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A snapshot in time: Study captures fleeting genetic mutations that can alter disease risk

July 1, 2019

Using a series of genetic snapshots, a team of scientists from Johns Hopkins University and the University of Chicago captured evidence of a so-called “butterfly effect”—a term popularized in film and literature as the ability for even a small action in the past to have major, sometimes life-changing effects in the future—in heart muscle cell development. They say this new view into the sequence of gene expression activity may lead to a better understanding of disease risk.

The study, published June 28 in Science, identifies hundreds of DNA regions that are associated with differences in gene expression between individuals.

“The human genome has been studied extensively, but how each person’s cells use the genome is complex, dynamic, and not as well understood. In this study we looked for cases where genetic differences between people change during cell development,” says Alexis Battle, an associate professor in the Department of Biomedical Engineering at Johns Hopkins University and one of the paper’s senior authors. Working with Battle was Ben Strober, lead author and a biomedical engineering PhD student.

Previous studies have identified thousands of regions of DNA that can affect gene expression—called expression quantitative trait locus, or eQTL—but they’ve relied on data collected at a single point in time, says Battle. Many of these differences in gene expression can occur at different stages of development or vary depending on environment, leading researchers to potentially miss important disease associations that can’t be studied in fully-developed tissue.

“Those associations are like shooting stars,” says Yoav Gilad, chief of genetic medicine at the University of Chicago and the other senior author of the study. “They appear at one point and never again during development, and they might actually be important to the phenotype of the mature tissue and maybe even disease. But unless you study those particular cell types at that particular time, you’ll never see them.”

To find these fleeting associations, the team used induced pluripotent stem cells, a type of master stem cell that can become nearly any type of cell. For the study, the research team sampled RNA from the stem cells of 19 people once a day over the course of 16 days as they differentiated into cardiomyocytes, or heart muscle cells. To Battle’s knowledge, this effort is the first large-scale time-course study of gene expression in heart muscle cells in multiple individuals, with the largest number of time points sampled.

By obtaining data every day, the researchers gained important information about gene expression during the in-between stages when a cell is neither a new stem cell nor a fully-formed heart muscle cell.

These small mutations that occur during cellular development could potentially account for differences in risk for complex diseases such as cancer, heart disease, or diabetes that aren’t caused by a single genetic mutation, but possibly hundreds. The new research demonstrates that, on their own, each of these small “shooting star” genetic differences don’t affect overall health dramatically, but together they can elevate risk for particular diseases.

“To fully understand how genetics impacts disease risk, we’ll ultimately have to consider all the different cell types, developmental time points, and environmental conditions that could be relevant to different diseases. This study is one step in that direction,” says Battle.

Because the research team’s method of using stem cells and sampling RNA expression at regular intervals is still resource-intensive, it’s not likely to be a commonly-used diagnostic tool anytime soon. Battle hopes, however, the approach can be used to help identify genes that affect disease and guide efforts to design effective, targeted interventions.

– Chanapa Tantibanchachai