A time-invariant principle of genome evolution

Abstract

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...

Somatic rearrangements across cancer reveal classes of samples with distinct patterns of DNA breakage and rearrangement-induced hypermutability

“…4B). The relationship between hypermutability and rearrangements was noted previously in various contexts (De and Babu 2010), and we also previously showed it specifically for prostate cancer (Berger et al 2011). Here we demonstrate that this is true across many cancer types.…”

MECHANISMS IN ENDOCRINOLOGY: Gut microbiota in patients with type 2 diabetes mellitus

“…De Filippo et al (43) compared children from Italy consuming a western diet with African children consuming a rural diet and observed substantial differences in gut microbiota between these two groups. The authors hypothesise that the gut microbiota coevolve with the diet consumed, allowing the African children to maximise energy intake from fibres and speculate that the reduced richness in the Italian children could signify that the consumption of a western diet is depriving our microbial gene pool and thus limiting the adaptive potential of our gut microbiota (43). Long-term dietary habits seem to associate with the grouping of gut bacteria into enterotypes (44).…”

Damage-induced localized hypermutability

“…In this second alignment all reads which matched in more than one site in the pre-reference genome were HARs could also reflect increased mutability around meiotic DSBs which can be further enhanced by endogenous damage to ssDNA formed around breaks. Recently, based on analysis of vast amounts of human sequencing data, it was concluded that the increased rates of base substitutions over evolutionary, population and even single tumor or cell line timescales are associated with rearrangement breakpoints, and could thereby be associated with hypermutability of break-associated ssDNA 78 and references therein. Increased frequency of mutations around rearrangement breakpoints was also reported for prostate cancer genomes.…”