Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes

Bacolla, Albino; Zhu, Xiao; Chen, Hanning; Howells, Katy; Cooper, David Neil; Vásquez, Karen M.

doi:10.1093/nar/gkv364

Cited by 19 publications

(21 citation statements)

References 65 publications

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“…Likewise, we have previously reported that in melanoma guanines at G RA motifs undergo ~twofold more frequent substitutions than guanines at G R(C|T|G) motifs (Bacolla et al 2013 ). Finally, SBSs along mononucleotide repeats are often heavily influenced by long-range interactions caused by charge transfer mechanisms along the DNA (Bacolla et al 2015 ).…”

Section: Introductionmentioning

confidence: 99%

The somatic autosomal mutation matrix in cancer genomes

et al. 2015

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DNA damage in somatic cells originates from both environmental and endogenous sources, giving rise to mutations through multiple mechanisms. When these mutations affect the function of critical genes, cancer may ensue. Although identifying genomic subsets of mutated genes may inform therapeutic options, a systematic survey of tumor mutational spectra is required to improve our understanding of the underlying mechanisms of mutagenesis involved in cancer etiology. Recent studies have presented genome-wide sets of somatic mutations as a 96-element vector, a procedure that only captures the immediate neighbors of the mutated nucleotide. Herein, we present a 32 × 12 mutation matrix that captures the nucleotide pattern two nucleotides upstream and downstream of the mutation. A somatic autosomal mutation matrix (SAMM) was constructed from tumor-specific mutations derived from each of 909 individual cancer genomes harboring a total of 10,681,843 single-base substitutions. In addition, mechanistic template mutation matrices (MTMMs) representing oxidative DNA damage, ultraviolet-induced DNA damage, 5mCpG deamination, and APOBEC-mediated cytosine mutation, are presented. MTMMs were mapped to the individual tumor SAMMs to determine the maximum contribution of each mutational mechanism to the overall mutation pattern. A Manhattan distance across all SAMM elements between any two tumor genomes was used to determine their relative distance. Employing this metric, 89.5 % of all tumor genomes were found to have a nearest neighbor from the same tissue of origin. When a distance-dependent 6-nearest neighbor classifier was used, 86.9 % of all SAMMs were assigned to the correct tissue of origin. Thus, although tumors from different tissues may have similar mutation patterns, their SAMMs often display signatures that are characteristic of specific tissues.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-015-1566-1) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The somatic autosomal mutation matrix in cancer genomes

et al. 2015

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“…S2), no significant homologies were discernable. Next, we examined the occurrence of static bending near (within ±100 bp) the duplication junctions, which would suggest local hypermutability and increased DNA melting . DNA bending was prominent around two junctions in cases 3/6 and 4 (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

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et al. 2020

Movement Disorders

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Background SNCA multiplication is a genomic cause of familial PD, showing dosage‐dependent toxicity. Until now, nonallelic homologous recombination was suggested as the mechanism of SNCA duplication, based on various types of repetitive elements found in the spanning region of the breakpoints. However, the sequence at the breakpoint was analyzed only for 1 case. Objectives We have analyzed the breakpoint sequences of 6 patients with PD who had duplicated SNCA using whole‐genome sequencing data to elucidate the mechanism of SNCA duplication. Methods Six patient samples with SNCA duplication underwent whole‐genome sequencing. The duplicated regions were defined with nucleotide‐resolution breakpoints, which were confirmed by junction polymerase chain reaction and Sanger sequencing. The search for potential non‐B DNA‐forming sequences and stem‐loop structure predictions was conducted. Results Duplicated regions ranged from the smallest region of 718.3 kb to the largest one of 4,162 kb. Repetitive elements were found at 8 of the 12 breakpoint sequences on each side of the junction, but none of the pairs shared overt homologies. Five of these six junctions had microhomologies (2–4 bp) at the breakpoint, and a short stretch of sequences was inserted in 3 cases. All except one junction were located within or next to stem‐loop structures. Conclusion Our study has determined that homologous recombination mechanisms involving repetitive elements are not the main cause of the duplication of SNCA. The presence of microhomology at the junctions and their position within stem‐loop structures suggest that replication‐based rearrangements may be a common mechanism for SNCA amplification. © 2020 International Parkinson and Movement Disorder Society

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“…Direct repeats, and in particular A-tracts, displayed the strongest association with deletion breakpoints. A-tracts possess unique structural determinants, including the generation of static bending ( 89 – 91 ), a high degree of stiffness imparted by water coordination along the minor groove ( 92 , 93 ), directional narrowing of the minor groove ( 94 , 95 ), and flexible junctions, which appear to have been responsible for generating preferred sites for short (<200 bp) indels in the human population ( 95 ). A-tracts may form slipped structures as a result of misalignment during replication or transcription, as well as triplex DNA.…”

Section: Discussionmentioning

confidence: 99%

Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences

et al. 2016

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Gross chromosomal rearrangements (including translocations, deletions, insertions and duplications) are a hallmark of cancer genomes and often create oncogenic fusion genes. An obligate step in the generation of such gross rearrangements is the formation of DNA double-strand breaks (DSBs). Since the genomic distribution of rearrangement breakpoints is non-random, intrinsic cellular factors may predispose certain genomic regions to breakage. Notably, certain DNA sequences with the potential to fold into secondary structures [potential non-B DNA structures (PONDS); e.g. triplexes, quadruplexes, hairpin/cruciforms, Z-DNA and single-stranded looped-out structures with implications in DNA replication and transcription] can stimulate the formation of DNA DSBs. Here, we tested the postulate that these DNA sequences might be found at, or in close proximity to, rearrangement breakpoints. By analyzing the distribution of PONDS-forming sequences within ±500 bases of 19 947 translocation and 46 365 sequence-characterized deletion breakpoints in cancer genomes, we find significant association between PONDS-forming repeats and cancer breakpoints. Specifically, (AT)n, (GAA)n and (GAAA)n constitute the most frequent repeats at translocation breakpoints, whereas A-tracts occur preferentially at deletion breakpoints. Translocation breakpoints near PONDS-forming repeats also recur in different individuals and patient tumor samples. Hence, PONDS-forming sequences represent an intrinsic risk factor for genomic rearrangements in cancer genomes.

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Local DNA dynamics shape mutational patterns of mononucleotide repeats in human genomes

Cited by 19 publications

References 65 publications

The somatic autosomal mutation matrix in cancer genomes

The somatic autosomal mutation matrix in cancer genomes

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Translocation and deletion breakpoints in cancer genomes are associated with potential non-B DNA-forming sequences

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