Guest Seminar - Dr. Jacob Kitzman, University of Michigan
Speaker: Dr. Jacob Kitzman
Institution: University of Michigan
Host: Dr. Fritz Roth
Date: Monday, September 16th, 2024
Time: 2:30 PM
Location: Red Room, Donnelly Centre
Title: Saturation variant-to-function mapping across DNA repair pathways
Abstract:
Understanding how individual variants impact gene function and contribute to disease risk is a central challenge in human genetics, even for the most intensively studied genes.
To address this challenge, we employ high-throughput mutagenic screens to exhaustively test all possible coding variants in clinically impactful human disease genes. I will describe scaling these approaches across the entire DNA mismatch repair (MMR) pathway, a frequent mutational target in sporadic cancers as well as Lynch Syndrome, an inherited colorectal and endometrial cancer risk syndrome that affects approximately 1 in 300 individuals worldwide.
We have measured the functional status of over 98% of the possible missense variants across four key MMR genes (MSH2, MLH1, MSH6, and PMS2) and observe near-perfect concordance with existing clinical interpretations and previous functional studies. Several variants were identified where discordance between clinical interpretation and our functional measurement can be explained by the presence of a second variant in affected families. These exceptions underscore the importance of genetic context and motivate ongoing combinatorial mutagenesis screens.
Our variant-to-function maps have enabled the resolution of thousands of standing variants of uncertain significance (VUS) and are now assisting clinical variant interpretation in practice. Finally, I will share how we are extending these approaches to other key DNA repair pathways.