Posted By: Kylee Spencer, PhD, Assistant Editor, AJHG
Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month we check in with Doug to discuss his recent paper “Will Variants of Uncertain Significance Still Exist in 2030?”.
KS: What motivated you to start working on this project?
DF: I initially trained as a chemist, so I’m surprised to have written this paper about variants of uncertain significance. I moved from chemistry to genomics because it was, and still is, a hotbed of technological development. As a postdoc with Stan Fields, I developed a method, deep mutational scanning, that leveraged the then-new power of high-throughput DNA sequencing to measure the effect of genetic variants at scale. I didn’t envision deep mutational scanning with human genetic variants in mind, applying it initially to better understand protein function. In 2016 I, along with my close collaborator Lea Starita, was invited to an NHGRI genomic medicine meeting. At that meeting, I realized that deep mutational scanning and methods like it could help solve a real problem in the clinic – interpreting variants of uncertain significance. As a consequence, I shifted much of my focus to solving this problem.
KS: What about this paper/project most excites you?
DF: The paper is an update of predictions Heidi Rehm and I made in response to one of the NHGRI’s “Bold Predictions for Human Genomics by 2030,” that variants of uncertain significance would no longer be a problem. What excited me about writing the paper was describing the huge progress that has been made in the past three years. For example, organizations like the Atlas of Variant Effects Alliance and the Impact of Genomic Variation on Function Consortium have helped to drive the broad deployment of technologies like deep mutational scanning, resulting in swathes of variant functional data. Variant effect predictors have gotten more powerful and data-sharing efforts have enabled clinicians to learn from each other. Thus, we feel that the NHGRI’s prediction may well turn out to be accurate–variants of uncertain significance can largely be resolved by 2030.
KS: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
DF: Often, a person who gets a genetic test receives an uncertain result, which is not useful from the perspective of making a diagnosis or deciding on a treatment. Our paper describes efforts to help avoid this outcome, making genetics more useful in the clinic. The paper also highlights how working across disciplines, in this case genomic technology and clinical genetics, can have a big impact.
KS: What advice do you have for trainees/young scientists?
DF: Work on something that matters, even if it means taking big risks. Invest in cultivating skilled and supportive mentoring relationships–these will last a lifetime and make a huge difference in your career.
KS: And for fun, tell us something about your life outside of the lab.
DF: I, along with a surprising number of my colleagues, enjoy playing a game called Warhammer 40k. The game is super complex, and you have to paint the models used in the game. I find the painting very challenging!