Spatial chromatin architecture alteration by structural variations in human genomes at the population scale

Michal Wlasnowolski,Przemyslaw Szalaj,Dariusz Plewczynski,Yijun Ruan,Zhonghui Tang,Agnieszka Kraft,Michal Sadowski

doi:10.1186/s13059-019-1728-x

Abstract

BackgroundThe number of reported examples of chromatin architecture alterations involved in the regulation of gene transcription and in disease is increasing. However, no genome-wide testing has been performed to assess the abundance of these events and their importance relative to other factors affecting genome regulation. This is particularly interesting given that a vast majority of genetic variations identified in association studies are located outside coding sequences. This study attempts to address this lack by analyzing the impact on chromatin spatial organization of genetic variants identified in individuals from 26 human populations and in genome-wide association studies.ResultsWe assess the tendency of structural variants to accumulate in spatially interacting genomic segments and design an algorithm to model chromatin conformational changes caused by structural variations. We show that differential gene transcription is closely linked to the variation in chromatin interaction networks mediated by RNA polymerase II. We also demonstrate that CTCF-mediated interactions are well conserved across populations, but enriched with disease-associated SNPs. Moreover, we find boundaries of topological domains as relatively frequent targets of duplications, which suggest that these duplications can be an important evolutionary mechanism of genome spatial organization.ConclusionsThis study assesses the critical impact of genetic variants on the higher-order organization of chromatin folding and provides insight into the mechanisms regulating gene transcription at the population scale, of which local arrangement of chromatin loops seems to be the most significant. It provides the first insight into the variability of the human 3D genome at the population scale.

Highlights

The number of reported examples of chromatin architecture alterations involved in the regulation of gene transcription and in disease is increasing
We inspected the anchoring sites of PET clusters identified by the CTCF ChIA-PET experiment for the cooccupancy by CTCF and cohesin (SMC3 and RAD21 subunits), to select the set of high-quality chromatin interactions mediated by CTCF in GM12878 cell
Our algorithm models individual chromatin loops, meaning that the remodeling effect of a genetic variant disrupting a single pair of interacting genomic segments will be represented in the model (Fig. 3a). 3D-GNOME is an optimization algorithm which returns models that fulfill spatial constraints coming from genomic interaction data

Summary

Introduction

The number of reported examples of chromatin architecture alterations involved in the regulation of gene transcription and in disease is increasing. No genome-wide testing has been performed to assess the abundance of these events and their importance relative to other factors affecting genome regulation. This is interesting given that a vast majority of genetic variations identified in association studies are located outside coding sequences. Around 20 million base pairs of a normal human genome (0.6%) are under structural variations, including deletions, duplications, insertions, and inversions. This makes structural variants (SVs) the most prominent source of genetic variation among human individual genomes. Larger variants are significantly depleted in gene regions [6]

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Conclusion