Intrinsic base substitution patterns in diverse species reveal links to cancer and metabolism

Abstract

Analyses of large-scale sequencing data reveal that mutagenic processes create distinctive patterns of base substitutions, called mutational signatures. Here, we analyzed substitution patterns from seven model species and single nucleotide polymorphisms (SNPs) in 42 species, totalling >1.9 billion variants. We found that the base substitution patterns for many species most closely match mutational signature 5 in cancers. Signature 5 is also ubiquitous in cancers and normal human cells, suggesting similar patterns of mutation across species are likely due to conserved biochemistry. Finally, we present evidence from yeast that sugar metabolism is directly linked to this form of DNA damage. We propose that conserved metabolic processes in cells are coupled to continuous generation of mutations, which are acted upon by genetic selection to drive the evolution of species, and cancers. One Sentence SummaryEnergy metabolism produces DNA damage leading to similar patterns of base substitutions in many species and in human cancers.