期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：5
页码：1897-1902
DOI：10.1073/pnas.1314423111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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: pol32{Delta} and rad27{Delta} (replication), msh2{Delta} (mismatch repair), tsa1{Delta} (oxidative stress), mre11{Delta} (recombination), mec1{Delta} tel1{Delta} (DNA damage/S-phase checkpoints), pif1{Delta} (maintenance of mitochondrial genome and telomere length), cac1{Delta} cac3{Delta} (nucleosome deposition), and clb5{Delta} (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 clb5{Delta}/CCNB1, mec1{Delta}/ATR, tel1{Delta}/ATM, and rad27{Delta}/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.
