A general calculus of fitness landscapes finds genes under selection in cancers
- Teng-Kuei Hsu1,12,
- Jennifer Asmussen2,12,
- Amanda Koire3,
- Byung-Kwon Choi2,
- Mayur A. Gadhikar4,
- Eunna Huh5,
- Chih-Hsu Lin3,
- Daniel M. Konecki3,
- Young Won Kim6,
- Curtis R. Pickering4,
- Marek Kimmel7,8,
- Lawrence A. Donehower9,
- Mitchell J. Frederick10,
- Jeffrey N. Myers4,
- Panagiotis Katsonis2 and
- Olivier Lichtarge1,2,3,5,6,11
- 1Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
- 3Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, Texas 77030, USA;
- 4Department of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 5Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 6Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA;
- 7Departments of Statistics and Bioengineering, Rice University, Houston, Texas 77005, USA;
- 8Department of Systems Engineering and Biology, Silesian University of Technology, 44-100 Gliwice, Poland;
- 9Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA;
- 10Department of Otolaryngology–Head and Neck Surgery, Baylor College of Medicine, Houston, Texas 77030, USA;
- 11Computational and Integrative Biomedical Research Center, Baylor College of Medicine, Houston, Texas 77030, USA
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↵12 These authors contributed equally to this work.
Abstract
Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits. Over cancer cohorts, integration identified 460 likely tumor-driving genes. Many have literature and experimental support but had eluded prior genomic searches for positive selection in tumors. Beyond providing cancer insights, these results introduce a general calculus of evolution to quantify the genotype–phenotype relationship and discover genes associated with complex traits and diseases.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.275811.121.
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Freely available online through the Genome Research Open Access option.
- Received May 25, 2021.
- Accepted March 14, 2022.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
