Source of genome-wide deleterious variation in a global cattle cohort

Background Identifying deleterious DNA changes underpins efforts to improve animal health, welfare, and sustainable breeding. In cattle, current variant prioritization focuses on coding changes, uses single annotation types, and gives limited resolution in non-coding sequence. Results We developed BovCADD (bovine Combined Annotation-Dependent Depletion), a nucleotide-level deleteriousness score for substitutions in Bos taurus and Bos indicus, combining evolutionary constraint, sequence context, epigenetic and regulatory annotations, and gene and protein features. A logistic regression model trained on 41.9 million high-frequency derived alleles from about 3,700 cattle, contrasted with context-matched simulated variants, scored all 8.1 billion possible substitutions. BovCADD distinguished known pathogenic variants from background variation, discriminated among variants within the same consequence class, and scored intronic and intergenic sites. Aggregating scores identified genes carrying rare deleterious variation and revealed elevated genetic load at trait-relevant loci and in bottlenecked, intensively selected populations. Conclusions BovCADD provides the first genome-wide, nucleotide-resolution measure of deleteriousness in cattle, extending variant interpretation to non-coding sequences and linking variant-level prioritization to population-level patterns of mutational burden. Precomputed scores for all substitutions are publicly available.