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• W1983553246 abstract "Uncovering general principles of genome evolution that are time-invariant 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 single-nucleotide 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 single-nucleotide 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." @default.
• W1983553246 created "2016-06-24" @default.
• W1983553246 creator A5036093562 @default.
• W1983553246 creator A5056494907 @default.
• W1983553246 date "2010-07-06" @default.
• W1983553246 modified "2023-09-27" @default.
• W1983553246 title "A time-invariant principle of genome evolution" @default.
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• W1983553246 doi "https://doi.org/10.1073/pnas.0914454107" @default.
• W1983553246 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2919972" @default.
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• W1983553246 hasPublicationYear "2010" @default.
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