White horses – non-coding sequences drive premature hair greying and predisposition to melanoma.
Abstract: The Grey allele in horses is causing premature hair greying and susceptibility to melanoma. The causal mutation is a 4.6 kb tandem duplication in intron 6 of the Syntaxin 17 gene. A recent study demonstrated that the most common allele at the Grey locus (G3) involves three tandem copies of this sequence, whilst a more rare allele (G2) has two tandem copies and the wild-type allele (G1) only one copy. The G3 allele is causing fast greying and high incidence of skin melanoma, whereas the G2 allele is causing slow greying and no obvious increase in melanoma incidence. Further somatic copy number expansion has been documented in melanoma tissue from Grey horses. Functional studies showed that this intronic sequence acts as a weak melanocyte-specific enhancer that becomes substantially stronger by the copy number expansion. The Grey mutation is associated with upregulated expression of both Syntaxin 17 and the neighbouring NR4A3 gene in Grey horse melanomas. It is still an open question which of these genes is most important for the phenotypic effects or if causality is due to the combined effect of upregulation of both genes. Interestingly, RNAseq data in the Human Protein Atlas give support for a possible role of NR4A3 because it is particularly upregulated in human skin cancer, and it belongs to a cluster of genes associated with skin cancer and melanin biosynthesis. The Grey mutation and its association with melanoma provide a possibility to study the path to tumour development in numerous Grey horses carrying exactly the same predisposing mutation.
© 2024 The Author(s). Published by Upsala Medical Society.
Publication Date: 2024-04-02 PubMed ID: 38571883PubMed Central: PMC10989212DOI: 10.48101/ujms.v129.10626Google Scholar: Lookup
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Summary
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This research discusses a specific allele in horses, which is responsible for causing premature hair greying and an increased risk of melanoma. The mutation, identified in a gene called STX17, leads to the expression of certain characteristics. These findings help in understanding the connection between genetic mutation, skin pigmentation, and cancer risk.
Study Overview
- The study focused on understanding why white horses experience premature greying and have a heightened risk of developing melanoma, a form of skin cancer.
- The researchers traced this to an allele, present in the STX17 gene, connected to premature hair greying and susceptibility to melanoma.
- This allele was found to have a genetic mutation in the form of a 4.6 kb tandem duplication in intron 6 of the STX17 gene.
Gene Variations and Impact
- Various alleles at the STX17 locus were studied. An allele labeled G3 had three tandem copies of the sequence, whereas another allele called G2 had two copies. The wild-type allele (labeled G1) had only one copy of the sequence.
- The G3 allele was identified as the one leading to rapid greying and a higher incidence rate of skin melanoma.
- In contrast, horses carrying the G2 allele displayed a slower greying process and did not present an increased melanoma risk. This displayed how different gene variants could lead to varying phenotypic outcomes.
Functional Analysis and Implications
- A functional analysis showed that the 4.6 kb sequence acts as a weak enhancer, which becomes significantly stronger with an expansion in copy number, triggering melanocyte activity.
- Both STX17 and a neighboring gene, NR4A3, show upregulated expression in Grey horse melanomas. The most decisive factor for these phenotypic effects—whether it’s either of these genes or both—is still under investigation.
- The upregulation of NR4A3, in particular, could hint at its role in skin cancer, given it’s particularly upregulated in human skin cancer. It is also associated with a gene cluster connected to skin cancer and melanin biosynthesis.
Research Implications and Future Studies
- The findings simplify gene variations that make Grey horses prone to melanoma, which can aid further study in this area and provide insights for understanding similar paths towards tumour development in other species, including humans.
- The observations also offer a unique model to study the progression from a harmless mole to malignant melanoma, considering many Grey horses carry this predisposing mutation, acting as a readily available study group.
Cite This Article
APA
Andersson L.
(2024).
White horses – non-coding sequences drive premature hair greying and predisposition to melanoma.
Ups J Med Sci, 129.
https://doi.org/10.48101/ujms.v129.10626 Publication
Researcher Affiliations
- Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
MeSH Terms
- Humans
- Melanoma / genetics
- Melanoma / veterinary
- Skin Neoplasms / genetics
- Skin Neoplasms / veterinary
- Qa-SNARE Proteins / genetics
- Qa-SNARE Proteins / metabolism
- Mutation
- Hair / metabolism
- Hair / pathology
Conflict of Interest Statement
The author reports no conflicts of interest.
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