Abstract
BackgroundThe detailed study of breakpoints associated with copy number variants (CNVs) can elucidate the mutational mechanisms that generate them and the comparison of breakpoints across species can highlight differences in genomic architecture that may lead to lineage-specific differences in patterns of CNVs. Here, we provide a detailed analysis of Drosophila CNV breakpoints and contrast it with similar analyses recently carried out for the human genome.ResultsBy applying split-read methods to a total of 10x coverage of 454 shotgun sequence across nine lines of D. melanogaster and by re-examining a previously published dataset of CNVs detected using tiling arrays, we identified the precise breakpoints of more than 600 insertions, deletions, and duplications. Contrasting these CNVs with those found in humans showed that in both taxa CNV breakpoints fall into three classes: blunt breakpoints; simple breakpoints associated with microhomology; and breakpoints with additional nucleotides inserted/deleted and no microhomology. In both taxa CNV breakpoints are enriched with non-B DNA sequence structures, which may impair DNA replication and/or repair. However, in contrast to human genomes, non-allelic homologous-recombination (NAHR) plays a negligible role in CNV formation in Drosophila. In flies, non-homologous repair mechanisms are responsible for simple, recurrent, and complex CNVs, including insertions of de novo sequence as large as 60 bp.ConclusionsHumans and Drosophila differ considerably in the importance of homology-based mechanisms for the formation of CNVs, likely as a consequence of the differences in the abundance and distribution of both segmental duplications and transposable elements between the two genomes.
Highlights
The detailed study of breakpoints associated with copy number variants (CNVs) can elucidate the mutational mechanisms that generate them and the comparison of breakpoints across species can highlight differences in genomic architecture that may lead to lineage-specific differences in patterns of CNVs
While transposable elements comprise approximately 50% of the human genome, they only correspond to 20% of the fly genome, where they are mostly restricted to pericentromeric regions and the fourth chromosome [27]. (The same holds true for segmental duplications [26].) Our goal was to take advantage of the differences in genome architecture between flies and humans in order to dissect the contribution of different genomic features to the formation of CNVs
We employ a different approach to detect CNVs based on split-read mapping that is capable of detecting CNVs with precise breakpoint resolution
Summary
The detailed study of breakpoints associated with copy number variants (CNVs) can elucidate the mutational mechanisms that generate them and the comparison of breakpoints across species can highlight differences in genomic architecture that may lead to lineage-specific differences in patterns of CNVs. In addition to selection, mutational processes impact the genomic distribution of CNVs [7,8,9,10]. The distribution of these variants is not uniform across the genome; instead, CNVs accumulate in discrete regions as a consequence of local increases in the mutation rate. Current efforts aimed at the identification of the causal CNVs of both deleterious and adaptive phenotypes could be greatly enhanced by a better understanding of the mutational processes underlying the formation of CNVs and the genomic features associated with elevated mutation rates
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