{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:44:26Z","timestamp":1790473466349,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1012066","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000}}],"reference-count":115,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Classical population genetics provides a robust, quantitative framework for modeling how natural selection acts on alleles that influence phenotypes with invariant fitness consequences for their carriers, such as running speed or drug resistance. By contrast, modifier theory considers the evolution of alleles that influence population genetic parameter values in their carriers, such as mutation or recombination rates. This is a more complicated problem. First, the fitness effects of modifier alleles reflect independently realized stochastic phenotype perturbations they induce in their carriers. And second, the association between modifier alleles and their induced phenotypes can decay over generations. Consequently, general results in modifier theory have been few. Here, we propose recasting modifier theory as exploring the evolution of alleles that influence the amount of stochasticity in inheritance, be it genetic, epigenetic, cytoplasmic or somatic transmission. We then present a toy model that predicts the existence of a selectively optimal amount of such \u201creproductive noise,\u201d which depends on the rate of environment change, the timescale of association between noise allele and induced phenotype, and population size. Next, we suggest that the same framework can be applied to the evolution of alleles that influence \u201cdevelopmental noise,\u201d i.e., the amount of stochastic phenotypic variation among genetically identical organisms reared in identical environments. This theoretical connection is timely, because high throughput assays are now demonstrating widespread heritability in the amount of developmental noise. Our approach also resolves the long-standing teleological criticism of the hypothesis that evolvability can evolve by natural selection. Taken together, this work demonstrates the opportunities for a robust, quantitative population genetic theory of alleles that influence the amount of biological noise.<\/jats:p>","DOI":"10.1371\/journal.pgen.1012066","type":"journal-article","created":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T17:38:34Z","timestamp":1773423514000},"page":"e1012066","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Wanted: A population genetic theory of biological noise regulation"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1424-7541","authenticated-orcid":true,"given":"Daniel M.","family":"Weinreich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-6067","authenticated-orcid":true,"given":"Tom","family":"Sgouros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1608-9479","authenticated-orcid":true,"given":"Yevgeniy","family":"Raynes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6384-8064","authenticated-orcid":true,"given":"Hlib","family":"Burtsev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edison","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8225-0788","authenticated-orcid":true,"given":"Sanyu","family":"Rajakumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3389-3389","authenticated-orcid":true,"given":"Ignacio G.","family":"Bravo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2715-8759","authenticated-orcid":true,"given":"Csenge","family":"Petak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"issue":"1","key":"pgen.1012066.ref001","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1146\/annurev-ecolsys-110316-022722","article-title":"Variability in fitness effects can preclude selection of the fittest","volume":"48","author":"CJ Graves","year":"2017","journal-title":"Annu Rev Ecol Evol Syst"},{"key":"pgen.1012066.ref002","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1515\/9781400848065-035","article-title":"Evolution of modifier genes and biological systems.","volume-title":"Princeton Guide to Evolution","author":"S. Otto","year":"2013"},{"issue":"12","key":"pgen.1012066.ref003","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/1521-1878(200012)22:12<1057::AID-BIES3>3.0.CO;2-W","article-title":"The evolution of mutation rates: separating causes from consequences","volume":"22","author":"PD Sniegowski","year":"2000","journal-title":"Bioessays"},{"issue":"3","key":"pgen.1012066.ref004","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1093\/genetics\/57.3.625","article-title":"Modification of linkage intensity by natural selection","volume":"57","author":"M Nei","year":"1967","journal-title":"Genetics"},{"issue":"3","key":"pgen.1012066.ref005","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/0040-5809(72)90007-X","article-title":"Selection for linkage modification. I. Random mating populations","volume":"3","author":"MW Feldman","year":"1972","journal-title":"Theor Popul Biol"},{"issue":"12","key":"pgen.1012066.ref006","doi-asserted-by":"crossref","first-page":"3611","DOI":"10.1073\/pnas.69.12.3611","article-title":"The evolutionary development of modifier genes","volume":"69","author":"S Karlin","year":"1972","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pgen.1012066.ref007","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/0040-5809(74)90052-5","article-title":"Towards a theory of the evolution of modifier genes","volume":"5","author":"S Karlin","year":"1974","journal-title":"Theor Popul