Transcription as a source of genome instability

Kim, Nayun; Jinks-Robertson, Sue

doi:10.1038/nrg3152

Cited by 260 publications

(250 citation statements)

References 124 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: 72%

Precise estimates of mutation rate and spectrum in yeast

Zhu

Siegal

Hall

et al. 2014

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

391

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: 72%

Precise estimates of mutation rate and spectrum in yeast

Zhu

Siegal

Hall

et al. 2014

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

391

444

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“…T:A transversions is higher in late replicated regions of Chr1 and Chr2 (see Figure 5A), a remarkable finding considering that early replicated genes on Chr1 and Chr2 are expressed more, which has been shown to induce G:C . T:A transversions independently of replication (Klapacz and Bhagwat 2002;Kim and Jinks-Robertson 2012;Alexander et al 2013). Thus, we suggest that late replicating DNA is inherently predisposed to increased rates of G:C .…”

Section: Discussionmentioning

confidence: 76%

The Rate and Molecular Spectrum of Spontaneous Mutations in the GC-Rich Multichromosome Genome of Burkholderia cenocepacia

et al. 2015

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Spontaneous mutations are ultimately essential for evolutionary change and are also the root cause of many diseases. However, until recently, both biological and technical barriers have prevented detailed analyses of mutation profiles, constraining our understanding of the mutation process to a few model organisms and leaving major gaps in our understanding of the role of genome content and structure on mutation. Here, we present a genome-wide view of the molecular mutation spectrum in Burkholderia cenocepacia, a clinically relevant pathogen with high %GC content and multiple chromosomes. We find that B. cenocepacia has low genome-wide mutation rates with insertion-deletion mutations biased toward deletions, consistent with the idea that deletion pressure reduces prokaryotic genome sizes. Unlike prior studies of other organisms, mutations in B. cenocepacia are not AT biased, which suggests that at least some genomes with high %GC content experience unusual base-substitution mutation pressure. Importantly, we also observe variation in both the rates and spectra of mutations among chromosomes and elevated G:C . T:A transversions in late-replicating regions. Thus, although some patterns of mutation appear to be highly conserved across cellular life, others vary between species and even between chromosomes of the same species, potentially influencing the evolution of nucleotide composition and genome architecture.KEYWORDS mutation rate; genome evolution; replication timing; mutation spectra A S the ultimate source of genetic variation, mutation is implicit in every aspect of genetics and evolution. However, as a result of the genetic burden imposed by deleterious mutations, remarkably low mutation rates have evolved across all of life, making detection of these rare events technologically challenging and accurate measures of mutation rates and spectra exceedingly difficult (Kibota and Lynch 1996;Lynch and Walsh 1998;Sniegowski et al. 2000;Lynch 2011;Fijalkowska et al. 2012;Zhu et al. 2014). Until recently, most estimates of mutational properties have been derived indirectly using comparative genomics at putatively neutral sites (Graur and Li 2000;Wielgoss et al. 2011) or by extrapolation from small reporter-construct studies (Drake 1991). Both of these methods are subject to potentially significant biases, as many putatively neutral sites are subject to selection and mutation rates can vary substantially among different genomic regions (Lynch 2007).To avoid the potential biases of these earlier methods, pairing classic mutation accumulation (MA) with wholegenome sequencing (WGS) has become the preferred method for obtaining direct measures of mutation rates and spectra (Lynch et al. 2008;Denver et al. 2009;Ossowski et al. 2010;Lee et al. 2012; Sung et al. 2012a,b;Heilbron et al. 2014). Using this strategy, a single clonal ancestor is used to initiate several replicate lineages that are subsequently passaged through repeated single-cell bottlenecks for several thousand generations. The complete genomes of ea...

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“…2B and Table 2; see also below). As this state has high transcriptional potential, it might also host transcription-associated mutagenesis (35). Subtelomeric effects and functional activity here appear to override previously observed associations between substitution rates and some genomic features; contrary to previous reports (8,36,37) The reduction in divergence in the deletion/substitution-warm state vs. hot state may be due to longer distance from the telomeres (median 20.8 Mb vs. 12.4 Mb), lower male recombination rate (median 0.895 cM/Mb vs. 1.148 cM/Mb) and lower GC content (38.3% vs. 45%).…”

Section: Resultsmentioning

confidence: 99%

Segmenting the human genome based on states of neutral genetic divergence

Don¹,

Ananda

Chiaromonte³

et al. 2013

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

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Many studies have demonstrated that divergence levels generated by different mutation types vary and covary across the human genome. To improve our still-incomplete understanding of the mechanistic basis of this phenomenon, we analyze several mutation types simultaneously, anchoring their variation to specific regions of the genome. Using hidden Markov models on insertion, deletion, nucleotide substitution, and microsatellite divergence estimates inferred from human-orangutan alignments of neutrally evolving genomic sequences, we segment the human genome into regions corresponding to different divergence states-each uniquely characterized by specific combinations of divergence levels. We then parsed the mutagenic contributions of various biochemical processes associating divergence states with a broad range of genomic landscape features. We find that high divergence states inhabit guanine-and cytosine (GC)-rich, highly recombining subtelomeric regions; low divergence states cover inner parts of autosomes; chromosome X forms its own state with lowest divergence; and a state of elevated microsatellite mutability is interspersed across the genome. These general trends are mirrored in human diversity data from the 1000 Genomes Project, and departures from them highlight the evolutionary history of primate chromosomes. We also find that genes and noncoding functional marks [annotations from the Encyclopedia of DNA Elements (ENCODE)] are concentrated in high divergence states. Our results provide a powerful tool for biomedical data analysis: segmentations can be used to screen personal genome variants-including those associated with cancer and other diseases-and to improve computational predictions of noncoding functional elements. W hole-genome sequencing studies have demonstrated that divergence estimates for several mutation types (e.g., nucleotide substitutions, insertions, and deletions) vary substantially across the human genome. This phenomenon has been studied at various genomic scales and evolutionary distances (reviewed in ref. 1), and-whereas initially of interest solely to evolutionary biologists-is now entering the purview of main biomedical research. Specifically, human population (e.g., ref.2) and cancer (3, 4) genome resequencing projects have revealed that incidences of single nucleotide polymorphisms (SNPs), insertions and deletions (indels), and copy number variants (CNVs) vary across the genome. Divergence estimates for different mutation types also covary across the genome (5, 6)-e.g., substitution rates increase in regions with high indel rates (7)-suggesting that regional variation is an important and general characteristic of mutations.Variation in divergence is often linked to genomic landscape features such as base composition, replication timing, and recombination rates (1). For instance, nucleotide substitution rates are elevated in late-replicating regions because of an accumulation of single-stranded DNA susceptible to endogenous damage (8) and are affected by chromatin structure (9) and ...

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Transcription as a source of genome instability

Cited by 260 publications

References 124 publications

Precise estimates of mutation rate and spectrum in yeast

Precise estimates of mutation rate and spectrum in yeast

The Rate and Molecular Spectrum of Spontaneous Mutations in the GC-Rich Multichromosome Genome of Burkholderia cenocepacia

Segmenting the human genome based on states of neutral genetic divergence

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