Abstract
Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Here we report on the epigenomic effects of the prominent large deletion CNVs on chromosome 22q11.2 and on chromosome 1q21.1. We use Hi-C analysis of long-range chromosome interactions, including haplotype-specific Hi-C analysis, ChIP-Seq analysis of regulatory histone marks, and RNA-Seq analysis of gene expression patterns. We observe changes on all the levels of analysis, within the deletion boundaries, in the deletion flanking regions, along chromosome 22q, and genome wide. We detect gene expression changes as well as pronounced and multilayered effects on chromatin states, chromosome folding and on the topological domains of the chromatin, that emanate from the large CNV locus. These findings suggest basic principles of how such large genomic deletions can alter nuclear organization and affect genomic molecular activity.
Highlights
Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism
Two of the most exciting discoveries in human genetics of the past decade are that small-to-medium-sized copy number variants (CNVs) are very common in the human genome and that there is a group of large CNVs that are strongly associated with brain development and neuropsychiatric disorders, such as schizophrenia and the autism spectrum disorders (ASDs)[1,2]
There already have been a number of transcriptome-wide studies that at least hint at certain network effects emanating from the large CNVs8–12
Summary
Large copy number variants (CNVs) in the human genome are strongly associated with common neurodevelopmental, neuropsychiatric disorders such as schizophrenia and autism. Two of the most exciting discoveries in human genetics of the past decade are that small-to-medium-sized copy number variants (CNVs) are very common in the human genome and that there is a group of large CNVs that are strongly associated with brain development and neuropsychiatric disorders, such as schizophrenia and the autism spectrum disorders (ASDs)[1,2] These large CNVs are widely considered to be enticing points of entry to the analysis of the strong but complex genetic, molecular, and possibly even cellular, basis of these common disorders. Large CNVs, typically sized from hundreds of thousands to millions of base pairs of genomic DNA sequence, were previously known to be in strong association with often severe but rare congenital malformations, or found in cancer genomes It was a striking discovery when a series of studies[1,2] showed that there is a group of more than ten large CNVs that are strongly associated with aberrant brain development and a resulting neuropsychiatric phenotype such as schizophrenia or ASD. There are an increasing number of studies that show a potentially very important role of chromatin regulation in the molecular etiology of neuropsychiatric disorder[13,14,15,16,17,18,19]
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