Beating the Odds: How People Stay Healthy When Their Genomes Should Be Causing Disease

There are a lot of challenges in interpreting genomes. We’re still learning the language of DNA, for one. We’re still cataloging all of the genetic variants that exist in nature. And, perhaps most of all, we’re continually thwarted by elements we thought we understood — only to find out they don’t behave the way we expect in the real world. (And by “we,” of course, I mean “highly trained scientists.” Me, I can’t tell the difference between a retrotransposon and a selfish tycheposon.)

That’s why a new study from scientists at leading research institutions in the U.S., Europe, and Australia caught my eye. This team banded together to find an answer to a particularly vexing question in understanding genome function.

Here’s the paradox: there are certain variants known to cause disease — they’re called pathogenic variants — but sometimes they’re found in totally healthy people. I first encountered this through the Personal Genome Project, which kicked off in the early 2000s with a goal of sequencing 10 individuals and publicly releasing the results. One of them had a genetic variant that by all accounts should have caused a life-threatening cardiac disorder. But the participant was absolutely fine. Perhaps a little confused by how alarmed the scientists were when they found the variant, but otherwise fine.

It turns out that this case was just the tip of the iceberg. What makes some people seemingly impervious to variants that cause serious problems for most others? That’s what the scientists wanted to figure out in this new study, published in Nature Communications. To do this, they needed a lot of data to identify these rare events. They turned to a massive genomics database known as gnomAD (pronounced “nomad”) where they could mine genome-wide information from more than 807,000 people.

Next, they homed in on a specific type of variant associated with severe, early-onset diseases. A deep dive into 734 of these variants — presumed to be from healthy adults, based on how they were enrolled in the database — led to answers in 95% of cases. Much of the time, that answer was the equivalent of hitting the genetic jackpot: people with these pathogenic variants also happened to have other variants that effectively counteracted the disease-causing variant.

This study underscores the complexity of interpreting genomic data. It’s not enough to scan through a genome and spot variants known to cause disease; each one must also be assessed in the full context of the DNA around it to understand potential function. While this was a research study, its implications are important for genetic tests used in the clinical today, such as carrier screening and newborn screening.

There’s another take-home message here about the incredible value of large, publicly available genomic databases. Spotting enough of these rare events in a regular research project would have been all but impossible. Having access to variant data from more than three-quarters of a million people was the game-changer. These databases don’t spring up on their own; they require steady, continued investment in science and research infrastructure over decades. Projects such as the UK Biobank or the Million Veterans Program and the All of Us research initiative here in the U.S. are other population-scale resources that will enable countless health-related discoveries as long as they remain funded and prioritized by the government.

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