Ride the wavelet: A multiscale analysis of genomic contexts flanking small insertions and deletions

Kvikstad, Erika; Chiaromonte, Francesca; Makova, Kateryna D.

doi:10.1101/gr.088922.108

Cited by 27 publications

(26 citation statements)

References 58 publications

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“…Consistent with this view, Ball et al [2005] reported strong similarities between microinsertions and microdeletions in terms of the sequence characteristics and repetitivity of the flanking DNA sequence, the overrepresentation of motifs known to play a role in recombination, mutation, cleavage, and rearrangement, and the likely involvement of various types of repetitive sequence element in the mutational mechanism. Similar conclusions have been drawn from studies of microdeletions and microinsertions identified in an evolutionary context [Zhang and Gerstein, 2003; Taylor et al, 2004; Messer and Arndt, 2007; Tanay and Siggia, 2008; Kvikstad et al, 2009; Sjödin et al, 2010]. Taken together, these results are consistent with the view that microdeletions and microinsertions are generated by very similar sequence-directed molecular mechanisms.…”

Section: Microdeletions Microinsertions and Indelssupporting

confidence: 87%

On the sequence-directed nature of human gene mutation: The role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease

et al. 2011

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Different types of human gene mutation may vary in size, from structural variants (SVs) to single base-pair substitutions, but what they all have in common is that their nature, size and location are often determined either by specific characteristics of the local DNA sequence environment or by higher-order features of the genomic architecture. The human genome is now recognized to contain ‘pervasive architectural flaws’ in that certain DNA sequences are inherently mutation-prone by virtue of their base composition, sequence repetitivity and/or epigenetic modification. Here we explore how the nature, location and frequency of different types of mutation causing inherited disease are shaped in large part, and often in remarkably predictable ways, by the local DNA sequence environment. The mutability of a given gene or genomic region may also be influenced indirectly by a variety of non-canonical (non-B) secondary structures whose formation is facilitated by the underlying DNA sequence. Since these non-B DNA structures can interfere with subsequent DNA replication and repair, and may serve to increase mutation frequencies in generalized fashion (i.e. both in the context of subtle mutations and SVs), they have the potential to serve as a unifying concept in studies of mutational mechanisms underlying human inherited disease.

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Section: Microdeletions Microinsertions and Indelssupporting

confidence: 87%

On the sequence-directed nature of human gene mutation: The role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease

et al. 2011

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“…Recent studies on the mechanisms of insertion, deletion, DNA repair, and replication (16,(34)(35)(36)(37)(38)(39) provide possible explanations for our observations. The generation of structural alteration (e.g., insertion or deletion) requires single-stranded and double-stranded breaks.…”

Section: Resultsmentioning

confidence: 62%

A time-invariant principle of genome evolution

Babu

2010

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

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Uncovering general principles of genome evolution that are timeinvariant and that operate in germ and somatic cells has implications for genome-wide association studies (GWAS), gene therapy, and disease genomics. Here we investigate the relationship between structural alterations (e.g., insertions and deletions) and singlenucleotide substitutions by comparing the following genomes that diverged at different times across germ-and somatic-cell lineages: (i) the reference human and chimpanzee genome (in million years), (ii) the reference human and personal genomes (in tens of thousands of years), and (iii) structurally altered regions in cancer and genetically engineered cells (in days). At the species level, genes with structural alteration in nearby regions show increased singlenucleotide changes and tend to evolve faster. In personal genomes, the single-nucleotide substitution rate is higher near sites of structural alteration and decreases with increasing distance. In human cancer cell populations and in cells genetically engineered using zinc-finger nucleases, single-nucleotide changes occur frequently near sites of structural alterations. We present evidence that structural alteration induces single-nucleotide changes in nearby regions and discuss possible molecular mechanisms that contribute to this phenomenon. We propose that the low fidelity of nonreplicative error-prone repair polymerases, which are used during insertion or deletion, result in break-repair-induced single-nucleotide mutations in the vicinity of structural alteration. Thus, in the mutational landscape, structural alterations are linked to single-nucleotide changes across different time scales in both somatic-and germ-cell lineages. We discuss implications for genome evolution, GWAS, disease genomics, and gene therapy and emphasize the need to investigate both types of mutations within a single framework.single-nucleotide substitution | structural alteration | mutation | DNA repair U nderstanding how mutations contribute to genetic variation in a population and drive the evolution of new species is a fundamental problem in the postgenomic era. In recent years, intermediate-scale mutations (e.g., insertion, deletion, translocation, and inversion) that result in structural variation have gained considerable attention (1). Although the genome-wide impact of mutations of different sizes (e.g., single-nucleotide changes and structural alterations such as insertion or deletion of genetic material) has been investigated separately, it has long been speculated (2, 3), and increasing evidence suggests, that mutations of different sizes are correlated in prokaryotes and eukaryotes (4-13). Although these studies have provided evidence for such a relationship, how this phenomenon affects functional elements in the genome has not been systematically investigated in humans. Specifically, the implications for sequence (protein and nucleic acid) evolution and the nature of such dependence in genomes that "diverged" at different time scales, i.e., at the tim...

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“…Although we observed more aneuploidy and small indel events than ever before, there were too few total events to perform the analyses possible in SNMs. Specifically, small indels showed a potential bias toward deletions and net loss of genic material, but it was impossible to clarify whether this bias was due to selection against strongly deleterious mutations or a true bias in the mechanisms that generate indels (59)(60)(61)(62)(63)(64). Lastly, measuring the individual fitness effects of each new mutation is also critical (65).…”

Section: Discussionmentioning

confidence: 99%

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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Ride the wavelet: A multiscale analysis of genomic contexts flanking small insertions and deletions

Cited by 27 publications

References 58 publications

On the sequence-directed nature of human gene mutation: The role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease

On the sequence-directed nature of human gene mutation: The role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease

A time-invariant principle of genome evolution

Precise estimates of mutation rate and spectrum in yeast

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