Biol"},{"issue":"2","key":"pgen.1012066.ref008","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1093\/genetics\/152.2.485","article-title":"Mutators, Population Size, Adaptive Landscape and the Adaptation of Asexual Populations of Bacteria","volume":"152","author":"O Tenaillon","year":"1999","journal-title":"Genetics"},{"issue":"6023","key":"pgen.1012066.ref009","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1126\/science.1198914","article-title":"Second-order selection for evolvability in a large Escherichia coli population","volume":"331","author":"RJ Woods","year":"2011","journal-title":"Science"},{"key":"pgen.1012066.ref010","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1017\/S0016672308009579","article-title":"The hitch-hiking effect of a favourable gene","volume":"89","author":"JM Smith","year":"2007","journal-title":"Genet Res"},{"issue":"4","key":"pgen.1012066.ref011","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1093\/genetics\/134.4.1289","article-title":"The effect of deleterious mutations on neutral molecular variation","volume":"134","author":"B Charlesworth","year":"1993","journal-title":"Genetics"},{"issue":"896","key":"pgen.1012066.ref012","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1086\/497114","article-title":"The Evolution of Altruistic Behavior","volume":"97","author":"WD Hamilton","year":"1963","journal-title":"The American Naturalist"},{"issue":"4924","key":"pgen.1012066.ref013","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1038\/2011145a0","article-title":"Group selection and kin selection","volume":"201","author":"JM Smith","year":"1964","journal-title":"Nature"},{"issue":"5805","key":"pgen.1012066.ref014","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1126\/science.1133755","article-title":"Five rules for the evolution of cooperation","volume":"314","author":"MA Nowak","year":"2006","journal-title":"Science"},{"issue":"18","key":"pgen.1012066.ref015","doi-asserted-by":"crossref","first-page":"11555","DOI":"10.1128\/JVI.79.18.11555-11558.2005","article-title":"Adaptive value of high mutation rates of RNA viruses: separating causes from consequences","volume":"79","author":"SF Elena","year":"2005","journal-title":"J Virol"},{"issue":"29","key":"pgen.1012066.ref016","doi-asserted-by":"crossref","first-page":"10233","DOI":"10.1073\/pnas.0501062102","article-title":"The cost of replication fidelity in an RNA virus","volume":"102","author":"V Furi\u00f3","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pgen.1012066.ref017","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrg761","article-title":"Resolving the paradox of sex and recombination","volume":"3","author":"SP Otto","year":"2002","journal-title":"Nat Rev Genet"},{"issue":"12","key":"pgen.1012066.ref018","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1619655114","article-title":"Unified reduction principle for the evolution of mutation, migration, and recombination","volume":"114","author":"L Altenberg","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6634","key":"pgen.1012066.ref019","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/42701","article-title":"Evolution of high mutation rates in experimental populations of E. coli","volume":"387","author":"PD Sniegowski","year":"1997","journal-title":"Nature"},{"issue":"1","key":"pgen.1012066.ref020","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1073\/pnas.1219574110","article-title":"Mutation rate dynamics in a bacterial population reflect tension between adaptation and genetic load","volume":"110","author":"S Wielgoss","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"13","key":"pgen.1012066.ref021","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.1073\/pnas.1715996115","article-title":"Sign of selection on mutation rate modifiers depends on population size","volume":"115","author":"Y Raynes","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"pgen.1012066.ref022","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1093\/genetics\/117.3.559","article-title":"Selection, generalized transmission and the evolution of modifier genes. I. The reduction principle","volume":"117","author":"L Altenberg","year":"1987","journal-title":"Genetics"},{"issue":"1","key":"pgen.1012066.ref023","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1003167","article-title":"Mutational spectrum drives the rise of mutator bacteria","volume":"9","author":"A Couce","year":"2013","journal-title":"PLoS Genet"},{"issue":"5","key":"pgen.1012066.ref024","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1073\/pnas.1314423111","article-title":"Mutational landscape of yeast mutator strains","volume":"111","author":"A Serero","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1012066.ref025","doi-asserted-by":"crossref","first-page":"101953","DOI":"10.1016\/j.gde.2022.101953","article-title":"Recent insights into the evolution of mutation rates in yeast","volume":"76","author":"RH Melde","year":"2022","journal-title":"Curr Opin Genet Dev"},{"issue":"22","key":"pgen.1012066.ref026","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2207355120","article-title":"Shifts in mutation spectra enhance access to beneficial mutations","volume":"120","author":"M Sane","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pgen.1012066.ref027","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1038\/s41467-019-11217-6","article-title":"Mutation bias and GC content shape antimutator invasions","volume":"10","author":"A