Machine learning analysis of gene regulation reveals new dimension of biological variability
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.
Researchers have developed a new tool called FIRE, which combines machine learning with advanced DNA sequencing, to analyze gene regulation and reveal new dimensions of biological variability. Changes in our genes, such as those affecting heart disease and cancer risk, are crucial to health, but the way genes are turned on and off is equally important.
While most genes come in pairs—one from each parent—these copies may not be regulated in sync. When this differential gene regulation goes wrong, it can lead to serious health problems. Identifying copy-specific differences in gene regulation has been challenging until now.
The FIRE tool, co-developed by Mitchell R. Vollger, Ph.D., assistant professor of human genetics at the University of Utah Health, uses machine learning to disentangle differential gene regulation between maternally and paternally inherited chromosomes. This new approach could help pinpoint the DNA changes behind hereditary diseases and provide an unprecedented look at previously mysterious regions of the genome.
Vollger notes that only about 1% to 2% of the genome codes for proteins, leaving the remaining 98% consisting of switches that control gene activity. The team discovered that lasting changes in gene regulation can occur even when there are no genetic differences between the two copies of DNA. These changes, passed down through cell division, suggest a new dimension of biological variability that isn't solely determined by genetics.
Using FIRE, researchers found how changes in DNA sequence affect the regulation of health-critical parts of the genome. They identified tens of thousands of previously overlooked DNA regions likely to be important for gene regulation. These regions are more likely to contain DNA changes associated with human disease, indicating their potential undiscovered roles in health.
FIRE also enabled researchers to search for parts of DNA regulated differently between maternally and paternally inherited chromosomes. Surprisingly, in most cases, differences in gene regulation could be linked to differences in the DNA itself. However, a significant minority of cases showed genetically identical copies with different regulatory patterns. Vollger emphasizes that about 40% of the time, regulatory differences between inherited chromosomes have no corresponding genetic differences.
By linking genetic code changes to functional differences in gene regulation, FIRE aims to help identify which genetic variations cause human diseases—a crucial step toward developing therapies that edit DNA to treat or cure hereditary diseases. This tool represents a significant advance in understanding the complex interplay between our genes and their regulation, potentially paving the way for more effective genetic medicine.
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