Adaptive reversions of a frameshift mutation in arrested Saccharomyces cerevisiae cells by simple deletions in mononucleotide repeats

Adaptive mutations are characterised as the outcome of an as yet unknown mechanism, which allows a few individuals of a cell population to overcome a starvation-induced cell cycle arrest and to proliferate. A release from such a non-lethal growth limitation is accomplished by mutations generated without DNA replication. Originally adaptive mutations were described in Escherichia coli, but more recently also in a simple eukaryote, the budding yeast Saccharomyces cerevisiae. We are studying the adaptive reversion of a frameshift allele which occurs when an auxotrophic yeast strain is starved for the amino acid essential for its proliferation. In this communication, we report on the DNA sequences from the locus concerned. Comparison between sequences from revertant clones which arose several days after growth arrest by starvation and those from revertants produced during proliferation shows significantly different mutation spectra: for replication-dependent revertants nucleotide gains and losses in a variety of sequence contexts are reasonably balanced, whereas for the replication-independent, i.e. adaptive, revertants mainly simple deletions in mononucleotide repeats were observed. These mutations resemble those known to originate from DNA polymerase slippage errors which were miscorrected or had escaped correction by the mismatch repair machinery. Our data present strong evidence for differences in the mechanistic origins of adaptive versus DNA replication-dependent mutations in a eukaryote. Most probably, mutations in non-replicating cells contribute to evolution, and if conserved in mammals, to human carcinogenesis.