scholarly journals A genome-wide screen identifies genes that suppress the accumulation of spontaneous mutations in young and aged yeast cells

2018 ◽  
Author(s):  
Daniele Novarina ◽  
Georges Janssens ◽  
Koen Bokern ◽  
Tim Schut ◽  
Noor van Oerle ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Genome Stability ◽  
Genome Instability ◽  
Spontaneous Mutation ◽  
Yeast Cells ◽  
Spontaneous Mutations ◽  
Genome Maintenance ◽  
Spontaneous Mutation Rate ◽  
Genome Wide ◽  
A Genome

To ensure proper transmission of genetic information, cells need to preserve and faithfully replicate their genome, and failure to do so leads to genome instability, a hallmark of both cancer and aging. Defects in genes involved in guarding genome stability cause several human progeroid syndromes, and an age-dependent accumulation of mutations has been observed in different organisms, from yeast to mammals. However, it is unclear if the spontaneous mutation rate changes during aging, and if specific pathways are important for genome maintenance in old cells. We developed a high-throughput replica-pinning approach to screen for genes important to suppress the accumulation of spontaneous mutations during yeast replicative aging. We found 13 known mutation suppression genes, and 31 genes that had no previous link to spontaneous mutagenesis, and all acted independently of age. Importantly, we identified PEX19, encoding an evolutionarily conserved peroxisome biogenesis factor, as an age-specific mutation suppression gene. While wild-type and pex19Δ young cells have similar spontaneous mutation rates, aged cells lacking PEX19 display an elevated mutation rate. This finding suggests that functional peroxisomes are important to preserve genome integrity specifically in old cells, possibly due to their role in reactive oxygen species metabolism.

scholarly journals Low Spontaneous Mutation Rate and Pleistocene Radiation of Pea Aphids

2020 ◽  
Vol 37 (7) ◽  
pp. 2045-2051
Author(s):  
Varvara Fazalova ◽  
Bruno Nevado
Keyword(s):  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Pea Aphid ◽  
Spontaneous Mutation Rate ◽  
Host Races ◽  
Climatic Oscillations ◽  
Genome Wide ◽  
A Genome ◽  
Pea Aphids ◽  
Aphid Host

Abstract Accurate estimates of divergence times are essential to understand the evolutionary history of species. It allows linking evolutionary histories of the diverging lineages with past geological, climatic, and other changes in environment and shed light on the processes involved in speciation. The pea aphid radiation includes multiple host races adapted to different legume host plants. It is thought that diversification in this system occurred very recently, over the past 8,000–16,000 years. This young age estimate was used to link diversification in pea aphids to the onset of human agriculture, and led to the establishment of the pea aphid radiation as a model system in the study of speciation with gene flow. Here, we re-examine the age of the pea aphid radiation, by combining a mutation accumulation experiment with a genome-wide estimate of divergence between distantly related pea aphid host races. We estimate the spontaneous mutation rate for pea aphids as 2.7×10-10 per haploid genome per parthenogenic generation. Using this estimate of mutation rate and the genome-wide genetic differentiation observed between pea aphid host races, we show that the pea aphid radiation is much more ancient than assumed previously, predating Neolithic agriculture by several hundreds of thousands of years. Our results rule out human agriculture as the driver of diversification of the pea aphid radiation, and call for re-assessment of the role of allopatric isolation during Pleistocene climatic oscillations in divergence of the pea aphid complex.

scholarly journals Low spontaneous mutation rate and Pleistocene radiation of pea aphids

2019 ◽  
Author(s):  
Varvara Fazalova ◽  
Bruno Nevado
Keyword(s):  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Pea Aphid ◽  
Spontaneous Mutation Rate ◽  
Host Races ◽  
Climatic Oscillations ◽  
Genome Wide ◽  
A Genome ◽  
Pea Aphids ◽  
Aphid Host

