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Frederick (Fritz) Roth

Frederick (Fritz) Roth, Ph.D.
Professor and John K. Vries Chair

Ph.D. in Biophysics, Harvard University
Fritz Roth

Phone: (412) 648-3332

Research Summary

We use both computational and large-scale experimental approaches to measure functional impacts of human sequence variation, and to map dynamic protein-protein interactions.

My team develops and applies experimental and computational genomic technology, and loves interdisciplinary collaborations.

The major focus of the lab is on generating comprehensive experimental maps of functional sequence variation and establishing their clinical utility (‘variant effect maps’). We continue computational efforts related to variant effect mapping, including methods and tools for imputing missing data, estimating uncertainty in variant impact scores, and refining functional scores. We continue to maintain a platform for international community coordination for variant effect mapping, and tools for prioritizing variant effect mapping projects. We are further developing VARITY, currently the best-performing supervised pathogenicity predictor for rare human missense variants. Experimentally, my lab continues to generate variant effect maps for human proteins (beyond the 20+ proteins targeted thus far), using both humanized yeast and human cells as model systems, with increasing focus on understanding the environment- and context-dependence of variant effect maps, and on applications assisting clinical variant interpretation and revealing new gene-trait associations.

Another focus is on the systematic discovery of protein interactions, especially environment- and genetic background-dependent protein interactions, using massively-multiplexed interaction assays enabled by next-generation sequencing. We are currently extending the barcode fusion genetics strategy we developed in yeast for large-scale protein interaction screening in cultured human cells, and developing a technology with the potential to measure dynamic time-courses of protein interaction at proteome scale with ~10 minute temporal resolution.

Recent Publications
Kim DK, Lin CW, Knapp JJ, Dugied G, Zanzoni A, Pons C, Tofaute MJ, Maseko SB, Spirohn K, Laval F, Lambourne L, Kishore N, Rayhn A, Sauer M, Young V, Halder H, Marin-de la, Pogoutse O, Strobel A, Schwehn P, Li R, Rothballer S, Altmann M, Cassonnet P, Dugied G, Cote AG, Vergara LE, Hazelwood I, Liu BB, Nguyen M, Pandiarajan R, Dohei B, Coloma PAR, Poirson J, Guiliana P, Willems L, Taipale M, Jacob Y, Hao T, Hill DE, Brun C, Twizere JC, Krapmann D, Heinig M, Falter C, Aloy P, Demeret C, Vidal M, Calderwood MA, Roth FP, Falter-Braun P (2024) A proteome-scale map of the SARS-CoV-2 human contactome Nature Biotechnology. 41: 140-149

vanLoggerenberg W, Sowlati-Hashjin S, Weile J, Hamilton R, Chawla A, Fresard L, Mustajoki S, Pischik E, Di Pie, Barbaro M, Floderus Y, Schmitt C, Gouya L, Colavin A, Nussbaum R, Friesema ECH, Kauppinen R, To-Figueras J, Aarsand AK, Desnick RJ, Garton M, Roth FP (2023) Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation American Journal of Human Genetics. 110: 1769-1786

Wu Y, Li R, Sun S, Weile J, Roth FP (2021) Improved pathogenicity prediction for rare human missense variants American Journal of Human Genetics. 108: 1891-1906