Transcription-associated mutagenesis in yeast is directly proportional to the level of gene expression and influenced by the direction of DNA replication

Kim, Nayun; Abdulovic, Amy L.; Gealy, Regan; Lippert, Malcolm J.; Jinks-Robertson, Sue

doi:10.1016/j.dnarep.2007.02.023

Cited by 103 publications

(128 citation statements)

References 44 publications

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“…We found no genome-wide correlation in mutation rate with local GC content in yeast, suggesting that GC contentrelated effects on substitution rate are largely due to postmutation selection or selection-like processes such as biased gene conversion. Next, we looked at highly transcribed genes that are thought to have elevated mutation rates due to transcription-associated mutagenesis (49)(50)(51)(52). In our data, we found no genome-wide correlation in mutation rate with transcription rate.…”

Section: Discussionmentioning

confidence: 35%

Precise estimates of mutation rate and spectrum in yeast

Zhu

Siegal

Hall

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

392

444

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Mutation is the ultimate source of genetic variation. The most direct and unbiased method of studying spontaneous mutations is via mutation accumulation (MA) lines. Until recently, MA experiments were limited by the cost of sequencing and thus provided us with small numbers of mutational events and therefore imprecise estimates of rates and patterns of mutation. We used whole-genome sequencing to identify nearly 1,000 spontaneous mutation events accumulated over ∼311,000 generations in 145 diploid MA lines of the budding yeast Saccharomyces cerevisiae. MA experiments are usually assumed to have negligible levels of selection, but even mild selection will remove strongly deleterious events. We take advantage of such patterns of selection and show that mutation classes such as indels and aneuploidies (especially monosomies) are proportionately much more likely to contribute mutations of large effect. We also provide conservative estimates of indel, aneuploidy, environment-dependent dominant lethal, and recessive lethal mutation rates. To our knowledge, for the first time in yeast MA data, we identified a sufficiently large number of single-nucleotide mutations to measure context-dependent mutation rates and were able to (i) confirm strong AT bias of mutation in yeast driven by high rate of mutations from C/G to T/A and (ii) detect a higher rate of mutation at C/G nucleotides in two specific contexts consistent with cytosine methylation in S. cerevisiae.neighbor-dependent mutation rate | strongly deleterious mutation S pontaneous mutations are the source of all genetic variation in nature. The rate of emergence of new mutations and the relative proportions of advantageous, neutral, and deleterious mutations are key determinants in how species evolve and adapt to new selective challenges. Unfortunately, our knowledge of the properties of spontaneous mutations remains incomplete primarily due to the difficulty of observing large enough numbers of mutational events in an unbiased way.Analyzing patterns of divergence in nonfunctional sequences is a statistically powerful method used to study relative rates of different mutation classes. This method is applicable to most organisms and now can generally be carried out on a genomewide scale. However, this approach relies crucially on the assumption that mutations in certain regions, such as pseudogenes or fourfold degenerate codon positions, are not affected by selection and are thus reliable approximations of true mutation rate. It is now becoming apparent that selection or selectionlike processes, such as biased gene conversion, are acting even at these sequences and can substantially bias the observed patterns (1-5).Studies focusing on mutations in reporter genes use a more restrictive method that can be applied only in model organisms. In some cases, such reporter genes can be placed genome-wide and thus provide estimates of genomic variation in mutation rates. However, this approach is limited by the inability to detect mutations without a visible phenotype and thus ...

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Section: Discussionmentioning

confidence: 35%

Precise estimates of mutation rate and spectrum in yeast

Zhu

Siegal

Hall

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

392

444

View full text Add to dashboard Cite

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“…Mutagenesis by g-rays and methylmethane sulfonate is also lowered in rev3 mutants [4,10,13], and the frequency of spontaneous point mutations is reduced by at least half [14][15][16]. Spontaneous mutation in S. cerevisiae is proportional to transcription level at some loci, and this transcription-associated mutagenesis is also Rev3-dependent [17]. These results indicate that the majority of mutagenic bypass events in budding yeast involve pol ζ.…”

Section: Dna Pol ζ In Saccharomyces Cerevisiaementioning

confidence: 73%

DNA polymerase zeta (pol ζ) in higher eukaryotes

et al. 2007

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Most current knowledge about DNA polymerase zeta (pol ζ) comes from studies of the enzyme in the budding yeast Saccharomyces cerevisiae, where pol ζ consists of a complex of the catalytic subunit Rev3 with Rev7, which associates with Rev1. Most spontaneous and induced mutagenesis in yeast is dependent on these gene products, and yeast pol ζ can mediate translesion DNA synthesis past some adducts in DNA templates. Study of the homologous gene products in higher eukaryotes is in a relatively early stage, but additional functions for the eukaryotic proteins are already apparent. Suppression of vertebrate REV3L function not only reduces induced point mutagenesis but also causes larger-scale genome instability by raising the frequency of spontaneous chromosome translocations. Disruption of Rev3L function is tolerated in Drosophila, Arabidopsis, and in vertebrate cell lines under some conditions, but is incompatible with mouse embryonic development. Functions for REV3L and REV7(MAD2B) in higher eukaryotes have been suggested not only in translesion DNA synthesis but also in some forms of homologous recombination, repair of interstrand DNA crosslinks, somatic hypermutation of immunoglobulin genes and cell-cycle control. This review discusses recent developments in these areas.

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“…In Saccharomyces cereviseae by genome wide analysis it was shown that replication fork is paused by RNAP II in highly transcribed genes (Azvolinsky et al 2009). Other studies on yeast showed that genome integrity is compromised by impairment of the replisome during head-on collisions with RNAP II which might promote transcription associated recombination (Kim et al 2007;Prado et al 2005). All these findings relate directly to the mechanisms of overcoming obstacles by the two machineries with major emphasis on the outcome of the replisome in terms of its integrity and stability that clearly is affected depending on the directionality of the collisions.…”

Section: The Effects Of Rnap On Replication and Genome Integritymentioning

confidence: 96%