AbstractAccurate estimates of divergence times are essential to understand the evolutionary history of species. It allows linking evolutionary histories of the diverging lineages with past geological, climatic and other changes in environment and shed light on the processes involved in speciation. The pea aphid radiation includes multiple host races adapted to different legume host plants. It is thought that diversification in this system occurred very recently, over the past 8,000 to 16,000 years. This young age estimate was used to link diversification in pea aphids to the onset of human agriculture, and lead to the establishment of the pea aphid radiation as a model system in the study of speciation with gene flow. Here, we re-examine the age of the pea aphid radiation, by combining a mutation accumulation experiment with a genome-wide estimate of divergence between distantly related pea aphid host races. We estimate the spontaneous mutation rate for pea aphids as 2.27 × 10−10 per haploid genome per parthenogenic generation. Using this estimate of mutation rate and the genome-wide genetic differentiation observed between pea aphid host races, we show that the pea aphid radiation is much more ancient than assumed previously, predating Neolithic agriculture by several hundreds of thousands of years. Our results rule out human agriculture as the driver of diversification of the pea aphid radiation, and call for re-assessment of the role of allopatric isolation during Pleistocene climatic oscillations in divergence of the pea aphid complex.

scholarly journals Low genetic variation is associated with low mutation rate in the giant duckweed

2018 ◽  
Author(s):  
Shuqing Xu ◽  
Jessica Stapley ◽  
Saskia Gablenz ◽  
Justin Boyer ◽  
Klaus J. Appenroth ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Population Size ◽  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Effective Population ◽  
Spontaneous Mutation Rate ◽  
Low Genetic Diversity ◽  
Genome Wide ◽  
Census Population Size

AbstractMutation rate and effective population size (Ne) jointly determine intraspecific genetic diversity, but the role of mutation rate is often ignored. We investigate genetic diversity, spontaneous mutation rate andNein the giant duckweed (Spirodela polyrhiza). Despite its large census population size, whole-genome sequencing of 68 globally sampled individuals revealed extremely low within-species genetic diversity. Assessed under natural conditions, the genome-wide spontaneous mutation rate is at least seven times lower than estimates made for other multicellular eukaryotes, whereasNeis large. These results demonstrate that low genetic diversity can be associated with large-Nespecies, where selection can reduce mutation rates to very low levels, and accurate estimates of mutation rate can help to explain seemingly counterintuitive patterns of genome-wide variation.One Sentence SummaryThe low-down on a tiny plant: extremely low genetic diversity in an aquatic plant is associated with its exceptionally low mutation rate.

scholarly journals Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

2021 ◽  
Author(s):  
Marit Geijer ◽  
Di Zhou ◽  
Kathiresan Selvam ◽  
Barbara Steurer ◽  
Bastiaan Evers ◽  
...  
Keyword(s):  
Dna Damage ◽  
Rna Polymerase Ii ◽  
Genome Stability ◽  
Genome Instability ◽  
Excision Repair ◽  
Elongation Factor ◽  
Transcription Inhibition ◽  
Genome Wide ◽  
A Genome ◽  
Nucleotide Excision

Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA Polymerase II (Pol II), causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions (TBLs). However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR/cas9 screen, we identified elongation factor ELOF1 as an important new factor in the transcription stress response upon DNA damage. We show that ELOF1 has an evolutionary conserved role in Transcription-Coupled Nucleotide Excision Repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair TBLs and resume transcription. Additionally, ELOF1 modulates transcription to protect cells from transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage by two distinct mechanisms.

scholarly journals A genome‐wide screen identifies genes that suppress the accumulation of spontaneous mutations in young and aged yeast cells

Aging Cell ◽  
2019 ◽  
Vol 19 (2) ◽  
Author(s):  
Daniele Novarina ◽  
Georges E. Janssens ◽  
Koen Bokern ◽  
Tim Schut ◽  
Noor C. Oerle ◽  
...  
Keyword(s):  
Yeast Cells ◽  
Spontaneous Mutations ◽  
Genome Wide ◽  
A Genome

scholarly journals Inactivation of DNA Mismatch Repair by Increased Expression of Yeast MLH1

