The term “junk DNA” is thought to date back to the discovery of DNA’s double helical structure when Dr. Francis Crick described the genetic gibberish surrounding the small pieces of DNA that coded for proteins (called exons) as “little better than junk.” In 2000, scientists of the Human Genome Project suggested that 97% of the human sequence had no apparent function. It wasn’t until 2012 that scientists began to appreciate that there were hidden switches and regulatory regions embedded in this so-called junk DNA. New research provides even more compelling evidence that “junk DNA” might be involved in regulating risk of Alzheimer’s disease.
The majority of human DNA is non-coding DNA – regions of the genome that do not directly translate into proteins. In addition, most of the disease-risk genetic variants are located in non-coding regions of the genome. As a result, non-coding regions of the DNA are increasingly being recognized as important for Alzheimer’s disease risk since these areas of the genome contain enhancers – short-regions of DNA that can change the odds that a specific protein is made.
In research published in Science under the direction of Dr. Christopher Glass, M.D., Ph.D at the Salk Institute of the University of California, San Diego, it was shown that disease risk for neurodegeneration is often linked to specific enhancer regions in specific cell types – in this case, in the immune cells of the brain called microglia. This paper adds an added layer of complexity to how genetic variants in one cell type influence disease risk.
In this study, tissue was obtained from six patients in order to isolate four different kinds of cell types in different brain regions. In this case, the brain cell types included neurons, microglia, oligodendrocytes, and astrocytes. Investigating different cell types revealed that variants in transcriptional enhancers in neurons were more commonly associated with psychiatric disorders. Alzheimer’s disease risk variants, for late-onset forms of the disease, were almost exclusively confined to microglia enhancers.
“In an interview with Science, Dr. Glass explained: “We show preferential enrichment in disease risk variants in enhancers that are selectively active in microglia. This finding substantially extends prior studies linking microglia to late-onset Alzheimer’s disease.””
The research went a step further by creating a map between the enhancers and the genes they regulate. This provided novel insights into the differences seen across different cell types in the brain. While the sample size was limited, this paper suggests that creating a cell type-specific promoter-enhaner interactome has the potential to help interpret risk alleles associated with neurological and psychiatric diseases.