Posted By: Alyson Barnes, PhD, Deputy 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 Fritz (@fritzroth.bsky.social) to discuss his recent paper “A missense variant effect map for the human tumor suppressor protein CHK2.”
Photo Credit: John Franzos
AB: What motivated you to start working on this project?
My lab used to be more yeast-focused and, back in 2018, CHEK2 was on a short list of human genes that complement loss of the corresponding yeast genes. Really though it was Sean Tavtigian at University of Utah (thanks Sean!) who first persuaded me of CHEK2‘s importance and its substantial burden of variants of uncertain significance (VUS).
AB: What about the papers/project most excites you?
CHK2 is an interesting protein for many reasons, but I am most excited by the potential for our variant effect map, especially when combined with another similar study from McCarthy-Leo et al, to address ‘the VUS problem’ for CHEK2 and make genetic testing for breast and ovarian cancer more informative.
Another thing that excites me is that we finished it! These papers cannot capture the blood, sweat and tears that go into the process. In this case, we had the first three quarters of the map finished quickly, then encountered vexing technical difficulties with the C-terminal region that set us back repeatedly. Then, of course, once the data is in hand, the challenge of learning from it has only just begun. So, major shout out here to Marinella Gebbia who led (and persevered through) experimental aspects of the project, and to Daniel Zimmerman who led the analysis. Finally, I am excited that the relevant ClinGen Variant Curation Expert Panel (“Hereditary Breast, Ovarian and Pancreatic Cancer”) is actively thinking about how best to integrate these new datasets into best practices for clinical variant interpretation.
AB: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?
Zooming way out, it is exciting to consider that the community is ~1% of the way towards the goal of having an Atlas of Variant Effects for every human disease-associated protein. That may seem like paltry progress, but the pace is accelerating, and I expect we will be asymptotically approaching this goal within my lifetime (as long as I cross the street carefully).
AB: What advice do you have for trainees/young scientists?
Take risks! Don’t be afraid to ask questions! Also, come do science with us at the University of Pittsburgh! 🙂
AB: And for fun, tell us something about your life outside of the lab.
I am completely addicted to puzzle/strategy games. Right now, it’s Queens and Slay the Spire.
Frederick (Fritz) Roth, PhD is a Professor and John K. Vries Chair in the Department of Computational and Systems Biology at the University of Pittsburgh School of Medicine, and Professor in the Donnelly Centre at the University of Toronto.