Characterization of systemic genomic instability in budding yeast

Abstract

Conventional models of genome evolution are centered around the principle that mutations form independently of each other and build up slowly over time. We characterized the occurrence of bursts of genome-wide loss-of-heterozygosity (LOH) in Saccharomyces cerevisiae, providing support for an additional nonindependent and faster mode of mutation accumulation. We initially characterized a yeast clone isolated for carrying an LOH event at a specific chromosome site, and surprisingly found that it also carried multiple unselected rearrangements elsewhere in its genome. Whole-genome analysis of over 100 additional clones selected for carrying primary LOH tracts revealed that they too contained unselected structural alterations more often than control clones obtained without any selection. We also measured the rates of coincident LOH at two different chromosomes and found that double LOH formed at rates 14- to 150-fold higher than expected if the two underlying single LOH events occurred independently of each other. These results were consistent across different strain backgrounds and in mutants incapable of entering meiosis. Our results indicate that a subset of mitotic cells within a population can experience discrete episodes of systemic genomic instability, when the entire genome becomes vulnerable and multiple chromosomal alterations can form over a narrow time window. They are reminiscent of early reports from the classic yeast genetics literature, as well as recent studies in humans, both in cancer and genomic disorder contexts. The experimental model we describe provides a system to further dissect the fundamental biological processes responsible for punctuated bursts of structural genomic variation.

Genomic characterization of a pathogenic isolate of Saccharomyces cerevisiae reveals an extensive and dynamic landscape of structural variation

“…Acquisition of this extrachromosomal sequence by S. cerevisiae is posited to have occurred through a horizontal gene transfer event, and numerous distinct insertions of this sequence have been identified in the genomes of other strains, primarily in those isolated from wine-making environments 23 . The specific insertion of the Z. bailii circle at this locus on Chr6 appears to be shared by other wild isolates of S. cerevisiae, as we recently identified an identical insertion in one of the Chr6 homologs in the diploid genome of the industrial strain JAY270 24 .…”

Systemic aneuploidization events drive phenotype switching in Saccharomyces cerevisiae

“…The potential impacts of aneuploidy-driven phenotype switching on population diversity are further heightened when framed within the emergent concept of systemic genomic instability (SGI) 23,24,43,44 . Recent work from our group demonstrated that aneuploidization events often impart systemic genomic changes, with the potential to impact the transmission of many, if not all, chromosomes in the cell concurrently.…”

Origin, Regulation, and Fitness Effect of Chromosomal Rearrangements in the Yeast Saccharomyces cerevisiae

“…Most information about the rates of these events was based on the genetic assay system involving single genes or partial chromosomes [ 51 , 52 ]. More recently, subculturing of yeast strains over many generations for mutation accumulation (MA) followed by whole-genome sequencing has allowed a more global analysis of chromosomal rearrangements [ 53 , 54 , 55 , 56 ]. Sui et al [ 53 ] performed MA experiments in a diploid S. cerevisiae strain ( spo11/spo11 ; unable to enter meiosis), identifying chromosomal rearrangements throughout the genome by deep-coverage genome sequencing.…”

“…Most strikingly, this work demonstrated that spontaneous chromosomal rearrangements generally involve homologous recombination between non-allelic dispersed repeats in the yeast genome. In a recent study by Sampaio et al [ 55 ], the authors showed that two LOH events coincided at two different chromosomes at rates 14- to 150-fold higher than predicted if these two events originated independently of each other. This finding suggested that multiple genomic alterations can occur simultaneously during a limited time window, possibly as short as a single cycle of cell division [ 55 ].…”

“…In a recent study by Sampaio et al [ 55 ], the authors showed that two LOH events coincided at two different chromosomes at rates 14- to 150-fold higher than predicted if these two events originated independently of each other. This finding suggested that multiple genomic alterations can occur simultaneously during a limited time window, possibly as short as a single cycle of cell division [ 55 ]. What is the nature of recombinogenic lesions under spontaneous conditions?…”