title: Dominant Red Coat Color in Holstein Cattle Is Associated with a Missense Mutation in the Coatomer Protein Complex, Subunit Alpha (COPA) Gene.
abstract: Coat color in Holstein dairy cattle is primarily controlled by the melanocortin 1 receptor (MC1R) gene, a central determinant of black (eumelanin) vs. red/brown pheomelanin synthesis across animal species. The major MC1R alleles in Holsteins are Dominant Black (MC1RD) and Recessive Red (MC1Re). A novel form of dominant red coat color was first observed in an animal born in 1980. The mutation underlying this phenotype was named Dominant Red and is epistatic to the constitutively activated MC1RD. Here we show that a missense mutation in the coatomer protein complex, subunit alpha (COPA), a gene with previously no known role in pigmentation synthesis, is completely associated with Dominant Red in Holstein dairy cattle. The mutation results in an arginine to cysteine substitution at an amino acid residue completely conserved across eukaryotes. Despite this high level of conservation we show that both heterozygotes and homozygotes are healthy and viable. Analysis of hair pigment composition shows that the Dominant Red phenotype is similar to the MC1R Recessive Red phenotype, although less effective at reducing eumelanin synthesis. RNA-seq data similarly show that Dominant Red animals achieve predominantly pheomelanin synthesis by downregulating genes normally required for eumelanin synthesis. COPA is a component of the coat protein I seven subunit complex that is involved with retrograde and cis-Golgi intracellular coated vesicle transport of both protein and RNA cargo. This suggests that Dominant Red may be caused by aberrant MC1R protein or mRNA trafficking within the highly compartmentalized melanocyte, mimicking the effect of the Recessive Red loss of function MC1R allele.
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Department of Animal and Poultry Sciences, Virginia Tech, Blacksburg, Virginia, United States of America.
authors.forename: Ben
authors.initials: B
authors.lastname: Dorshorst
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
authors.forename: Corneliu
authors.initials: C
authors.lastname: Henegar
authors.affiliation: Livestock Gentec, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liao
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Sällman Almén
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Carl-Johan
authors.initials: CJ
authors.lastname: Rubin
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi, Japan.
authors.forename: Shosuke
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Wakamatsu
authors.affiliation: Livestock Gentec, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Stothard
authors.affiliation: Canadian Dairy Network, Guelph, Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Van Doormaal
authors.affiliation: Livestock Gentec, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Graham
authors.initials: G
authors.lastname: Plastow
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America; Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
authors.affiliation: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Science for Life Laboratory, Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Andersson
mesh_terms: D000818:Animals; D002417:Cattle / Q000235:genetics; D002874:Chromosome Mapping; D020756:Coatomer Protein / Q000235:genetics*; D017124:Conserved Sequence / Q000235:genetics; D019143:Evolution, Molecular; D005799:Genes, Dominant; D056726:Genetic Association Studies; D016678:Genome; D006200:Hair Color / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D012880:Skin Pigmentation / Q000235:genetics*
chemical_list: D020756:Coatomer Protein; D044102:Receptor, Melanocortin, Type 1