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. 2019 Apr 8;47(6):2766-2777.
doi: 10.1093/nar/gkz103.

Chromatin Organization Modulates the Origin of Heritable Structural Variations in Human Genome

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Free PMC article

Chromatin Organization Modulates the Origin of Heritable Structural Variations in Human Genome

Tanmoy Roychowdhury et al. Nucleic Acids Res. .
Free PMC article

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.

Figures

Figure 1.
Figure 1.
Biased distribution of different SV classes. (A) Clustering of SV classes based on their enrichments by Z-score in 5 compartments, identified from Hi-C studies. Two major clusters can be observed. (B) Normalized distribution of replication timing for different Alus. Alu insertion and deletions were further classified as rare or common (minor allele frequency threshold, 1%). (C) Positive and negative Z-scores mean enrichment and depletion, respectively, of SVs across topologically associated domain (TAD) boundary or loop anchor. (D) Clustering of SV classes and functional states based on distribution of breakpoints in the states. The states were inferred from chromHMM segmentation of histone marks. Descriptions of each state are provided in supplementary Table S1. Dashed lines show three categories of states by enrichment with SV breakpoints. * represents adjusted P-value < 0.05 (Z-test with Bonferroni correction). Abbreviations: Variable number of tandem repeats (VNTR), Tandem duplications (TDUP), Deletions with multiple transposable elements (MTE-del).
Figure 2.
Figure 2.
(A) Fold enrichment (Log2 scale) of real NAHR breakpoints, simulated homologous breakpoints, spontaneous and meiotic DSB in five compartments, relative to uniform distribution based on compartment lengths. P values were calculated using chi-square test (* indicates P < 0.05; **P < 0.005; ***P < 0.0005). (B) Differences in the number of observed and predicted NAHR events (using a multiple linear regression model) along each compartment segment. Values closer to zero imply better prediction. Dotted lines represent 3 standard deviations from the mean. Bins with values outside the dotted lines represent discordant predictions. (C) Cumulative density of Hi-C interaction observed between breakpoints of SVs in different classes, advance simulated NAHR breakpoints, and random points. Original interaction values were normalized based on a background distribution for each compartment. This eliminated the effect of overall stronger interactions in B compartments, facilitating an unbiased comparison (Supplementary Figure S7). (D) Cumulative density of normalized Hi-C interaction for NAHR breakpoints with only spontaneous DSB or only meiotic DSB within 1 kb.
Figure 3.
Figure 3.
(A) NHEJ breakpoints are enriched with DNase I hypersensitive sites, unlike NHrepl breakpoints. (B) No enrichment/depletion of normalized nucleosome signal around 1 kb of repair related deletions. (C) Aggregations for spontaneous DSB peaks are similar to those for DNase sites. (D) Aggregation of spontaneous DSBs around regulatory elements. The largest enrichment is observed for transcription factor (TF) binding site inside DNase sites. (E) Meiotic DSBs are enriched only around NAHR breakpoints; however, the enrichment is not as high as would be expected if all NAHR events were of meiotic origin. (F) Enrichment of meiotic DSBs was observed around germline NAHR but not around somatic NAHR in cancer.
Figure 4.
Figure 4.
(A) No enrichment/depletion of DNase sites is observed around retrotransposons discovered as insertions. (B) Depletion of DNase sites is observed around breakpoints of deleted retrotransposons as well as non-variable Alu elements, suggesting that the effect is due to compromised read mapping around repeats. Insertion sites of processed pseudogenes are enriched with DNase sites. (C) Retrotransposon insertion sites are depleted with nucleosome signal. TEI, non-variable Alu, and processed pseudogenes also support depletion of the nucleosome signal around breakpoint. The peak at the center of the X-axis (lower panel) represents the normalized mean nucleosome signal within element boundaries. (D) DNase signal is enriched only around pseudogenes where length is away from nucleosome periodicity (∼150 bp).

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