University of Washington scientists will help decode how variations in DNA influence health and disease with $16 million in new funding.
The funding is part of a 5-year, $185 million initiative at the U.S. National Institutes of Health called the “Impact of Genomic Variation on Function (IGVF)” consortium. The UW will be one of 30 research sites in the consortium, the NIH announced Thursday.
Variations in the four-letter genetic code are what make us all different — an A for a T here, a C for a G there. Sometimes larger spans of DNA are swapped out, deleted or duplicated. Such variants not only determine things like eye and hair color but can also influence how susceptible people are to different diseases.
In a UW press release, professor of genome sciences Jay Shendure called the NIH project “the third phase” of human genome research. Decoding the sequence of the human genome was much of the first phase. Finding many of the variants connected with disease was part of the second, said Shendure, who is also director of the Brotman Baty Institute.
But many questions are unanswered, including how some variants lead to particular conditions and how much they contribute. “In this phase, the third phase, we’re trying to bring this work all together,” said Shendure in the release.
The new NIH initiative will expand research into how variants affect the operation of genes and cells and plumb their effects on health. It will involve two projects at the UW.
Shendure will lead one of the projects, examining more than one million stretches of DNA known as regulatory elements. These elements affect how genes function, such as whether they are turned on or off. They can also affect whether a cell becomes skin, bone or muscle and how organisms develop and grow.
Not only are there millions of regulatory elements, there are billions of variants that may affect their function. Shendure and his team are turning to computational approaches to make sense of it all.
The team will train artificial intelligence programs on data they will generate on variant functions. Their goal will be to create computational models that can predict the effect of variants on genes and cells. The project will also involve researchers at the University of California, San Francisco, and at Charité Universitätsmedizin Berlin in Germany.
A second project will more closely examine to what degree variants contribute to disease. That project will be led by Lea Starita, UW assistant professor of genome sciences and co-director of Brotman Baty Advanced Technology Lab, and Douglas Fowler, UW associate professor of genome sciences.
Some of that research will take place at a new group to be developed at UW Medicine, the Center for Actionable Variant Analysis.
The researchers will examine 200,000 variants in 32 genes involved in cancer and other diseases. Their aim is to experimentally measure the effects of so-called ‘actionable’ variants on disease. These are variants that are likely to affect patient care.
The new funding “will make genetic testing more impactful for more people by helping to eliminate variants of uncertain significance as a test result,” said Starita in the release. Other researchers involved in Starita’s project are at the Walter and Eliza Hall Institute in Melbourne, Australia and at Seattle Children’s Research Institute.
Starita also helps lead a recently launched international consortium, the Atlas of Variants Effects (AVE) Alliance, and Fowler is on its executive committee.
The goal of the Alliance, according to its website, is to “bring together data generators, curators and consumers, along with funders and other stakeholders, to set standards, share tools and develop strategy” around the analysis of variants. The atlas will support the creation of “maps” of the effects of variants with the ultimate aim of improving genetic diagnoses.
That goal dovetails with that of the new NIH initiative.
The new UW projects will not only help scientists and patients better understand how DNA affects disease, they could also lead to new treatments down the line.
“As a field, we are very good at reading genome sequences, but we are still pretty terrible at understanding what we find,” said Starita in the UW release.
