Loss of heterozygosity results in rapid but variable genome homogenization across genetic backgrounds in yeast
Abstract
The dynamics and diversity of the appearance of genetic variants play an essential role in the evolution of the genome and the shaping of biodiversity. Recent population-wide genome sequencing surveys have highlighted the importance of loss-of-heterozygosity (LOH) events and have shown that they are a neglected part of the genetic diversity landscape. To assess the extent, variability, and spectrum, we explored the accumulation of LOH events in 169 heterozygous diploid Saccharomyces cerevisiae mutation accumulation lines across nine genetic backgrounds. In total, we detected a large set of 22,828 LOH events across distinct genetic backgrounds with a heterozygous level ranging from 0.1 to 1%. LOH events are very frequent with a rate consistently much higher than the mutation rate, showing their importance for genome evolution. We observed that the interstitial LOH (I-LOH) events, resulting in internal short LOH tracts, were much frequent (n = 19,660) than the terminal LOH (T-LOH) events, i.e., tracts extending to the end of the chromosome (n = 3,168). However, the spectrum, the rate, and the fraction of the genome under LOH vary across genetic backgrounds. Interestingly, we observed that the more the ancestors were heterozygous, the more they accumulated T-LOH events. In addition, frequent short I-LOH tracts are a signature of the lines derived from hybrids with low spore fertility. Finally, we found lines showing almost complete homozygotization during vegetative progression. Overall, our results highlight that the variable dynamics of the LOH accumulation across distinct genetic backgrounds might lead to rapid differential genome evolution during vegetative growth.
Data availability
Sequence data are available from National Centre for Biotechnology Information Sequence Read Archive under accession number: PRJEB43186.
Article and author information
Author details
Funding
European Research Council (772505)
- Joseph Schacherer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Dutta et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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The sustained success of Mycobacterium tuberculosis as a pathogen arises from its ability to persist within macrophages for extended periods and its limited responsiveness to antibiotics. Furthermore, the high incidence of resistance to the few available antituberculosis drugs is a significant concern, especially since the driving forces of the emergence of drug resistance are not clear. Drug-resistant strains of Mycobacterium tuberculosis can emerge through de novo mutations, however, mycobacterial mutation rates are low. To unravel the effects of antibiotic pressure on genome stability, we determined the genetic variability, phenotypic tolerance, DNA repair system activation, and dNTP pool upon treatment with current antibiotics using Mycobacterium smegmatis. Whole-genome sequencing revealed no significant increase in mutation rates after prolonged exposure to first-line antibiotics. However, the phenotypic fluctuation assay indicated rapid adaptation to antibiotics mediated by non-genetic factors. The upregulation of DNA repair genes, measured using qPCR, suggests that genomic integrity may be maintained through the activation of specific DNA repair pathways. Our results, indicating that antibiotic exposure does not result in de novo adaptive mutagenesis under laboratory conditions, do not lend support to the model suggesting antibiotic resistance development through drug pressure-induced microevolution.
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