,Evolution, Molecular ,Cellular and Molecular Neuroscience ,Species Specificity ,Gene silencing ,Animals ,Humans ,Epigenetics ,Biology (General) ,Epigenesis ,Genetics ,Mammals ,epigenetics ,food and beverages ,General Medicine ,DNA Transposable Elements ,RNA, Small Untranslated ,transposable elements ,Reprogramming - Abstract
Transposable elements (TEs) make up a large proportion of mammalian genomes and are a strong evolutionary force capable of rewiring regulatory networks and causing genome rearrangements. Additionally, there are many eukaryotic epigenetic defense mechanisms able to transcriptionally silence TEs. Furthermore, small RNA molecules that target TE DNA sequences often mediate these epigenetic defense mechanisms. As a result, epigenetic marks associated with TE silencing can be reestablished after epigenetic reprogramming – an event during the mammalian life cycle that results in widespread loss of parental epigenetic marks. Furthermore, targeted epigenetic marks associated with TE silencing may have an impact on nearby gene expression. Therefore, TEs may have driven species evolution via their ability to heritably alter the epigenetic regulation of gene expression in mammals.
- Published
- 2014
29. variant implicated in suspected pyknodysostosis in a domestic cat
- Author
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Maria Lyraki, Angie Hibbert, Sorrel Langley-Hobbs, Philippa Lait, Reuben M Buckley, Wesley C Warren, and Leslie A Lyons
- Subjects
Veterinary medicine ,SF600-1100 - Abstract
Case summary A 9-month-old entire male domestic longhair cat presented with a history of pathological fractures, chronic musculoskeletal pain and poor growth. Multiple facial and skeletal abnormalities were identified on physical examination and advanced imaging (CT and radiographs). A variant in CTSK was identified in the affected cat following whole-exome sequencing (WES). The cat was managed symptomatically with diet, environmental modifications and analgesia. Relevance and novel information This is the first report of a cat with a similar clinical presentation and genetic variant to the hereditary human genetic disorder pyknodysostosis. In this case, WES was performed, which often facilitates the diagnosis of various hereditary disorders (ie, a conceptual framework for practicing feline genomic medicine). Despite the severe skeletal and appendicular abnormalities described, the cat was alive more than 2 years after its initial presentation.
- Published
- 2022
- Full Text
- View/download PDF
30. A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism.
- Author
-
Reuben M Buckley, Brian W Davis, Wesley A Brashear, Fabiana H G Farias, Kei Kuroki, Tina Graves, LaDeana W Hillier, Milinn Kremitzki, Gang Li, Rondo P Middleton, Patrick Minx, Chad Tomlinson, Leslie A Lyons, William J Murphy, and Wesley C Warren
- Subjects
Genetics ,QH426-470 - Abstract
The domestic cat (Felis catus) numbers over 94 million in the USA alone, occupies households as a companion animal, and, like humans, suffers from cancer and common and rare diseases. However, genome-wide sequence variant information is limited for this species. To empower trait analyses, a new cat genome reference assembly was developed from PacBio long sequence reads that significantly improve sequence representation and assembly contiguity. The whole genome sequences of 54 domestic cats were aligned to the reference to identify single nucleotide variants (SNVs) and structural variants (SVs). Across all cats, 16 SNVs predicted to have deleterious impacts and in a singleton state were identified as high priority candidates for causative mutations. One candidate was a stop gain in the tumor suppressor FBXW7. The SNV is found in cats segregating for feline mediastinal lymphoma and is a candidate for inherited cancer susceptibility. SV analysis revealed a complex deletion coupled with a nearby potential duplication event that was shared privately across three unrelated cats with dwarfism and is found within a known dwarfism associated region on cat chromosome B1. This SV interrupted UDP-glucose 6-dehydrogenase (UGDH), a gene involved in the biosynthesis of glycosaminoglycans. Importantly, UGDH has not yet been associated with human dwarfism and should be screened in undiagnosed patients. The new high-quality cat genome reference and the compilation of sequence variation demonstrate the importance of these resources when searching for disease causative alleles in the domestic cat and for identification of feline biomedical models.
- Published
- 2020
- Full Text
- View/download PDF
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