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Drug resistance in diploid yeast is acquired through dominant alleles, haploinsufficiency, gene duplication and aneuploidy
- Source :
- PLoS Genetics, PLoS Genetics, Vol 17, Iss 9, p e1009800 (2021)
- Publication Year :
- 2021
- Publisher :
- Public Library of Science (PLoS), 2021.
-
Abstract
- Previous studies of adaptation to the glucose analog, 2-deoxyglucose, by Saccharomyces cerevisiae have utilized haploid cells. In this study, diploid cells were used in the hope of identifying the distinct genetic mechanisms used by diploid cells to acquire drug resistance. While haploid cells acquire resistance to 2-deoxyglucose primarily through recessive alleles in specific genes, diploid cells acquire resistance through dominant alleles, haploinsufficiency, gene duplication and aneuploidy. Dominant-acting, missense alleles in all three subunits of yeast AMP-activated protein kinase confer resistance to 2-deoxyglucose. Dominant-acting, nonsense alleles in the REG1 gene, which encodes a negative regulator of AMP-activated protein kinase, confer 2-deoxyglucose resistance through haploinsufficiency. Most of the resistant strains isolated in this study achieved resistance through aneuploidy. Cells with a monosomy of chromosome 4 are resistant to 2-deoxyglucose. While this genetic strategy comes with a severe fitness cost, it has the advantage of being readily reversible when 2-deoxyglucose selection is lifted. Increased expression of the two DOG phosphatase genes on chromosome 8 confers resistance and was achieved through trisomies and tetrasomies of that chromosome. Finally, resistance was also mediated by increased expression of hexose transporters, achieved by duplication of a 117 kb region of chromosome 4 that included the HXT3, HXT6 and HXT7 genes. The frequent use of aneuploidy as a genetic strategy for drug resistance in diploid yeast and human tumors may be in part due to its potential for reversibility when selection pressure shifts.<br />Author summary Yeast and fast-growing human tumor cells share metabolic similarities in that both cells use fermentation of glucose for energy and both are highly sensitive to the glucose analog 2-deoxyglucose. In an earlier study, we examined the genetic mechanism used by haploid yeast cells to acquire resistance to 2-deoxyglucose. Here, we conducted the same genetic selection on diploid cells. Diploid cells use dominant alleles, haploinsufficiency, gene duplication and aneuploidy to achieve drug resistance. The frequent use of aneuploidy as a genetic strategy for drug resistance in diploid yeast and human tumors may be in part due to its potential for reversibility when selection pressure shifts.
- Subjects :
- Cancer Research
Yeast and Fungal Models
Haploinsufficiency
QH426-470
Ploidy
Gene Duplication
Gene duplication
Genetics (clinical)
Genes, Dominant
Genetics
Organic Compounds
Monosaccharides
Eukaryota
Chemistry
Experimental Organism Systems
Physical Sciences
Saccharomyces Cerevisiae
Chromosomes, Fungal
Research Article
Monosomy
Carbohydrates
Deoxyglucose
Biology
Research and Analysis Methods
Saccharomyces
Model Organisms
Drug Resistance, Fungal
medicine
Allele
Molecular Biology
Gene
Alleles
Ecology, Evolution, Behavior and Systematics
Evolutionary Biology
Whole Genome Sequencing
Population Biology
Organic Chemistry
Organisms
Fungi
Chemical Compounds
Biology and Life Sciences
Chromosome
Aneuploidy
medicine.disease
Diploidy
Yeast
Glucose
Chromosome 4
Genetic Loci
Mutation
Animal Studies
Departures from Diploidy
Population Genetics
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- PLOS Genetics
- Accession number :
- edsair.doi.dedup.....0902a76488d641c0990e9edf745329de