Trajectory_and_Uniqueness_of_Mutational_Signatures_in_Yeast_Mutators

The acquisition of mutations plays critical roles in adaptation, evolution, senescence and tumorigenesis. Massive genome sequencing has allowed extraction of specific features of many mutational landscapes but it remains difficult to retrospectively determine the mechanistic origin(s), selective forces and trajectories of transient or persistent mutations and genome rearrangements. Here, we conducted the prospective reciprocal approach to inactivate 13 single or multiple evolutionary-conserved genes involved in distinct genome maintenance processes and characterize de novo mutations in 274 diploid S. cerevisiae mutation accumulation lines. This approach revealed the diversity, complexity and ultimate uniqueness of mutational landscapes, differently composed of base substitutions, small InDels, structural variants and/or ploidy variations. Several landscapes parallel the repertoire of mutational signatures in human cancers while others are either novel or composites of sub-signatures resulting from distinct DNA damage lesions. Notably, the increase of base substitutions in the homologous recombination deficient Rad51 mutant, specifically dependent on the Polz translesion polymerase, yields COSMIC Signature 3 observed in BRCA1/BRCA2-mutant breast cancer tumors. Furthermore, “mutome” analyses in highly polymorphic diploids and single-cell bottleneck lineages revealed a diverse spectrum of loss-of-heterozygosity (LOH) signatures characterized by interstitial and terminal chromosomal events resulting from inter-homolog mitotic crossovers. Following the appearance of heterozygous mutations, the strong stimulation of LOHs in the rad27/FEN1 and tsa1/PRDX1 backgrounds leads to fixation of homozygous mutations or their loss along the lineage. Overall, these “Mutomes” and their trajectories provide a mechanistic framework to understand the origin and dynamics of genome variations that accumulate during clonal evolution.