Parental kinship influences global methylation and epigenetic age estimation in Peromyscus

Kinship relationships between parents affect offspring fitness. Beyond its effects in heterozygosity or its impact in deleterious alleles that can be reduced to homozygosity and decrease the individuals' fitness, the consequences of parental relatedness in the offspring remain understudied. By leveraging the availability of detailed pedigrees of captive Peromyscus, we explored how parental relatedness impacts the methylome and the epigenetic age estimation of the offspring. Global CpG methylation analysis showed that parental relatedness positively impacts lifespan expectancy and reduces epigenetic ageing, contributing about 13% of variancein epigenetic age estimation. Global hypermethylation due to relatedness was considerably higher than hypomethylation, was more pronounced in the male offspring, and mainly affected chromosomal loci associated with development. A relatedness-associated methylation signature was described that predicts parental relatedness with high accuracy, providing the proof of concept that kinship relationships can be inferred by epigenetic analyses. These findings identify parental relatedness as a modifier of epigenetic ageing and global methylation, suggesting that kinship relations should be considered when epigenetic, and potentially transcriptomic data are interpreted in the context of ageing and of other pathophysiological processes.