FIRE tool finds no DNA difference behind about 40% of maternal-paternal gene regulation gaps

The 40% is a ratio, so the denominator matters. Mitchell R. Vollger, assistant professor of human genetics at University of Utah Health and co-lead author of the Cell study ^[2], said: "About 40% of the time that we see a regulatory difference between the copies we inherited from mom and dad, there's no genetic difference between them at that spot." ^[3] Phys.org's account does not say how many people or cell types were sequenced, or what share of reads FIRE could assign to a parent.

Vollger called the 40% the most surprising result. "I think the most surprising result of this work was finding the limits of how much our genetics can determine our gene regulation," he said. ^[14] In most cases the regulatory difference did trace back to the DNA itself ^[4]. For the rest, the team reports that two identical copies of a stretch of DNA can be regulated differently, and that the difference is passed down as cells divide ^[12]. The function of most of these changes is unknown. The team says they suggest a new dimension of biological variability that is not determined by genetics ^[12].

Accessibility alone is a noisy signal. A highlighted region can be a regulatory element, or it can simply be open at that moment ^[6]. FIRE adds a machine-learning analysis that can check every highlighted region ^[7].

The celiac case shows what combining the two methods adds. Earlier studies had tied a genetic difference to celiac risk, but nobody knew whether it changed how genes work or was an innocent bystander ^[8]. FIRE placed it in a switch next to an immune gene also linked to celiac ^[9]. Changing that one letter in lab experiments was enough to change how open the switch was ^[9]. The researchers say this suggests that, out of thousands of nearby genetic differences, it is likely the single one that changes gene regulation ^[10]. In our view the experiment settles the first question, whether the letter alters regulation, and leaves the second, whether that alteration drives celiac risk, to later work. It is also one case.

The tens of thousands of new regions get a weaker test. They are more likely than other parts of the genome to contain DNA changes associated with disease ^[11]. The enrichment is an association between regions and disease-linked changes and does not show cause. It tells researchers where to look.

Vollger put the scale this way: "Only about 1% or 2% of our genome codes for proteins." He added: "This gives us a much sharper lens on the other 98%, which includes the switches that turn our genes on and off." ^[13]