Education & Training
- BA-Physics and Molecular & Cell Biology, Univ. of California, Berkeley, 1990
- PhD-Biophysics, Harvard University, 1998
Research Interest Summary
Research Categories
Research Interests
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.
Representative Publications
DK Kim*, B Weller*, CW Lin*, D Sheykhkarimli*, JJ Knapp*, G Dugied, A Zanzoni, C Pons, MJ Tofaute, SB Maseko, K Spirohn, F Laval, L Lambourne, N Kishore, A Rayhan, M Sauer, V Young, H Halder, N Marin-de la Rosa, O Pogoutse, A Strobel, P Schwehn, R Li, S Rothballer, M Altmann, P Cassonnet, G Dugied, AG Cote, LE Vergara, I Hazelwood, BB Liu, M Nguyen, R Pandiarajan, B Dohai, PAR Coloma, J Poirson, P Giuliana, L Willems, M Taipale, Yves Jacob, Tong Hao, DE Hill, C Brun, JC Twizere, D Krapmann, M Heinig, C Falter, P Aloy, C Demeret†, M Vidal†, MA Calderwood†, FP Roth†, P Falter-Braun†. A proteome-scale map of the SARS-CoV-2 human contactome. Nature Biotechnology 41(1):140-149 (2023).
Y Wu, R Li, S Sun, J Weile, FP Roth†. Improved pathogenicity prediction for rare human missense variants. American Journal of Human Genetics 108(10):1891-1906 (2021).
W van Loggerenberg*, S Sowlati-Hashjin*, J Weile, R Hamilton, A Chawla, L Fresard, S Mustajoki, E Pischik, E Di Pierro, M Barbaro, Y Floderus, C Schmitt, L Gouya, A Colavin, R Nussbaum, ECH Friesema, R Kauppinen, J To-Figueras, AK Aarsand, RJ Desnick‡, M Garton†‡, FP Roth†‡. Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation. American Journal of Human Genetics 110(10):1769-1786 (2023).
A Celaj, M Gebbia, L Musa, AG Cote, J Snider, V Wong, M Ko, T Fong, P Bansal, JC Mellor, G Seesankar, M Nguyen, S Zhou, L Wang, N Kishore, I Stagljar, Y Suzuki, N Yachie† & FP Roth†. Highly combinatorial genetic interaction analysis reveals a multi-drug transporter influence network. Cell Systems 9:1-14 (2020).
J Weile, N Kishore, S Sun, R Maaieh, M Verby, R Li, I Fotiadou, J Kitaygorodsky, Y Wu, A Holenstein, Cé Bürer, L Blomgren, S Yang, R Nussbaum, R Rozen, D Watkins, M Gebbia, V Kozich, M Garton, DS Froese, FP Roth†. Shifting landscapes of human MTHFR missense variant effects. American Journal of Human Genetics 108(7):1283-1300 (2021).
K Luck*, D-K Kim*, L Lambourne*, K Spirohn*, BE Begg, W Bian, R Brignall, T Cafarelli, FJ Campos-Laborie, B Charloteaux, D Choi, AG Cote, M Daley, S Deimling, A Desbuleux, A Dricot, M Gebbia, MF Hardy, N Kishore, JJ Knapp, IA Kovács, I Lemmens, MW Mee, JC Mellor, C Pollis, C Pons, AD Richardson, S Schlabach, B Teeking, A Yadav, M Babor, D Balcha, O Basha, S-F Chin, SG Choi, C Colabella, G Coppin, C D'Amata, D De Ridder, S De Rouck, M Duran-Frigola, H Ennajdaoui, F Goebels, A Gopal, G Haddad, M Helmy, Y Jacob, Y Kassa, R Li, N van Lieshout, A MacWilliams, D Markey, JN Paulson, S Rangarajan, J Rasla, A Rayhan, T Rolland, A San Miguel, Y Shen, D Sheykhkarimli, GM Sheynkman, E Simonovsky, M Tasan, A Tejeda, J-C Twizere, Y Wang, R Weatheritt, J Weile, Y Xia, X Yang, E Yeger-Lotem, Q Zhong, P Aloy, GD Bader, J De Las Rivas, S Gaudet, T Hao, J Rak, J Tavernier, V Tropepe, DE Hill†, M Vidal†, FP Roth†, MA Calderwood†. A reference map of the human protein interactome. Nature 580(7803):402-408 (2020).
S Sun*, J Weile*,†, M Verby, Y Wu, Wang, Y, AG Cote, I Fotiadou, J Kitaygorodsky, M Vidal, J Rine, P Ješina, V Kozich†, FP Roth†. A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase. Genome Medicine 12(1):13 (2020).
JJ Diaz-Mejia, A Celaj, JC Mellor, A Cote, A Balint, B Ho, P Bansal, F Shaeri, M Gebbia, J Weile, M Verby, A Karkhanina, Y Zhang, C Wong, J Rich, D Prendergast, G Gupta, S Ozturk, D Durocher, GW Brown, FP Roth†. Mapping DNA-damage-dependent genetic interactions in yeast via party mating and barcode fusion genetics. Molecular Systems Biology (2018).
J Weile, S Sun, AG Cote, J Knapp, M Verby, JC Mellor, Y Wu, C Pons, C Wong, N van Lieshout, F Yang, M Tasan, G Tan, S Yang, DM Fowler, R Nussbaum, JD Bloom, M Vidal, DE Hill, P Aloy & FP Roth†. A framework for exhaustively mapping functional missense variants. Molecular Systems Biology 13(12):957 (2017).
J van Leeuwen*, C Pons*, JC Mellor, TN Yamaguchi, H Friesen, J Koschwanez, MM Ušaj, M Pechlaner, M Takar, M Ušaj, B VanderSluis, K Andrusiak, P Bansal, A Baryshnikova, C Boone, J Cao, A Cote, M Gebbia, G Horecka, I Horecka, E Kuzmin, N Legro, W Liang, N van Lieshout, M McNee, B-J San Luis, F Shaeri, E Shuteriqi, S Sun, Lu Yang, J-Y Youn, M Yuen, M Costanzo, A-C Gingras, P Aloy, C Oostenbrink, A Murray, TR Graham, CL Myers†, BJ Andrews†, FP Roth† & C Boone†. Exploring genetic suppression interactions on a global scale. Science 354(6312):pii:aag0839 (2016).