Human genomic tools to assess missense variant pathogenicity in domestic mammals using a mock-variant strategy

Predicting the pathogenicity of missense variants is a crucial step in animal breeding, farming, and veterinary medicine. While some predictive tools for non-human species exist, many are not as specialized or effective as those developed for humans. Existing human genomic tools can provide insights that may be beneficial when appropriately adapted for animal use due to protein sequence similarities between humans and other mammals.

This study aimed to evaluate the applicability of three widely used human genomic prediction tools-AlphaMissense, ESM-1b, and PolyPhen-2-to assess the pathogenicity of missense variants in domestic mammals.

Missense variants in domestic mammals were sourced from the Online Mendelian Inheritance in Animals database, comprising 284 variants annotated as "deleterious" and 90 as "non-deleterious." These variants were converted into mock human variants and classified as pathogenic or benign using the three human genomic tools. Predictive performance was assessed by calculating the sensitivity, specificity, and area under the receiver operating characteristic curve (auROC).

The tools showed sensitivity values between 0.77 and 0.90, indicating a strong ability to identify pathogenic variants, but low specificity values from 0.20 to 0.46 suggest challenges in correctly identifying benign variants, with auROC values indicating moderate predictive performance ranging from 0.55 to 0.61. The low specificity may stem from the interpretation of "non-deleterious" variants, which may cause malfunctioning proteins that are often associated with traits such as coat color but are not linked to disease in animals.

A simple mock strategy can enable human genomic tools to predict the pathogenicity of rare missense variants in domestic mammals. Although specificity remains a limitation, and the strategy is primarily applicable to mutations on highly conserved amino acid residues, the results highlight the applicability for adapting human genomic prediction tools to advance veterinary genomics and animal research, with predictive performance potentially influenced by the sequence similarity between animal and human homologous proteins.