Background: Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Using Hi-C analysis of long-range chromosome interactions, including haplotype-specific Hi-C analysis, and ChIP-Seq analysis of regulatory histone marks, we studied the epigenomic effects of the prominent heterozygous large deletion CNV on chromosome 22q11.2 and also replicated a subset of the findings for the heterozygous large deletion CNV on chromosome 1q21.1. Results: There are local and global gene expression changes as well as pronounced and multilayered effects on chromatin states, chromosome folding and topological domains of the chromatin, that emanate from the large CNV locus. Regulatory histone marks are altered in the deletion flanking regions, and in opposing directions for activating and repressing marks. Histone marks are changed along chromosome 22q and genome wide. Chromosome interaction patterns are weakened within the deletion boundaries and strengthened between the deletion flanking regions. The long-range folding contacts between the telomeric end of chromosome 22q and the distal deletion-flanking region are increased. On the chromosome 22q with deletion the topological domain spanning the CNV boundaries is deleted in its entirety while neighboring domains interact more intensely with each other. Finally, there is a widespread and complex effect on chromosome interactions genome-wide, i.e. involving all other autosomes, with some of the effect directly tied to the deletion region on 22q11.2. Conclusions: These findings suggest novel principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.

Local and global chromatin interactions are altered by large genomic deletions associated with human brain development