Beyond the Genome: Project to Map DNA Modifications and Gene Activity Across Lifespan, Generations

The Human Genome Project changed everything. A map of the entire human sequence of DNA was the starting point for an enormous number of discoveries, from disease genes to how humans evolved.

But DNA sequence is only part of the picture. Long-term, heritable changes in gene activity—how and when each gene is turned on or off—fundamentally shape our biology, trigger many of our diseases, and set the clock on how we age. While these changes can be shaped by the environment, they can also be passed down from generation to generation, in a sort of biological memory scientists are just beginning to unravel. These heritable changes make up the “epigenome”—persistent patterns of DNA modifications that don’t alter the underlying gene sequences.

Now, two decades after the Human Genome Project, a team of Utah scientists led by principal investigator Deborah Neklason, PhD, are starting an ambitious new project to map epigenetic changes across the entire human genome. With $1.5M of new funding from the W. M. Keck Foundation, and the help of many of the original families who participated in the first map of the human genome, the team aims to discover how patterns of gene activity are inherited, track how DNA is modified as people age, and develop a comprehensive atlas of human epigenetic variation that will form an invaluable point of comparison for future studies.

Into uncharted territory

Aaron Quinlan, PhD, professor of human genetics and bioinformatics in the Spencer Fox Eccles School of Medicine (SFESOM) and a principal investigator on the project, says that an epigenetics project of this scale hasn’t been done before because the technology simply wasn’t there. “Think of the genome as the entire interstate system in the United States,” Quinlan says. “The techniques that have existed until very recently only allow us to look at the exits off the interstate.” But new advances in research tests can detect chemical modifications to DNA across vast swaths of the genome, he continues. “We’re going to study every inch.”

The team is especially interested in exploring how gene activity changes as people age. Here, an enormous asset is the participation of Utah families who have been involved with human genetics research for generations. In some cases, the team will be able to compare the landscape of DNA modifications for the same person across three timepoints forty years apart—an incredible resource for understanding the biology of healthy aging.

Because the families participating are large and generally healthy, the science team will be able to figure out what a “normal” level of epigenetic variation looks like, providing a crucial point of comparison for future studies looking into how epigenetics changes with disease. And they’ll be able to cross-reference DNA modifications with health conditions by integrating 25 years of electronic health records provided by the Utah Population Database (UPDB).

Nicola Camp, PhD, professor of internal medicine, Huntsman Cancer Institute investigator, director of the UPDB, and a principal investigator on the project, adds that a major strength of the newly funded research is how it will bring together multiple unique resources to answer previously unsolvable questions. “We’re going all the way from these amazing families to state-of-the-art genetics and epigenetics to the richest, deepest longitudinal health history,” Camp says. “The data we’re going to generate blows my mind.”

Rewriting risk

By working with multigenerational families, the researchers will also be able to get a better picture of which changes are inherited and which aren’t. DNA modifications themselves are wiped clean when sperm and egg fuse, but are replaced in patterns that sometimes recur, generation to generation. Some of the patterns are probably caused by underlying variation in the DNA sequence itself; others are triggered by environmental factors.

How and when DNA modifications are inherited is largely unknown, says Neklason, director of the Utah Genome Project and a research associate professor of internal medicine at SFESOM. “People are just starting to have glimpses into this.” But by comparing genetic and epigenetic information throughout participating families, the research team hopes to shed light on this mystery.

And intriguingly, because epigenetic changes can be affected by the environment, they can in theory be manipulated to improve health, says Camp. “If we can change how DNA expresses in the genes, then that actually gives a totally new opportunity to think about how we might change somebody’s risk profile for disease and health,” Camp says. The right epigenetic changes could potentially reverse someone’s inherited risk for disease.

Neklason says that the research team’s distinct, complementary skillsets—her genetics expertise, Camp’s knowledge of epidemiology, and Quinlan’s computational skills—will be key to the project’s success. “The coolest part is that it’s a team where we come together with completely different perspectives that will really make this work,” Neklason says. “I have huge confidence in this having a really big impact.”

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About University of Utah Health

University of Utah Health provides leading-edge and compassionate care for a referral area that encompasses Idaho, Wyoming, Montana, and much of Nevada. A hub for health sciences research and education in the region, U of U Health has a $522 million research enterprise and trains the majority of Utah’s physicians, and more than 1,670 scientists and 1,460 health care providers at its Colleges of Health, Nursing, and Pharmacy and Schools of Dentistry and Medicine. With more than 20,000 employees, the system includes 12 community clinics and five hospitals. U of U Health is recognized nationally as a transformative health care system and provider of world-class care.

About the W. M. Keck Foundation

Based in Los Angeles, the W. M. Keck Foundation was established in 1954 by the late W. M. Keck, founder of the Superior Oil Company. The Foundation’s grant making is focused primarily on pioneering efforts in the areas of medical research and science and engineering.  The Foundation also supports undergraduate education and maintains a Southern California Grant Program that provides support for the Los Angeles community, with a special emphasis on children and youth.  For more information, visit www.wmkeck.org