October 10, 2022 -- National Eye Institute (NEI) scientists have mapped the genetic architecture that determines gene expression and disease phenotype in age-related eye disorders including macular degeneration and glaucoma in humans.
Their study, published October 7 in the journal Nature Communications, offers a better understanding of how genetic architecture determines gene expression, tissue-specific function, and disease phenotype in these blinding diseases.
The relative stability of nondividing adult human retinal cells enables exploration of chromatin -- the fibers that package 3 billion DNA molecules. Long strands of DNA spool around histone proteins, which then fold into a highly compact structure that fits inside chromatin fibers. These fibers themselves then repeatedly loop to create a spaghetti-like ball within the retinal cell nucleus.
These millions of loops create millions of contact points along the fiber, which puts genetic sequences that code for proteins in close proximity to noncoding gene regulatory sequences that control which genes get expressed and when.
Using post-mortem human donor retinal samples along with deep Hi-C sequencing, a tool for studying 3D genome organization, the researchers created a high-resolution map showing 704 million contact points within retinal cell chromatin.
Integrating that chromatin topology map with datasets on retinal genes and regulatory elements revealed a dynamic picture of the interactions and patterns within chromatin over time. Similarities between mice and human chromatin organization underscores the relevance of these patterns for retinal gene regulation.
The researchers then integrated the chromatin topology map with previous data on genetic variants, enabling the identification of specific candidate genes responsible for age-related macular degeneration and glaucoma.
"This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration and glaucoma, two leading causes of vision loss and blindness," lead investigator Anand Swaroop, PhD, chief of NEI's Neurobiology Neurodegeneration and Repair Laboratory, said in a statement.