Variable Spontaneous Mutation and Loss of Heterozygosity among Heterozygous Genomes in Yeast.
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ABSTRACT:
SUBMITTER: Nguyen DT
PROVIDER: S-EPMC7825102 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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, that is, tracts extending to the end of the chromosome (n = 3168). 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.
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Project description:To obtain a broad perspective of the events leading to spontaneous loss of heterozygosity (LOH), we have characterized the genetic alterations that functionally inactivated the URA3 marker hemizygously or heterozygously situated either on chromosome III or chromosome V in diploid Saccharomyces cerevisiae cells. Analysis of chromosome structure in a large number of LOH clones by pulsed-field gel electrophoresis and PCR showed that chromosome loss, allelic recombination, and chromosome aberration were the major classes of genetic alterations leading to LOH. The frequencies of chromosome loss and chromosome aberration were significantly affected when the marker was located in different chromosomes, suggesting that chromosome-specific elements may affect the processes that led to these alterations. Aberrant-sized chromosomes were detected readily in approximately 8% of LOH events when the URA3 marker was placed in chromosome III. Molecular mechanisms underlying the chromosome aberrations were further investigated by studying the fate of two other genetic markers on chromosome III. Chromosome aberration caused by intrachromosomal rearrangements was predominantly due to a deletion between the MAT and HMR loci that occurred at a frequency of 3.1 x 10(-6). Another type of chromosome aberration, which occurred at a frequency slightly higher than that of the intrachromosomal deletion, appeared to be caused by interchromosomal rearrangement, including unequal crossing over between homologous chromatids and translocation with another chromosome.
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Project description:Hybridization is often considered maladaptive, but sometimes hybrids can invade new ecological niches and adapt to novel or stressful environments better than their parents. The genomic changes that occur following hybridization that facilitate genome resolution and/or adaptation are not well understood. Here, we examine hybrid genome evolution using experimental evolution of de novo interspecific hybrid yeast Saccharomyces cerevisiae × Saccharomyces uvarum and their parentals. We evolved these strains in nutrient-limited conditions for hundreds of generations and sequenced the resulting cultures identifying numerous point mutations, copy number changes, and loss of heterozygosity (LOH) events, including species-biased amplification of nutrient transporters. We focused on a particularly interesting example, in which we saw repeated LOH at the high-affinity phosphate transporter gene PHO84 in both intra- and interspecific hybrids. Using allele replacement methods, we tested the fitness of different alleles in hybrid and S. cerevisiae strain backgrounds and found that the LOH is indeed the result of selection on one allele over the other in both S. cerevisiae and the hybrids. This is an example where hybrid genome resolution is driven by positive selection on existing heterozygosity and demonstrates that even infrequent outcrossing may have lasting impacts on adaptation.
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Project description:CGH arrays for Smukowski Heil, et al MBE 2017. Hybridization is often considered maladaptive, but sometimes hybrids can invade new ecological niches and adapt to novel or stressful environments better than their parents. The genomic changes that occur following hybridization that facilitate genome resolution and/or adaptation are not well understood. Here, we address these questions using experimental evolution of de novo interspecific hybrid yeast Saccharomyces cerevisiae x Saccharomyces uvarum and their parentals. We evolved these strains in nutrient limited conditions for hundreds of generations and sequenced the resulting cultures to identify genomic changes. Analysis of 16 hybrid clones and 16 parental clones identified numerous point mutations, copy number changes, and loss of heterozygosity events, including species biased amplification of nutrient transporters. We focused on a particularly interesting example, in which we saw repeated loss of heterozygosity at the high affinity phosphate transporter gene PHO84 in both intra- and interspecific hybrids. Using allele replacement methods, we tested the fitness of different alleles in hybrid and S. cerevisiae strain backgrounds and found that the loss of heterozygosity is indeed the result of selection on one allele over the other in both S. cerevisiae and the hybrids. This is an example where hybrid genome resolution is driven by positive selection on existing heterozygosity, and demonstrates that even infrequent outcrossing may have lasting impacts on adaptation.
