The Influence of MUTYH on Repair Deficiencies on Germline and Somatic Mutagenesis Across Mammalian Species

Abstract

The Base Excision Repair (BER) gene MUTYH is essential for maintaining genomic integrity by preventing C>A transversions induced by oxidative stress. Prior research has established that mutations in MUTYH are associated with increased cancer susceptibility in humans as well as elevated germline mutation rates in mice. However, the evolutionary dynamics of germline mutator alleles like MUTYH, and the extent to which their functional variations are permitted or constrained across different species and cellular contexts, remain poorly understood. Specifically, it remains unclear how MUTYH variants influence mutagenesis in the human germline compared to their well-established role in human somatic cells, and how they affect mutagenesis in mouse somatic cells relative to their known impact on mouse germline mutation rates. To explore this, we examined MUTYH alleles in a human pedigree, identifying an association between a pathogenic MUTYH genotype and elevated C>A de novo mutations in the maternal germline. In parallel, we assessed murine Mutyh variation by sequencing colons and spleens from aged recombinantly inbred “BXD” mice, revealing aged-related increases in C>A somatic mutations in Mutyh-deficient strains as well as Mutyh associated single base substitution COSMIC cancer signatures in both tissues. Together, these findings advance our understanding of MUTYH’s role in cancer, germline mutagenesis, and sex-specific mutation patterns across mammalian species.