An intronic copy number variation in Syntaxin 17 determines speed of greying and melanoma incidence in Grey horses.
Abstract: The Greying with age phenotype in horses involves loss of hair pigmentation whereas skin pigmentation is not reduced, and a predisposition to melanoma. The causal mutation was initially reported as a duplication of a 4.6 kb intronic sequence in Syntaxin 17. The speed of greying varies considerably among Grey horses. Here we demonstrate the presence of two different Grey alleles, G2 carrying two tandem copies of the duplicated sequence and G3 carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. Our results reveal a remarkable dosage effect where the G3 allele is associated with fast greying and high incidence of melanoma whereas G2 is associated with slow greying and low incidence of melanoma. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (G2 and G3) and a drastically elevated risk of melanoma (G3 only). Our direct pedigree-based observation of the origin of a G2 allele from a G3 allele by copy number contraction demonstrates the dynamic evolution of this locus and provides the ultimate evidence for causality of the copy number variation of the 4.6 kb intronic sequence.
© 2024. The Author(s).
Publication Date: 2024-08-29 PubMed ID: 39209879PubMed Central: PMC11362437DOI: 10.1038/s41467-024-51898-2Google Scholar: Lookup
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Summary
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This research explores how variations in a specific gene, Syntaxin 17, influence the rate of hair greying and the frequency of melanoma occurrences in Grey horses. The study found two different Grey alleles with varying numbers of the duplicated sequence, affecting the speed of greying and melanoma incidence, thus revealing the role of gene dosage effect.
Objective and Background of the Research
- The purpose of this study is to understand the link between Syntaxin 17 gene variation and the rate of greying and incidence of melanoma in Grey horses.
- Previous research had identified that the duplication of a 4.6 kb intronic sequence of the Syntaxin 17 gene was responsible for the greying with age phenotype and a predisposition to melanoma in these horses.
- However, the speed at which horses grey can greatly vary, leading researchers to investigate this phenomenon further.
Findings of the Research
- The researchers discovered two distinct Grey alleles, labelled G2 and G3, each carrying a different number of tandem copies of the duplicated sequence.
- The G3 allele, which carries three copies, was found to be significantly more common, possibly due to strong selection for its associated stark white phenotype.
- This study showed a noticeable dosage effect: the G3 allele was associated with faster greying and a higher incidence of melanoma, while the G2 allele was linked to slower greying and a lower incidence of melanoma.
Significance of the Research
- The copy number increase in the Syntaxin 17 gene has a significant impact, transforming a weak enhancer to a strong melanocyte-specific enhancer. This alteration underlies hair greying and drastically increases the risk of melanoma, especially in instances of the G3 allele.
- The researchers were able to observe the origin of a G2 allele from a G3 allele by copy number contraction directly through pedigree analysis. This observation demonstrates the dynamic evolution of this locus and provides concrete evidence for the link between the variation in the 4.6 kb intronic sequence’s copy number and the rate of greying and prevalence of melanoma.
Cite This Article
APA
Rubin CJ, Hodge M, Naboulsi R, Beckman M, Bellone RR, Kallenberg A, J'Usrey S, Ohmura H, Seki K, Furukawa R, Ohnuma A, Davis BW, Tozaki T, Lindgren G, Andersson L.
(2024).
An intronic copy number variation in Syntaxin 17 determines speed of greying and melanoma incidence in Grey horses.
Nat Commun, 15(1), 7510.
https://doi.org/10.1038/s41467-024-51898-2 Publication
Researcher Affiliations
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
- Institute of Marine Research, Bergen, Norway.
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Department of Animal Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institute, Tomtebodavägen 18A, 17177, Stockholm, Sweden.
- Swedish Connemara Pony Breeders' Society, Falkenberg, Sweden.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA, USA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California-Davis, Davis, California, USA.
- Racehorse hospital, Miho Training Center, Japan Racing Association, Ibaraki, Japan.
- Hidaka Training and Research Center, Japan Racing Association, Hokkaido, Japan.
- Genetic Analysis Department, Laboratory of Racing Chemistry, Tochigi, Japan.
- Genetic Analysis Department, Laboratory of Racing Chemistry, Tochigi, Japan.
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA.
- Genetic Analysis Department, Laboratory of Racing Chemistry, Tochigi, Japan.
- Department of Animal Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. leif.andersson@imbim.uu.se.
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA. leif.andersson@imbim.uu.se.
MeSH Terms
- Horses / genetics
- Animals
- DNA Copy Number Variations / genetics
- Qa-SNARE Proteins / genetics
- Qa-SNARE Proteins / metabolism
- Melanoma / genetics
- Melanoma / veterinary
- Melanoma / epidemiology
- Introns / genetics
- Hair Color / genetics
- Alleles
- Pedigree
- Male
- Female
- Phenotype
- Incidence
- Horse Diseases / genetics
- Horse Diseases / epidemiology
- Skin Pigmentation / genetics
Grant Funding
- KAW 2023.0160 / Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation)
- FWF P35840 / Austrian Science Fund (Fonds zur Fu00f6rderung der Wissenschaftlichen Forschung)
Conflict of Interest Statement
R.R. Bellone, A. Kallenberg, and S. J'Usrey are affiliated with the UC Davis Veterinary Genetics Laboratory, which provides genetic diagnostic tests in horses and other species. The other authors declare no competing interest.
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