Technological advances in whole-genome sequencing (WGS) to study complex genetic disorders have outpaced innovations in the analysis of large genetic datasets. An ever-increasing amount of genetic data is being acquired, at a higher resolution, from patient populations numbering in the thousands. While this has led to the identification of many genes and genetic variants associated with increased risk for disorders, such as autism spectrum disorder (ASD), novel biological insight from these datasets has lagged behind.

Of the thousands of single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs) identified from genetic studies, over 90 percent are located in non-coding sequences. Understanding whether any of these distal risk loci are functionally relevant remains a major challenge. One prevailing theory is that mutations in non-coding DNA may alter the activity of transcription regulatory sequences. However, even though enhancers can now be identified using genomic approaches, finding target genes for genome-wide association study (GWAS) SNPs remains a major challenge, and there is a clear need to better annotate GWAS SNPs, genetic variants and small de novo CNVs with solid experimental evidence.

Guo-Li Ming and Fulai Jin propose a novel approach to evaluate 3D genomic architecture information and identify potential target genes of distal genetic variants associated with ASD in human cortical neural progenitors and neurons. Jin’s laboratory recently developed a technique that allows for the analysis of a small number of cells to generate 3D genome maps. In combination with cutting-edge bioinformatic identification of SNP-gene modules and approaches to functionally validate SNPs, Ming and Jin expect to produce a 3D map of chromatin contacts that will serve as a resource for the field to investigate genetic contributions to various neurodevelopmental disorders, including ASD.

This is a multidisciplinary collaborative project combining the expertise of investigators in the fields of induced pluripotent stem cells, epigenomics, bioinformatics, human genetics and developmental brain disorders. In additional to providing novel insights into ASD biology, this study will serve as a proof-of-concept study investigating the contribution of non-coding genetic variants to human diseases.