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Edited by Daniel E. Gottschling, Calico Life Sciences, South San Francisco, CA, and approved September 28, 2020 (received for review June 15, 2020)
Significance
Mutations are generally thought to accumulate independently and gradually over many generations. Here, we combined complementary experimental approaches in budding yeast to track the appearance of chromosomal changes resulting in loss-of-heterozygosity. In contrast to the prevailing model, our results provide evidence for the existence of a path for nonindependent accumulation of multiple chromosomal alteration events over a few generations. These results are analogous to recent reports of bursts of genomic instability in human cells. The experimental model we describe provides a system to further dissect the fundamental biological processes underlying such punctuated bursts of mutation accumulation.
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: lucas.argueso{at}colostate.edu.
Author contributions: N.M.V.S. and J.L.A. designed research; N.M.V.S., V.P.A., R.A.W., L.R.H., P.C., A.R.-P., E.P.M., and J.L.A. performed research; N.M.V.S., V.P.A., R.A.W., L.R.H., P.C., P.A.M., K.T.N., and J.L.A. analyzed data; and N.M.V.S., R.A.W., and J.L.A. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2010303117/-/DCSupplemental.
Data Availability.
The data that support the findings of this study are available in the article itself and the SI Appendix, specifically in SI Appendix, Figs. S1–S6, and in Datasets S1 and S2. All genome sequencing data associated with this study are available in the Sequence Read Archive (SRA) database, https://www.ncbi.nlm.nih.gov/sra (accession no. SRP082524).
Published under the PNAS license.
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Characterization of systemic genomic instability in budding yeast
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