title: Whole-Genome Sequencing of a Canine Family Trio Reveals a FAM83G Variant Associated with Hereditary Footpad Hyperkeratosis.
abstract: Over 250 Mendelian traits and disorders, caused by rare alleles have been mapped in the canine genome. Although each disease is rare in the dog as a species, they are collectively common and have major impact on canine health. With SNP-based genotyping arrays, genome-wide association studies (GWAS) have proven to be a powerful method to map the genomic region of interest when 10-20 cases and 10-20 controls are available. However, to identify the genetic variant in associated regions, fine-mapping and targeted resequencing is required. Here we present a new approach using whole-genome sequencing (WGS) of a family trio without prior GWAS. As a proof-of-concept, we chose an autosomal recessive disease known as hereditary footpad hyperkeratosis (HFH) in Kromfohrländer dogs. To our knowledge, this is the first time this family trio WGS-approach has been used successfully to identify a genetic variant that perfectly segregates with a canine disorder. The sequencing of three Kromfohrländer dogs from a family trio (an affected offspring and both its healthy parents) resulted in an average genome coverage of 9.2X per individual. After applying stringent filtering criteria for candidate causative coding variants, 527 single nucleotide variants (SNVs) and 15 indels were found to be homozygous in the affected offspring and heterozygous in the parents. Using the computer software packages ANNOVAR and SIFT to functionally annotate coding sequence differences, and to predict their functional effect, resulted in seven candidate variants located in six different genes. Of these, only FAM83G:c155G > C (p.R52P) was found to be concordant in eight additional cases, and 16 healthy Kromfohrländer dogs.
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden Research Center for Modeling and Simulation, National University of Sciences and Technology, Sector H-12, Islamabad, Pakistan.
authors.forename: Shumaila
authors.identifier: http://orcid.org/0000-0003-4127-4887
authors.initials: S
authors.lastname: Sayyab
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden.
authors.forename: Agnese
authors.identifier: http://orcid.org/0000-0003-3388-5020
authors.initials: A
authors.lastname: Viluma
authors.affiliation: Department of Clinical Sciences, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bergvall
authors.affiliation: Norwegian Centre for Organic Agriculture, NO-6630 Tingvoll, Norway.
authors.forename: Emma
authors.identifier: http://orcid.org/0000-0002-1523-3494
authors.initials: E
authors.lastname: Brunberg
authors.affiliation: Institute of Genetics, University of Bern, 3001 Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Institute of Genetics, University of Bern, 3001 Bern, Switzerland.
authors.forename: Tosso
authors.identifier: http://orcid.org/0000-0003-0553-4880
authors.initials: T
authors.lastname: Leeb
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden goran.andersson@slu.se tomas.bergstrom@slu.se.
authors.forename: Göran
authors.identifier: http://orcid.org/0000-0001-5131-3144
authors.initials: G
authors.lastname: Andersson
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, 750 07 Uppsala, Sweden goran.andersson@slu.se tomas.bergstrom@slu.se.
authors.forename: Tomas F
authors.identifier: http://orcid.org/0000-0002-7480-2669
authors.initials: TF
authors.lastname: Bergström
mesh_terms: D000818:Animals; D019295:Computational Biology; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000662:veterinary*; D014644:Genetic Variation; D016678:Genome; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D058977:Molecular Sequence Annotation; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results
chemical_list: D047908:Intracellular Signaling Peptides and Proteins
keywords: FAM83G; NGS; WGS; canine; whole-genome-sequencing