This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Changes in our genes affect health risks from heart disease to cancer, but how those genes are turned on and off is just as crucial to health. What's more, almost all genes occur as two copies—one from each parent—that aren't necessarily turned on and off in sync.
When that differential gene regulation goes awry, it can cause serious health problems. But until now, it's been difficult to detect copy-specific differences in gene regulation and understand which of them are important. Now, researchers have developed a tool that pairs machine learning with advanced DNA sequencing to disentangle differential gene regulation between maternally and paternally inherited chromosomes and find regions that are crucial for gene function.
Their new tool, called FIRE, could help researchers pinpoint the DNA changes behind hereditary diseases—a key step toward genetic medicines—and provides an unprecedented look at previously mysterious regions of the genome. "Only about 1% or 2% of our genome codes for proteins," says Mitchell R. Vollger, Ph.D., assistant professor of human genetics at University of Utah Health and co-lead author on a study describing the results published in the journal Cell.
"This gives us a much sharper lens on the other 98%, which includes the switches that turn our genes on and off." The team also discovered that lasting changes in gene regulation aren't always triggered by genetics. Two identical copies of the same stretch of DNA can be regulated differently, and those differences are passed down as our cells divide. The function of most of these newly discovered changes is unknown, but they suggest a new dimension of biological variability that isn't determined by genetics.
The researchers used FIRE to reveal how changes in DNA sequence affect the regulation of health-critical parts of the genome. Previous studies had found a genetic difference that was associated with risk of celiac disease, but no one knew if the difference actually affected how genes work or was just an innocent bystander—an important distinction for developing genetic medicines. The celiac-associated genetic difference sits in a gene "switch" next to an immune gene that has also been linked to celiac disease, the researchers found.
The DNA change disrupts a spot where gene-controlling proteins normally attach, and changing just that one DNA letter in lab experiments was enough to change how open the switch was. This suggests that, out of thousands of nearby genetic differences, this is likely the single one that changes gene regulation. Using FIRE, the team also identified tens of thousands of previously overlooked DNA regions that are likely to be important for gene regulation.
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