title: Endogenous retrovirus insertion in the KIT oncogene determines white and white spotting in domestic cats.
abstract: The Dominant White locus (W) in the domestic cat demonstrates pleiotropic effects exhibiting complete penetrance for absence of coat pigmentation and incomplete penetrance for deafness and iris hypopigmentation. We performed linkage analysis using a pedigree segregating White to identify KIT (Chr. B1) as the feline W locus. Segregation and sequence analysis of the KIT gene in two pedigrees (P1 and P2) revealed the remarkable retrotransposition and evolution of a feline endogenous retrovirus (FERV1) as responsible for two distinct phenotypes of the W locus, Dominant White, and white spotting. A full-length (7125 bp) FERV1 element is associated with white spotting, whereas a FERV1 long terminal repeat (LTR) is associated with all Dominant White individuals. For purposes of statistical analysis, the alternatives of wild-type sequence, FERV1 element, and LTR-only define a triallelic marker. Taking into account pedigree relationships, deafness is genetically linked and associated with this marker; estimated P values for association are in the range of 0.007 to 0.10. The retrotransposition interrupts a DNAase I hypersensitive site in KIT intron 1 that is highly conserved across mammals and was previously demonstrated to regulate temporal and tissue-specific expression of KIT in murine hematopoietic and melanocytic cells. A large-population genetic survey of cats (n = 270), representing 30 cat breeds, supports our findings and demonstrates statistical significance of the FERV1 LTR and full-length element with Dominant White/blue iris (P < 0.0001) and white spotting (P < 0.0001), respectively.
authors.affiliation: Laboratory of Genomic Diversity, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702.
authors.forename: Victor A
authors.initials: VA
authors.lastname: David
authors.affiliation: Laboratory of Genomic Diversity, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702 Marilyn.Menotti@gmail.com.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Menotti-Raymond
authors.affiliation: Laboratory of Genomic Diversity, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702.
authors.forename: Andrea Coots
authors.initials: AC
authors.lastname: Wallace
authors.affiliation: Leidos Biomedical Research Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702 Labooratory Animal Sciences Program (LASP) Bethesda Leidos Biomedical Research, Bethesda, Maryland 20892-2471.
authors.forename: Melody
authors.initials: M
authors.lastname: Roelke
authors.affiliation: Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20814.
authors.forename: James
authors.initials: J
authors.lastname: Kehler
authors.affiliation: Data Management Services, Inc., National Cancer Institute-Frederick, Frederick, Maryland 21702.
authors.forename: Robert
authors.initials: R
authors.lastname: Leighty
authors.affiliation: Faculdade de Biociências, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 90619-900, Brazil Instituto Pró-Carnívoros, Atibaia, Sao Paulo 12945-010, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eizirik
authors.affiliation: Nestlé Purina PetCare, St. Louis, Missouri 63164.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Hannah
authors.affiliation: BSP-CCR Genetics Core, Frederick National Laboratory, Frederick, Maryland 21702.
authors.forename: George
authors.initials: G
authors.lastname: Nelson
authors.affiliation: National Center for Biotechnology Information, National Institutes of Health, Bethesda, Maryland 20894.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Connelly
authors.affiliation: Laboratory of Genomic Diversity, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702 Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Brien
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Center for Hearing Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Ryugo
mesh_terms: D000818:Animals; D001947:Breeding; D002415:Cats; D020077:Endogenous Retroviruses / Q000235:genetics*; D008040:Genetic Linkage; D005828:Genetics, Population; D005838:Genotype; D034381:Hearing Loss / Q000473:pathology / Q000662:veterinary; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007438:Introns; D008407:Mast Cells / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D018626:Retroelements / Q000235:genetics; D017423:Sequence Analysis, RNA; D020079:Terminal Repeat Sequences / Q000235:genetics
chemical_list: D018626:Retroelements; D019009:Proto-Oncogene Proteins c-kit
keywords: FERV1; White; deaf; domestic cat; retrotransposition; white spotting
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