Mutational landscape of yeast mutator strains.
The acquisition of mutations is relevant to every aspect of genetics, including cancer and evolution of species on Darwinian selection. Genome variations arise from rare stochastic imperfections of cellular metabolism and deficiencies in maintenance genes. Here, we established the genome-wide spectrum of mutations that accumulate in a WT and in nine Saccharomyces cerevisiae mutator strains deficient for distinct genome maintenance processes: pol32Δ and rad27Δ (replication), msh2Δ (mismatch repair), tsa1Δ (oxidative stress), mre11Δ (recombination), mec1Δ tel1Δ (DNA damage/S-phase checkpoints), pif1Δ (maintenance of mitochondrial genome and telomere length), cac1Δ cac3Δ (nucleosome deposition), and clb5Δ (cell cycle progression). This study reveals the diversity, complexity, and ultimate unique nature of each mutational spectrum, composed of punctual mutations, chromosomal structural variations, and/or aneuploidies. The mutations produced in clb5Δ/CCNB1, mec1Δ/ATR, tel1Δ/ATM, and rad27Δ/FEN1 strains extensively reshape the genome, following a trajectory dependent on previous events. It comprises the transmission of unstable genomes that lead to colony mosaicisms. This comprehensive analytical approach of mutator defects provides a model to understand how genome variations might accumulate during clonal evolution of somatic cell populations, including tumor cells.
Recombination and Genetic Instability, Institut Curie Centre de Recherche, Centre National de la Recherche Scientifique Unité Mixte de Recherche 3244, Université Pierre et Marie Curie, 75248 Paris Cedex 05, France.
Alexandre
A
Serero
Claire
C
Jubin
Sophie
S
Loeillet
Patricia
P
Legoix-Né
Alain G
AG
Nicolas
D000782:Aneuploidy; D015825:Chromosomes, Fungal / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics; D005800:Genes, Fungal / Q000235:genetics; D006238:Haploidy; D009154:Mutation / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D017422:Sequence Analysis, DNA
MUTome; genetic instability; genome drift; mutation accumulation lines; mutation profile