1Mutations in genomic DNA are the starting material for evolution by natural 2 selection. Analyses of large-scale sequencing data have revealed that mu-3 tagenic processes often create distinctive patterns of base substitutions, 4 called mutational signatures. In this work, we analyzed the base substitu-5 tion patterns within mutational data from a large number of strains or indi-6 viduals among seven model species (totalling >784 million mutations), as 7 well as single nucleotide polymorphisms (SNPs) in 41 species from the 8 NCBI SNP database (>603 million SNPs). We found that the intrinsic base 9 substitution pattern for most of these species closely matches mutational 10 signature 5 from the Catalog of Somatic Mutations in Cancer (abbreviated 11 as COSMIC). Signature 5 is ubiquitous in cancers and normal human cells, 12suggesting that the similar patterns of mutation across many species are 13 likely due to conserved biochemical processes. Finally, we show that a 14 similar pattern of base substitutions can be obtained using a yeast model 15 system that allows controlled generation of genomic single-stranded DNA. 16Taken together, we propose that intrinsic biochemical processes in cells 17 are coupled to the continuous generation of mutations, which in turn, are 18 acted upon by natural selection to drive the evolution of species. 19 20

Formaldehyde (CH2O) and acetaldehyde (C2H4O) are reactive small molecules produced endogenously in cells as well as being environmental contaminants. Both of these small aldehydes are classified as human carcinogens, since they are known to damage DNA and exposure is linked to cancer incidence. However, the mutagenic properties of formaldehyde and acetaldehyde remain incompletely understood, at least in part because they are relatively weak mutagens. Here, we use a highly sensitive yeast genetic reporter system featuring controlled generation of long single-stranded DNA regions to show that both small aldehydes induced mutational patterns characterized by predominantly C/G → A/T, C/G → T/A, and T/A → C/G substitutions, each in similar proportions. We observed an excess of C/G → A/T transversions when compared to mock-treated controls. Many of these C/G → A/T transversions occurred at TC/GA motifs. Interestingly, the formaldehyde mutational pattern resembles single base substitution (SBS) signature 40 from the Catalog of Somatic Mutations in Cancer (COSMIC). SBS40 is a mutational signature of unknown etiology. We also noted that acetaldehyde treatment caused an excess of deletion events longer than four bases while formaldehyde did not. This latter result could be another distinguishing feature between the mutational patterns of these simple aldehydes. These findings shed new light on the characteristics of two important, commonly occurring mutagens.

Analyses of large-scale cancer sequencing data have revealed that mutagenic processes can create distinctive patterns of base substitutions, called mutational signatures. Interestingly, mutational patterns resembling some of these signatures can also be observed in normal cells. To determine whether similar patterns exist more generally, we analyzed large data sets of genetic variation, including mutations from seven model species and single nucleotide polymorphisms (SNPs) in 42 species, totalling >1.9 billion variants. We found that base substitution patterns for most species closely match single base substitution (SBS) mutational signature 5 in the Catalog of Somatic Mutations in Cancer (COSMIC) database. SBS5 is ubiquitous in cancers and also present in normal human cells, suggesting that similar patterns of genetic variation across so many species are likely due to conserved biochemistry. We investigated the mechanistic origins of the SBS5-like mutational pattern in Saccharomyces cerevisiae, and show that translesion DNA synthesis and sugar metabolism are directly linked to this form of mutagenesis. We propose that conserved metabolic processes in cells are coupled to continuous generation of genetic variants, which can be acted upon by selection to drive the evolution of biological entities.

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Formaldehyde (CH2O) and acetaldehyde (C2H4O) are reactive small molecules produced endogenously in cells as well as being environmental contaminants. Both of these small aldehydes are classified as human carcinogens, as they are known to damage DNA and cause mutations. However, the mutagenic properties of formaldehyde and acetaldehyde remain incompletely understood, at least in part because they are relatively weak mutagens. Here, we use a highly sensitive yeast genetic reporter system featuring controlled generation of long single-stranded DNA regions to show that both small aldehydes induced mutational patterns characterized by mostly C/G → A/T, C/G → T/A, and T/A → C/G substitutions, each in similar proportions. We also observed an excess of C/G → A/T transversions when compared to mock-treated controls. Many of these C/G → A/T transversions occurred at TC/GA motifs. Interestingly, the formaldehyde mutational pattern resembles single base substitution (SBS) signature 40 from the Catalog of Somatic Mutations in Cancer (COSMIC). SBS40 is a cancer mutational signature of unknown etiology. We also noted that acetaldehyde treatment caused an excess number of deletion events longer than four bases while formaldehyde did not. This latter result could be a distinguishing feature between the mutational patterns of these two simple aldehydes. These findings shed new light on the mutagenic characteristics of two important carcinogens.