Emerging opportunities for DNA methylation biomarkers in cattle improvement.

Improving economically important traits such as productivity, fertility, and health remains a central goal in modern cattle breeding. While genome-wide association studies (GWAS) have revolutionized genomics by identifying numerous trait-associated single nucleotide polymorphisms (SNPs), a significant proportion of phenotypic variation remains unexplained, often referred to as missing heritability. Furthermore, identifying causal genes and regulatory elements within complex GWAS loci is challenging. Population-scale multi-omics studies like FarmGTEx, particularly those focusing on epigenetics, offer new opportunities to uncover regulatory biomarkers beyond static SNPs. DNA methylation (DNAm) has emerged as a promising epigenetic layer that acts as a bridge between the genome and the phenome, mediating environmental and genetic influences on gene expression. Within this landscape, genomic regions containing stable single methylation polymorphisms (SMPs), known as Correlated Regions of Systemic Interindividual Variation (CoRSIVs) are gaining increasing recognition for its emerging potential. CoRSIVs exhibit stability across diverse tissues, high interindividual variability, and partial heritability, making them ideal, tissue-agnostic candidates for scalable and cost-effective epigenetic applications. This review highlights the growing relevance of SMPs, especially CoRSIVs, for improving biomarker discovery, enhancing prediction accuracy, and strengthening cattle management and breeding strategies.