Abstract
BackgroundThe Intergenic Breakage Model, which is the current model of structural genome evolution, considers that evolutionary rearrangement breakages happen with a uniform propensity along the genome but are selected against in genes, their regulatory regions and in-between. However, a growing body of evidence shows that there exists regions along mammalian genomes that present a high susceptibility to breakage. We reconsidered this question taking advantage of a recently published methodology for the precise detection of rearrangement breakpoints based on pairwise genome comparisons.ResultsWe applied this methodology between the genome of human and those of five sequenced eutherian mammals which allowed us to delineate evolutionary breakpoint regions along the human genome with a finer resolution (median size 26.6 kb) than obtained before. We investigated the distribution of these breakpoints with respect to genome organisation into domains of different activity. In agreement with the Intergenic Breakage Model, we observed that breakpoints are under-represented in genes. Surprisingly however, the density of breakpoints in small intergenes (1 per Mb) appears significantly higher than in gene deserts (0.1 per Mb).More generally, we found a heterogeneous distribution of breakpoints that follows the organisation of the genome into isochores (breakpoints are more frequent in GC-rich regions). We then discuss the hypothesis that regions with an enhanced susceptibility to breakage correspond to regions of high transcriptional activity and replication initiation.ConclusionWe propose a model to describe the heterogeneous distribution of evolutionary breakpoints along human chromosomes that combines natural selection and a mutational bias linked to local open chromatin state.
Highlights
The Intergenic Breakage Model, which is the current model of structural genome evolution, considers that evolutionary rearrangement breakages happen with a uniform propensity along the genome but are selected against in genes, their regulatory regions and in-between
Delineating mammalian evolutionary Breakpoint Regions A Breakpoint Region (BPR) on the human genome is defined as a region that underwent at least one large chromosomal structural change, or is orthologous to such a region in a non-human lineage
Mapping the whole set of BPRs from all lineages on the human genome, each group of intersecting BPRs was replaced by the intersection of all BPRs in the group when they could be explained by a unique rearrangement event, and by the union of all BPRs otherwise
Summary
The Intergenic Breakage Model, which is the current model of structural genome evolution, considers that evolutionary rearrangement breakages happen with a uniform propensity along the genome but are selected against in genes, their regulatory regions and in-between. The correlation between the localisations of breakpoints in these lineages and the distribution of several other genomic features such as segmental duplications [25,26], various repeated elements [27], experimental fragile sites [28,29], high GC content and CpG island density [24] provided further evidence suggesting that the distribution of breakpoint regions should be analysed in the context of a genome organisation In this regard, Peng et al [19] and Becker & Lenhard [5] proposed the Intergenic Breakage Model (IBM), where rearrangement breakages happen uniformly at random on the genome but are deleterious in genes, their regulatory regions, and in-between. If there seems to be strong evidence for the existence of some particular breakage hotspots, it remains unclear to which extent the model of evolution may deviate from the RBM, and what the alternative model would be
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