Chromatin structure analysis of rare likely pathogenic inherited Copy Number Variants

Chromatin structure has been shown to play important roles in the orchestration of gene expression programs during development. Spatio-temporal specific cis-regulatory sequences often lie at a long distance from the gene(s) they regulate, requiring spatial chromatin folding to move them in close proximity of their target promoters and fine-tune the time, place and level of gene expression. Interestingly, several whole-genome chromatin interaction analyses have also recently revealed the existence of topologically associated domains (TADs) which seem to act as fundamental regulatory units of the genome by delimiting the scope of action of regulatory elements in the 3D nuclear space. In other words, TADs organize the genome into regulatory islands by defining regions that interact more frequently with themselves than with the rest of the genome. Few studies have reported that the alteration of TADs by structural genomic rearrangements could disrupt the normal activity of TADs and play significant roles in human diseases. Copy-Number Variants (CNVs) are DNA sequence deletions or insertions of ≥50bp which have been shown to play important roles in human biology. The overall contribution of CNVs to human phenotypic variability and diseases is, however, still largely unclear. Few studies have now reported that deletion or duplication of DNA segments could alter gene expression regulation by disrupting, duplicating or shifting TADs boundaries causing gene(s) misexpression and diseases. Here, we propose to investigate the contribution of rare likely pathogenic CNVs into human disorders by analyzing theirs effect on chromatin architecture, and by extension on gene regulatory programs, in patients’ and controls’ derived cells. This project is part of a larger research effort that will combine our analyses with deep phenotyping, whole genome sequencing and evolutionary analyses in selected families to assess the contribution of rare likely pathogenic CNVs to phenotypic variability of developmental disorders.