2017-02-21 | GSE95086 | GEO
Project description:Erroneous repair of DNA double-strand breaks by homologous recombination (HR) leads to loss of heterozygosity (LOH). Analysing 22,392 and 74,415 LOH events in 363 glioblastoma and 513 ovarian cancer samples, respectively, and using three different metrics, we report that LOH selectively occurs in early replicating regions; this pattern differs from the trends for point mutations and somatic deletions, which are biased toward late replicating regions. Our results are independent of BRCA1 and BRCA2 mutation status. The LOH events are significantly clustered near RNA polII-bound transcription start sites, consistent with the reports that slow replication near paused RNA polII might initiate HR-mediated repair. The frequency of LOH events is higher in the chromosomes with shorter inter-homolog distance inside the nucleus. We propose that during early replication, HR-mediated rescue of replication near paused RNA polII using homologous chromosomes as template leads to LOH. The difference in the preference for replication timing between different classes of genomic alterations in cancer genomes also provokes a testable hypothesis that replicating cells show changing preference between various DNA repair pathways, which have different levels of efficiency and fidelity, as the replication progresses.
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Project description:The rate and spectrum of spontaneous mutations are critical parameters in basic and applied biology because they dictate the pace and character of genetic variation introduced into populations, which is a prerequisite for evolution. We use a mutation-accumulation approach to estimate mutation parameters from whole-genome sequence data from multiple genotypes from multiple populations of Daphnia magna, an ecological and evolutionary model system. We report extremely high base substitution mutation rates (µ-n,bs = 8.96 × 10-9/bp/generation [95% CI: 6.66-11.97 × 10-9/bp/generation] in the nuclear genome and µ-m,bs = 8.7 × 10-7/bp/generation [95% CI: 4.40-15.12 × 10-7/bp/generation] in the mtDNA), the highest of any eukaryote examined using this approach. Levels of intraspecific variation based on the range of estimates from the nine genotypes collected from three populations (Finland, Germany, and Israel) span 1 and 3 orders of magnitude, respectively, resulting in up to a ∼300-fold difference in rates among genomic partitions within the same lineage. In contrast, mutation spectra exhibit very consistent patterns across genotypes and populations, suggesting the mechanisms underlying the mutational process may be similar, even when the rates at which they occur differ. We discuss the implications of high levels of intraspecific variation in rates, the importance of estimating gene conversion rates using a mutation-accumulation approach, and the interacting factors influencing the evolution of mutation parameters. Our findings deepen our knowledge about mutation and provide both challenges to and support for current theories aimed at explaining the evolution of the mutation rate, as a trait, across taxa.
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Project description:Determining how adaptive possibilities do or do not become evolutionary realities is central to understanding the tempo and mode of evolutionary change. Some of the simplest evolutionary landscapes arise from underdominance at a single locus where the fitness valley consists of only one less-fit genotype. Despite their potential for rapid evolutionary change, few such examples have been investigated. We capitalized on an experimental system in which a significant evolutionary shift, the transition from uni-to-multicellularity, was observed in asexual diploid populations of Saccharomyces cerevisiae experimentally selected for increased settling rates. The multicellular phenotype results from recessive single-locus mutations that undergo loss-of-heterozygosity (LOH) events. By reconstructing the necessary heterozygous intermediate steps, we found that the evolution of multicellularity involves a decrease in size during the first steps. Heterozygous genotypes are 20% smaller in size than genotypes with functional alleles. Nevertheless, populations of heterozygotes give rise to multicellular genotypes more readily than unicellular genotypes with two functional alleles, by rapid LOH events. LOH drives adaptation that may enable rapid evolution in diploid yeast. Together these results show discordance between the phenotypic and genotypic multicellular transition. The evolutionary path to multicellularity, and the adaptive benefits of increased size, requires initial size reductions.
