David McCandlish

David McCandlish

Associate Professor
Cancer Center Member

Ph.D., Duke University, 2012

mccandlish@cshl.edu | 516-367-5286

Faculty Profile

Some mutations are harmful but others are benign. How can we predict the effects of mutations, both singly and in combination? Using data from experiments that simultaneously measure the effects of thousands of mutations, I develop computational tools to predict the functional impact of mutations and apply these tools to problems in protein design, molecular evolution, and cancer.

The McCandlish lab develops computational and mathematical tools to analyze and exploit data from high-throughput functional assays. The current focus of the lab is on analyzing data from so-called “deep mutational scanning” experiments. These experiments simultaneously determine, for a single protein, the functional effects of thousands of mutations. By aggregating information across the proteins assayed using this technique, we seek to develop data-driven insights into basic protein biology, improved models of molecular evolution, and more accurate methods for predicting the functional effects of mutations in human genome sequences.

Critically, these data also show that the functional effects of mutations often depend on which other mutations are present in the sequence. We are developing new techniques in statistics and machine learning to infer and interpret the complex patterns of genetic interaction observed in these experiments. Our ultimate goal is to be able to model these sequence-function relationships with sufficient accuracy to guide the construction of a new generation of designed enzymes and drugs, and to be able to predict the evolution of drug resistance phenotypes in both populations of cancer cells and rapidly evolving microbial pathogens.

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All Publications

Specificity, synergy, and mechanisms of splice-modifying drugs

29 Feb 2024 | Nature Communications | 15(1):1880
Ishigami, Yuma, Wong, Mandy, Martí-Gómez, Carlos, Ayaz, Andalus, Kooshkbaghi, Mahdi, Hanson, Sonya, McCandlish, David, Krainer, Adrian, Kinney, Justin

Evolutionary paths that link orthogonal pairs of binding proteins

13 Dec 2023 | Research Square Platform LLC
Avizemer, Ziv, Martí‐Gómez, Carlos, Hoch, Shlomo, McCandlish, David, Fleishman, Sarel

Interpreting cis -regulatory mechanisms from genomic deep neural networks using surrogate models

16 Nov 2023 | bioRxiv
Seitz, Evan, McCandlish, David, Kinney, Justin, Koo, Peter

Idiosyncratic and dose-dependent epistasis drives variation in tomato fruit size

20 Oct 2023 | Science | 382(6668):315-320
Aguirre, Lyndsey, Hendelman, Anat, Hutton, Samuel, McCandlish, David, Lippman, Zachary

Mutation and Selection Induce Correlations between Selection Coefficients and Mutation Rates

Oct 2023 | The American Naturalist | 202(4):534-557
Gitschlag, Bryan, Cano, Alejandro, Payne, Joshua, McCandlish, David, Stoltzfus, Arlin

Protein evolvability under rewired genetic codes

23 Jun 2023 | bioRxiv
Rozhoňová, Hana, Martí-Gómez, Carlos, McCandlish, David, Payne, Joshua

Mutation bias and the predictability of evolution

22 May 2023 | Philosophical Transactions of the Royal Society of London. Biological Sciences | 378(1877):20220055
Cano, Alejandro, Gitschlag, Bryan, Rozhoňová, Hana, Stoltzfus, Arlin, McCandlish, David, Payne, Joshua

Designed active-site library reveals thousands of functional GFP variants

20 May 2023 | Nature Communications | 14(1):2890
Weinstein, Jonathan, Martí-Gómez, Carlos, Lipsh-Sokolik, Rosalie, Hoch, Shlomo, Liebermann, Demian, Nevo, Reinat, Weissman, Haim, Petrovich-Kopitman, Ekaterina, Margulies, David, Ivankov, Dmitry, McCandlish, David, Fleishman, Sarel

Cachexia: A systemic consequence of progressive, unresolved disease

27 Apr 2023 | Cell | 186(9):1824-1845
Ferrer, Miriam, Anthony, Tracy, Ayres, Janelle, Biffi, Giulia, Brown, Justin, Caan, Bette, Cespedes Feliciano, Elizabeth, Coll, Anthony, Dunne, Richard, Goncalves, Marcus, Grethlein, Jonas, Heymsfield, Steven, Hui, Sheng, Jamal-Hanjani, Mariam, Lam, Jie, Lewis, David, McCandlish, David, Mustian, Karen, O'Rahilly, Stephen, Perrimon, Norbert, White, Eileen, Janowitz, Tobias

Evolutionary paths that link orthogonal pairs of binding proteins.

20 Apr 2023
Avizemer, Ziv, Martí-Gómez, Carlos, Hoch, Shlomo, McCandlish, David, Fleishman, Sarel

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