In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.

Deciphering the genomic regulatory code of enhancers is a key challenge in biology as this code underlies cellular identity. A better understanding of how enhancers work will improve the interpretation of non-coding genome variation, and empower the generation of cell type specific drivers for gene therapy. Here we explore the combination of deep learning and cross-species chromatin accessibility profiling to build explainable enhancer models. We apply this strategy to decipher the enhancer code in melanoma, a relevant case study due to the presence of distinct melanoma cell states. We trained and validated a deep learning model, called DeepMEL, using chromatin accessibility data of 26 melanoma samples across six different species. We demonstrate the accuracy of DeepMEL predictions on the CAGI5 challenge, where it significantly outperforms existing models on the melanoma enhancer of IRF4. Next, we exploit DeepMEL to analyse enhancer architectures and identify accurate transcription factor binding sites for the core regulatory complexes in the two different melanoma states, with distinct roles for each transcription factor, in terms of nucleosome displacement

Summary Reasons for performing study: Equine melanomas occur most commonly in grey horses at age 5 years or more. Generally, benign and malignant melanomas are distinguished by microscopy, but a more distinct classification would be helpful. Objectives: The objectives of this study were to gain further evidence concerning the occurrence of melanotic tumours, and to evaluate the impact of heredity on melanoma development. Methods: A clinical study was conducted on a defined population of 296 grey horses of Lipizzaner breed. Individuals were classified according to theirstage of disease using a 0–5 scale. Heritability was estimated on a sample of 296 grey horses with pedigrees traced back as far as 32 generations. Results: Of the 296 horses, dermal melanomas were present in 148 horses (50%), 68 of which were more than age 15 years; 51 of these were melanoma‐bearing. In 75.6% of cases, melanotic tumours were detected underneath the tail. Although melanoma‐bearing grey horses were encountered up to stage 4, none of the affected individuals suffered any severe clinical effect or was handicapped in performance. Statistical analysis revealed highly significant effects of stud and age (P<0.0001), explaining 28% of the total variability. Conclusions: In contrast to melanomas in solid‐coloured horses characterised by early metastases, melanomas in grey horses showed less malignancy. Affected individuals often had encapsulated nodules or structures similar to human blue nevi. Grey horse‐specific genetic factors inhibiting metastatic processes may be responsible for this phenomenon. Potential clinical relevance: Although the obtained heritability estimate of 0.36 with a standard error of 0.11 indicates a strong genetic impact on the development of melanoma in ageing grey horses, a possible influence of the genes with large effects was also suggested. Therefore, further analysis is required of melanoma development in the ageing grey horse.

Equine melanoma shows striking features particularly with regard to clinical development in grey horses: in contrast to malignant melanoma in humans and in solid coloured horses that are characterized by early onset of metastasis, pigment cell tumours display almost benign clinical features in ageing grey horses. Through evolution, grey horses appear to be in a favourable position in regard to the biological behaviour of melanomas. Yet unknown factors inhibiting or retarding early melanoma metastasis may be responsible for this phenomenon. In this study, immunostaining profiles and histopathologic patterns of equine vs. human melanotic tumours were compared. In addition, the expression of melanoma markers currently used in human melanoma detection and characterization were evaluated for their applicability in equine melanoma diagnosis. Immunohistopathologic investigations revealed that benign grey horse melanomas share common features with human blue nevi and with human malignant desmoplastic melanomas, whereas their resemblance to other types of human cutaneous malignant melanomas is less pronounced. Our data equally underline that S-100, proliferating cell nuclear antigen (PCNA), HMB-45, Ki-67, T-311 and CD44 can serve as reliable markers for horse melanomas. Further investigations aiming at identifying factors retarding metastasis in affected grey horses are needed, as they may contribute to the development of novel treatment strategies for human malignant melanoma.