Abstract
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 a 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 Saccharomyces cerevisiae mutation accumulation lines. This approach revealed the diversity, complexity, and ultimate uniqueness of mutational landscapes, differently composed of base substitutions, small insertions/deletions (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 subsignatures resulting from distinct DNA damage lesions. Notably, the increase of base substitutions in the homologous recombination-deficient Rad51 mutant, specifically dependent on the Polζ 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 interhomolog mitotic cross-overs. 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.
Highlights
| | | | mutator genes mutational profiles Pol zeta loss of heterozygosity dynamics of mutation accumulation
We established the mutational landscapes of 274 mutation accumulation (MA) lines generated in the isogenic BY and/or hybrid SK1/BY wild-type (WT) backgrounds
Since break-induced replication (BIR) depends on the activity of POL32 and PIF1 [51,52,53,54], we examined the effect of deleting these genes in the tsa1 mutant (Dataset S1)
Summary
| | | | mutator genes mutational profiles Pol zeta loss of heterozygosity dynamics of mutation accumulation. Spontaneous mutations in normal cells, exposure to environmental genotoxic compounds, and deficiencies in genome maintenance genes are prominent sources of subtle or drastic genome changes/ rearrangements and eventually functional and phenotypic variations [4, 5]. We conducted a reciprocal functional approach to inactivate one or several genes involved in distinct genome maintenance processes (replication, repair, recombination, oxidative stress response, or cell-cycle progression) in Saccharomyces cerevisiae diploids, establish the genome-wide mutational landscapes of mutation accumulation (MA) lines, explore the underlying mechanisms, and characterize the dynamics of mutation accumulation (and disappearance) along single-cell bottleneck passages
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