2001 ◽  
Vol 21 (3) ◽  
pp. 940-951 ◽  
Author(s):  
Polina V. Shcherbakova ◽  
Mark C. Hall ◽  
Marc S. Lewis ◽  
Samuel E. Bennett ◽  
Karla J. Martin ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Mutation Rate ◽  
Analytical Ultracentrifugation ◽  
Dna Mismatch Repair ◽  
Genome Instability ◽  
Spontaneous Mutation ◽  
Moderate Increase ◽  
Spontaneous Mutation Rate ◽  
Dna Mismatch ◽  
Mutator Effect

ABSTRACT Inactivation of DNA mismatch repair by mutation or by transcriptional silencing of the MLH1 gene results in genome instability and cancer predisposition. We recently found (P. V. Shcherbakova and T. A. Kunkel, Mol. Cell. Biol. 19:3177–3183, 1999) that an elevated spontaneous mutation rate can also result from increased expression of yeast MLH1. Here we investigate the mechanism of this mutator effect. Hybridization of poly(A)+ mRNA to DNA microarrays containing 96.4% of yeast open reading frames revealed that MLH1overexpression did not induce changes in expression of other genes involved in DNA replication or repair. MLH1overexpression strongly enhanced spontaneous mutagenesis in yeast strains with defects in the 3′→5′ exonuclease activity of replicative DNA polymerases δ and ɛ but did not enhance the mutation rate in strains with deletions of MSH2, MLH1, orPMS1. This suggests that overexpression ofMLH1 inactivates mismatch repair of replication errors. Overexpression of the PMS1 gene alone caused a moderate increase in the mutation rate and strongly suppressed the mutator effect caused by MLH1 overexpression. The mutator effect was also reduced by a missense mutation in the MLH1 gene that disrupted Mlh1p-Pms1p interaction. Analytical ultracentrifugation experiments showed that purified Mlh1p forms a homodimer in solution, albeit with a K d of 3.14 μM, 36-fold higher than that for Mlh1p-Pms1p heterodimerization. These observations suggest that the mismatch repair defect in cells overexpressingMLH1 results from an imbalance in the levels of Mlh1p and Pms1p and that this imbalance might lead to formation of nonfunctional mismatch repair complexes containing Mlh1p homodimers.

scholarly journals Genome-wide haploinsufficiency screen reveals a novel role for γ-TuSC in spindle organization and genome stability

2013 ◽  
Vol 24 (17) ◽  
pp. 2753-2763 ◽  
Author(s):  
John S. Choy ◽  
Eileen O'Toole ◽  
Breanna M. Schuster ◽  
Matthew J. Crisp ◽  
Tatiana S. Karpova ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Genome Stability ◽  
Genome Instability ◽  
Electron Tomography ◽  
Gene Dosage ◽  
Microtubule Assembly ◽  
Chromosome Loss ◽  
Genome Wide ◽  
A Genome ◽  
And Function

How subunit dosage contributes to the assembly and function of multimeric complexes is an important question with implications in understanding biochemical, evolutionary, and disease mechanisms. Toward identifying pathways that are susceptible to decreased gene dosage, we performed a genome-wide screen for haploinsufficient (HI) genes that guard against genome instability in Saccharomyces cerevisiae. This led to the identification of all three genes (SPC97, SPC98, and TUB4) encoding the evolutionarily conserved γ-tubulin small complex (γ-TuSC), which nucleates microtubule assembly. We found that hemizygous γ-TuSC mutants exhibit higher rates of chromosome loss and increases in anaphase spindle length and elongation velocities. Fluorescence microscopy, fluorescence recovery after photobleaching, electron tomography, and model convolution simulation of spc98/+ mutants revealed improper regulation of interpolar (iMT) and kinetochore (kMT) microtubules in anaphase. The underlying cause is likely due to reduced levels of Tub4, as overexpression of TUB4 suppressed the spindle and chromosome segregation defects in spc98/+ mutants. We propose that γ-TuSC is crucial for balanced assembly between iMTs and kMTs for spindle organization and accurate chromosome segregation. Taken together, the results show how gene dosage studies provide critical insights into the assembly and function of multisubunit complexes that may not be revealed by using traditional studies with haploid gene deletion or conditional alleles.

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