ArticleGenetics2016
Stochasticity in the Genotype-Phenotype Map: Implications for the Robustness and Persistence of Bet-Hedging.
Article in Genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 45 citations in OpenAlex.
- Reducing phenotype-structured partial differential equations models of cancer evolution to systems of ordinary differential equations: a generalised moment dynamics approach.Journal of mathematical biology · 2025Article
- EMT-driven plasticity prospectively increases cell-cell variability to promote therapeutic adaptation in breast cancer.Cancer cell international · 2025Article
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- Using chronobiology-based second-generation artificial intelligence digital system for overcoming antimicrobial drug resistance in chronic infections.Annals of medicine · 2023Review
- Phenotypic heterogeneity in human genetic diseases: ultrasensitivity-mediated threshold effects as a unifying molecular mechanism.Journal of biomedical science · 2023Review
- Multivalent state transitions shape the intratumoral composition of small cell lung carcinoma.Science advances · 2022Article
- Review
- Roadmap on plasticity and epigenetics in cancer.Physical biology · 2022Review
- Evolution of Bacterial Persistence to Antibiotics during a 50,000-Generation Experiment in an Antibiotic-Free Environment.Antibiotics (Basel, Switzerland) · 2022Article
- Cross-Resistance Among Sequential Cancer Therapeutics: An Emerging Issue.Frontiers in oncology · 2022Review
- Bet-hedging in innate and adaptive immune systems.Evolution, medicine, and public health · 2022Article
- Protein conformational dynamics and phenotypic switching.Biophysical reviews · 2021Review
- The role of memory in non-genetic inheritance and its impact on cancer treatment resistance.PLoS computational biology · 2021Article
- Group Behavior and Emergence of Cancer Drug Resistance.Trends in cancer · 2021Review
- Persistence as an Optimal Hedging Strategy.Biophysical journal · 2021Article
- Genotype networks of 80 quantitative Arabidopsis thaliana phenotypes reveal phenotypic evolvability despite pervasive epistasis.PLoS computational biology · 2020Article
- Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.Nature communications · 2020Article
- Understanding the role of phenotypic switching in cancer drug resistance.Journal of theoretical biology · 2020Article
- Evolutionary dynamics of competing phenotype-structured populations in periodically fluctuating environments.Journal of mathematical biology · 2020Article
- Model genotype-phenotype mappings and the algorithmic structure of evolution.Journal of the Royal Society, Interface · 2019Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Nongenetic variation in phenotypes, or bet-hedging, has been observed as a driver of drug resistance in both bacterial infections and cancers. Here, we study how bet-hedging emerges in genotype-phenotype (GP) mapping through a simple interaction model: a molecular switch. We use simple chemical reaction networks to implement stochastic switches that map gene products to phenotypes, and investigate the impact of structurally distinct mappings on the evolution of phenotypic heterogeneity. Bet-hedging naturally emerges within this model, and is robust to evolutionary loss through mutations to both the expression of individual genes, and to the network itself. This robustness explains an apparent paradox of bet-hedging-why does it persist in environments where natural selection necessarily acts to remove it? The structure of the underlying molecular mechanism, itself subject to selection, can slow the evolutionary loss of bet-hedging to ensure a survival mechanism against environmental catastrophes even when they are rare. Critically, these properties, taken together, have profound implications for the use of treatment-holidays to combat bet-hedging-driven resistant disease, as the efficacy of breaks from treatment will ultimately be determined by the structure of the GP mapping.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.