Abstract
Structural variations (SVs) in the human genome originate from different mechanisms related to DNA repair, replication errors, and retrotransposition. Our analyses of 26 927 SVs from the 1000 Genomes Project revealed differential distributions and consequences of SVs of different origin, e.g. deletions from non-allelic homologous recombination (NAHR) are more prone to disrupt chromatin organization while processed pseudogenes can create accessible chromatin. Spontaneous double stranded breaks (DSBs) are the best predictor of enrichment of NAHR deletions in open chromatin. This evidence, along with strong physical interaction of NAHR breakpoints belonging to the same deletion suggests that majority of NAHR deletions are non-meiotic i.e. originate from errors during homology directed repair (HDR) of spontaneous DSBs. In turn, the origin of the spontaneous DSBs is associated with transcription factor binding in accessible chromatin revealing the vulnerability of functional, open chromatin. The chromatin itself is enriched with repeats, particularly fixed Alu elements that provide the homology required to maintain stability via HDR. Through co-localization of fixed Alus and NAHR deletions in open chromatin we hypothesize that old Alu expansion had a stabilizing role on the human genome.
Highlights
Structural variations (SVs) are defined as large DNA variants that are longer than 50 bp [1,2,3]
Aided by the Breakseq tool [2,12], we classified SVs into different categories: non-allelic homologous recombination (NAHR) deletion, non-homologous deletion, single transposable element detected as a deletion (Alu/L1 deletion), deletion with multiple transposable elements, retrotransposon insertion (Alu, L1 and SVA), tandem duplication, and variable number of tandem repeats (Figure 1A and Supplementary Figure S1)
NAHR events likely reflect errors that occurred during directed recombination in meiosis or during homology-directed repair (HDR) of doublestranded breaks (DSBs)
Summary
Structural variations (SVs) are defined as large DNA variants (e.g. insertions, deletions, duplication) that are longer than 50 bp [1,2,3]. Number of events is smaller, these SVs represent a larger number of variable bases among personal genomes than SNVs [4]. To create a circular permutation, a random number from 1 to the length of the human genome was generated and added to the original coordinate of each SV. We obtained a new location for each SV ( shifted from the original locations), with their lengths unchanged from the original. This procedure was repeated 1000 times to generate 1000 sets of circularly permuted SVs. Calculation of any property generated a background distribution from 1000 instances.
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