Abstract

Variations in the DNA sequence are referred to as SNPs, or single nucleotide polymorphisms. In neurodevelopmental disorders (NDDs) and traits, copy number variants (CNVs) that map to putative transcriptional regulatory elements like enhancers are common. However, the genes that these enhancers control are still a mystery. In the past, it was thought that the gene promoter that was closest to an enhancer was affected by its activity and any possible changes caused by sequence variants. The discovery of genome-wide long-range interaction maps in the chromatin of neural cells challenges this idea because they demonstrate that enhancers frequently connect to promoters farther apart and skip genes in between. This perspective focuses on a number of recent studies that have used HiC, RNApolII ChIA-PET, Capture-HiC, or PLACseq to generate long-range interaction maps and overlap the identified long-range interacting DNA segments with DNA sequence variants associated with NDD (like schizophrenia, bipolar disorder, and autism) and traits (intelligence). Using this method, it was possible to connect the function of the enhancers that house the NDD-related sequence variants to a connected gene promoter that was away from the linear chromosome map. By identifying mutations in the gene's protein-coding regions (exons), some of these enhancer-connected genes had already been identified as contributing to the diseases, which validated the method. However, a significant number of the connected genes also contain genes whose exons had not previously been found to be mutated, suggesting novel NDD and trait causes. As a outcome, the DNA variants and long-range interaction maps uncovered by NDD can be used as "pointers" to locate novel candidate genes associated with the disease. Methods based on CRISPR-Cas9 are beginning to investigate the functional significance of the identified interactions as well as the enhancers and genes involved by functionally manipulating the long-range interaction network that includes promoters and enhancers. As a direct consequence of this, our comprehension of the pathology of neural development is improving.