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Genetic Variation in Brain Cell Types May Predict Disease Risk in People

Genetic Variation in Brain Cell Types May Predict Disease Risk in People
Date :6/18/2019 / Visit Count : 451 Source:source

One might think that the primary cause of most genetically linked diseases comes from mutations in coding DNA—alterations in coding regions of the genome that can lead directly to changes in the expression of particular proteins important for a healthy body.

But the majority of human DNA is non-coding DNA—regions of DNA that do not directly translate into functional proteins. These non-coding DNA regions contain functional elements, called enhancers, which can change the likelihood of a particular protein to be made, MedicalXpress reported.

Researchers are now finding particular genetic variations in some of these non-coding regulatory regions, called enhancers, determine whether or not proteins are expressed in specific cell types in the brain and may play a role in a person's risk of developing psychiatric or neurological conditions.

In a new study published November, 14, 2019 in Science, a team of researchers at University of California San Diego School of Medicine and the Salk Institute for Biological Studies used healthy tissue isolated from six patients to isolate four different kinds of brain cells—neurons, microglia, oligodendrocytes, and astrocytes—then looked at genetic variation associated with disease in the non-coding enhancer regions of each cell type, searching for variations that might be linked to disease risk.

Using novel molecular techniques, they were able to further map the connections between enhancer regions and their target genes, providing insights into how variations in enhancer regions can affect downstream gene expression in specific cell types.

"The brain is very complex, with lots of different cell types in different brain regions," said co-first-author Inge Holtman, Ph.D., a postdoctoral fellow at UC San Diego School of Medicine Department of Cellular and Molecular Medicine. "Currently, our understanding of the regulatory landscape in the brain is largely unclear. Past research has tried to generate a consensus regulatory landscape of the whole brain, but until now we didn't really know what it looked like in individual cell types. This work gives us a much better understanding of how genes are being regulated, which enhancers are there, and which enhancers are looping back to particular genes and affecting their expression, in particular cell types in the brain."

The findings showed that while many genes are expressed in many different cell types, the enhancer regions differ between cells—and that disease risk is often linked to specific enhancer regions in specific cell types.

"Focusing on genetic variation associated with Alzheimer's disease (AD), we show preferential enrichment in disease risk variants in enhancers that are selectively active in microglia, the major immune cell in the brain," said senior author Christopher Glass, MD, Ph.D., professor of cellular and molecular medicine and professor of medicine at UC San Diego School of Medicine. "This finding substantially extends prior studies linking microglia to late-onset Alzheimer's disease."

Beyond identifying genetic risk variants, the researchers validated their findings using pluripotent human stem cells. By targeting a particular enhancer region close to BIN1, a gene that has previously been linked to AD, they found that deleting that enhancer region led to a dramatic reduction in expression of BIN1 in microglia, but not in neurons or astrocytes, indicating that this BIN1-associated risk allele lies within a microglia-specific enhancer region.

"Often, it's hard to know in what cell type particular genes are important because they're expressed in all cell types in the brain," said co-first-author Nicole Coufal, MD, Ph.D., assistant adjunct professor of pediatrics, UC San Diego School of Medicine. "In Alzheimer's disease, it was previously assumed that BIN1 was most important in neurons, but this study indicates that it may actually be more important to understand the role of BIN1 in microglia."

 



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