Loss of heterozygosity results in rapid but variable genome homogenization across genetic backgrounds in yeast

  1. Abhishek Dutta
  2. Fabien Dutreux
  3. Joseph Schacherer  Is a corresponding author
  1. Université de Strasbourg, France
  2. Université de Strasbourg, CNRS, France

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.

The following data sets were generated

Article and author information

Author details

  1. Abhishek Dutta

    Université de Strasbourg, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2256-6956
  2. Fabien Dutreux

    Université de Strasbourg, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Joseph Schacherer

    Department of Genetics, Genomics and Microbiology, Université de Strasbourg, CNRS, Strasbourg, France
    For correspondence
    schacherer@unistra.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6606-6884

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.

Metrics

  • 3,032
    views
  • 242
    downloads
  • 29
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Abhishek Dutta
  2. Fabien Dutreux
  3. Joseph Schacherer
(2021)
Loss of heterozygosity results in rapid but variable genome homogenization across genetic backgrounds in yeast
eLife 10:e70339.
https://doi.org/10.7554/eLife.70339

Share this article

https://doi.org/10.7554/eLife.70339

Further reading

    1. Genetics and Genomics
    Yi Li, Long Gong ... Shangbang Gao
    Research Article

    Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.

    1. Genetics and Genomics
    Minsoo Noh, Xiangguo Che ... Sihoon Lee
    Research Article

    Osteoporosis, characterized by reduced bone density and strength, increases fracture risk, pain, and limits mobility. Established therapies of parathyroid hormone (PTH) analogs effectively promote bone formation and reduce fractures in severe osteoporosis, but their use is limited by potential adverse effects. In the pursuit of safer osteoporosis treatments, we investigated R25CPTH, a PTH variant wherein the native arginine at position 25 is substituted by cysteine. These studies were prompted by our finding of high bone mineral density in a hypoparathyroidism patient with the R25C homozygous mutation, and we explored its effects on PTH type-1 receptor (PTH1R) signaling in cells and bone metabolism in mice. Our findings indicate that R25CPTH(1–84) forms dimers both intracellularly and extracellularly, and the synthetic dimeric peptide, R25CPTH(1–34), exhibits altered activity in PTH1R-mediated cyclic AMP (cAMP) response. Upon a single injection in mice, dimeric R25CPTH(1–34) induced acute calcemic and phosphaturic responses comparable to PTH(1–34). Furthermore, repeated daily injections increased calvarial bone thickness in intact mice and improved trabecular and cortical bone parameters in ovariectomized (OVX) mice, akin to PTH(1–34). The overall results reveal a capacity of a dimeric PTH peptide ligand to activate the PTH1R in vitro and in vivo as PTH, suggesting a potential path of therapeutic PTH analog development.