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Project description:Mutation is the ultimate genetic source of evolution and biodiversity, but to what extent the environment impacts mutation rate and spectrum is poorly understood. Past studies discovered mutagenesis induced by antibiotic treatment or starvation, but its relevance and importance to long-term evolution is unclear because these severe stressors typically halt cell growth and/or cause substantial cell deaths. Here, we quantify the mutation rate and spectrum in Saccharomyces cerevisiae by whole-genome sequencing following mutation accumulation in each of seven environments with relatively rapid cell growths and minimal cell deaths. We find the point mutation rate per generation to differ by 3.6-fold among the seven environments, generally increasing in environments with slower cell growths. This trend renders the mutation rate per year more constant than that per generation across environments, which has implications for neutral evolution and the molecular clock. Additionally, we find substantial among-environment variations in mutation spectrum, such as the transition to transversion ratio and AT mutational bias. Other main mutation types, including small insertion or deletion, segmental duplication or deletion, and chromosome gain or loss also tend to occur more frequently in environments where yeast grows more slowly. In contrast to these findings from the nuclear genome, the yeast mitochondrial mutation rate rises with the growth rate, consistent with the metabolic rate hypothesis. Together, these observations indicate that environmental changes, which are ubiquitous in nature, influence not only natural selection, but also the amount and type of mutations available to selection, and suggest that ignoring the latter impact, as is currently practiced, may mislead evolutionary inferences.
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Project description:The yeast petite mutant was first discovered in the yeast Saccharomyces cerevisiae, which shows growth stress due to defects in genes encoding the respiratory chain. In a previous study, we described that deletion of the nuclear-encoded gene MRPL25 leads to mitochondrial genome (mtDNA) loss and the petite phenotype, which can be rescued by acquiring ATP3 mutations. The mrpl25Δ strain showed an elevated SNV (single nucleotide variant) rate, suggesting genome instability occurred during the crisis of mtDNA loss. However, the genome-wide mutation landscape and mutational signatures of mitochondrial dysfunction are unknown. In this study we profiled the mutation spectra in yeast strains with the genotype combination of MRPL25 and ATP3 in their wildtype and mutated status, along with the wildtype and cytoplasmic petite rho0 strains as controls. In addition to the previously described elevated SNV rate, we found the INDEL (insertion/deletion) rate also increased in the mrpl25Δ strain, reinforcing the occurrence of genome instability. Notably, although both are petites, the mrpl25Δ and rho0 strains exhibited different INDEL rates and transition/transversion ratios, suggesting differences in the mutational signatures underlying these two types of petites. Interestingly, the petite-related mutagenesis effect disappeared when ATP3 suppressor mutations were acquired, suggesting a cost-effective mechanism for restoring both fitness and genome stability. Taken together, we present an unbiased genome-wide characterization of the mutation rates and spectra of yeast strains with respiratory deficiency, which provides valuable insights into the impact of respiratory deficiency on genome instability.
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Project description:The rate at which new mutations arise in the genome is a key factor in the evolution and adaptation of species. Here we describe the rate and spectrum of spontaneous mutations for the fission yeast Schizosaccharomyces pombe, a key model organism with many similarities to higher eukaryotes. We undertook an ∼1700-generation mutation accumulation (MA) experiment with a haploid S. pombe, generating 422 single-base substitutions and 119 insertion-deletion mutations (indels) across the 96 replicates. This equates to a base-substitution mutation rate of 2.00 × 10(-10) mutations per site per generation, similar to that reported for the distantly related budding yeast Saccharomyces cerevisiae. However, these two yeast species differ dramatically in their spectrum of base substitutions, the types of indels (S. pombe is more prone to insertions), and the pattern of selection required to counteract a strong AT-biased mutation rate. Overall, our results indicate that GC-biased gene conversion does not play a major role in shaping the nucleotide composition of the S. pombe genome and suggest that the mechanisms of DNA maintenance may have diverged significantly between fission and budding yeasts. Unexpectedly, CpG sites appear to be excessively liable to mutation in both species despite the likely absence of DNA methylation.
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