A general calculus of fitness landscapes finds genes under selection in cancers
- Teng-Kuei Hsu1,
- Jennifer Kay Asmussen1,
- Amanda Michele Koire1,
- Byung-Kwon Choi1,
- Mayur Arvind Gadhikar1,
- Eunna Huh1,
- Chih-Hsu Lin1,
- Daniel Manuka Konecki1,
- Young Won Kim1,
- Curtis Pickering2,
- Marek Kimmel3,
- Lawrence Allen Donehower1,
- Mitchell Jay Frederick1,
- Jeffrey N Myers2,
- Panagiotis Katsonis1,4 and
- Olivier Lichtarge1
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.
- Received May 25, 2021.
- Accepted March 14, 2022.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International license), as described at http://creativecommons.org/licenses/by-nc/4.0/.
