3D Map of Retinal DNA Reveals New Genes Involved in Eye Diseases

NIH researchers have created a 3D map of DNA within human retina cells and identified new gene variants that could be risk factors for age-related macular degeneration and glaucoma.

Researchers at the National Eye Institute of the National Institutes of Health have mapped the DNA organization of human retina cells. In the journal Nature Communications, researchers discussed the 3D model they created of the gene regulatory network. This model provides insights into gene expression and retinal function in both rare and common eye diseases.

“This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness,” the study’s lead investigator, Anand Swaroop, Ph.D., senior investigator and chief of the Neurobiology Neurodegeneration and Repair Laboratory at the NEI, part of the National Institutes of Health, said in a press release.

NEI researchers explored the retinal cell chromatin; chromatin consists of protein, RNA, and DNA and packages them into compact structures that fit into chromosomes within each cell’s nucleus. Investigators used adult retinal cells, which do not divide, making them a stable environment to explore gene expression.

Investigators used samples from four human donors. Using deep Hi-C sequencing, a tool used for studying 3D genome organization, the researchers created a high-resolution map that included 704 million contact points within retinal cell chromatin. Within these contact points, the map was able to identify genetic sequences that code for proteins that can interact with gene regulatory sequences.

The researchers then integrated datasets of retinal genes and regulatory elements into the chromatin topology map. Using this integrated map, researchers were able to see gene activity hot spots. The study identified mutations of the CFDP1 gene that could be a risk factor for age-related macular degeneration, and they also identified mutations of the TFAP2B gene that could be a risk factor for glaucoma.

Study researchers said the integrated map can also assist in evaluating genes associated with other eye diseases such as diabetic retinopathy, determining missing heritability and understanding genotype-phenotype correlations in inherited retinal and macular diseases.

The study was supported by the NEI Intramural Research Program.