Couce","year":"2019","journal-title":"Nat Commun"},{"issue":"3","key":"pgen.1012066.ref028","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1093\/genetics\/156.3.1419","article-title":"Mutation-Selection Balance, Dominance and the Maintenance of Sex","volume":"156","author":"JR Chasnov","year":"2000","journal-title":"Genetics"},{"issue":"7320","key":"pgen.1012066.ref029","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/nature09449","article-title":"Higher rates of sex evolve in spatially heterogeneous environments","volume":"468","author":"L Becks","year":"2010","journal-title":"Nature"},{"key":"pgen.1012066.ref030","doi-asserted-by":"crossref","DOI":"10.5962\/bhl.title.27468","volume-title":"The genetical theory of natural selection","author":"RA Fisher","year":"1930"},{"issue":"2","key":"pgen.1012066.ref031","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/0040-5809(75)90012-X","article-title":"Modifier theory and meiotic drive","volume":"7","author":"DL Hartl","year":"1975","journal-title":"Theor Popul Biol"},{"issue":"6","key":"pgen.1012066.ref032","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.cell.2012.02.045","article-title":"Regulated noise in the epigenetic landscape of development and disease","volume":"148","author":"E Pujadas","year":"2012","journal-title":"Cell"},{"issue":"2","key":"pgen.1012066.ref033","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/j.1474-9726.2007.00281.x","article-title":"On the evolutionary origin of aging","volume":"6","author":"M Ackermann","year":"2007","journal-title":"Aging Cell"},{"issue":"1","key":"pgen.1012066.ref034","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1146\/annurev.ecolsys.39.110707.173441","article-title":"Nongenetic inheritance and its evolutionary implications","volume":"40","author":"R Bonduriansky","year":"2009","journal-title":"Annu Rev Ecol Evol Syst"},{"issue":"1","key":"pgen.1012066.ref035","doi-asserted-by":"crossref","first-page":"5141","DOI":"10.1038\/s41467-021-25315-x","article-title":"The microbiome extends host evolutionary potential","volume":"12","author":"LP Henry","year":"2021","journal-title":"Nat Commun"},{"issue":"10","key":"pgen.1012066.ref036","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1038\/s41556-024-01494-9","article-title":"Noncanonical inheritance of phenotypic information by protein amyloids","volume":"26","author":"M Eroglu","year":"2024","journal-title":"Nat Cell Biol"},{"key":"pgen.1012066.ref037","article-title":"Sign inversion in selection on ploidy","author":"Y Raynes","year":"2021","journal-title":"bioRxiv"},{"key":"pgen.1012066.ref038","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/1741-7007-9-24","article-title":"Polyploidization increases meiotic recombination frequency in Arabidopsis","volume":"9","author":"A Pecinka","year":"2011","journal-title":"BMC Biol"},{"issue":"24","key":"pgen.1012066.ref039","article-title":"The evolution of haploidy and diploidy","volume":"18","author":"SP Otto","year":"2008","journal-title":"Curr Biol"},{"issue":"5","key":"pgen.1012066.ref040","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1086\/587062","article-title":"A model for the evolution of assortative mating","volume":"171","author":"MAR de Cara","year":"2008","journal-title":"Am Nat"},{"issue":"1","key":"pgen.1012066.ref041","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1111\/j.1558-5646.1996.tb04504.x","article-title":"The role of genetic variation in adaptation and population persistence in a changing environment","volume":"50","author":"R Lande","year":"1996","journal-title":"Evolution"},{"issue":"4","key":"pgen.1012066.ref042","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1534\/genetics.113.151555","article-title":"Stabilizing selection, purifying selection, and mutational bias in finite populations","volume":"194","author":"B Charlesworth","year":"2013","journal-title":"Genetics"},{"issue":"11","key":"pgen.1012066.ref043","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1038\/s41559-024-02527-0","article-title":"Evolution of evolvability in rapidly adapting populations","volume":"8","author":"JT Ferrare","year":"2024","journal-title":"Nat Ecol Evol"},{"issue":"0","key":"pgen.1012066.ref044","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/BF02418571","article-title":"Sur les fonctions convexes et les in\u00e9galit\u00e9s entre les valeurs moyennes","volume":"30","author":"JLWV Jensen","year":"1906","journal-title":"Acta Math"},{"issue":"5","key":"pgen.1012066.ref045","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1093\/oxfordjournals.jhered.a111355","article-title":"The evolution of sex and recombination in a varying environment","volume":"84","author":"B Charlesworth","year":"1993","journal-title":"J Hered"},{"issue":"7","key":"pgen.1012066.ref046","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.0040216","article-title":"Environmental coupling of selection and heritability limits evolution","volume":"4","author":"AJ Wilson","year":"2006","journal-title":"PLoS Biol"},{"issue":"5513","key":"pgen.1012066.ref047","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1126\/science.1056421","article-title":"Costs and benefits of high mutation rates: adaptive evolution of bacteria in the mouse gut","volume":"291","author":"A Giraud","year":"2001","journal-title":"Science"},{"issue":"15","key":"pgen.1012066.ref048","doi-asserted-by":"crossref","first-page":"5792","DOI":"10.1073\/pnas.0801995105","article-title":"Differences in spontaneous mutation frequencies as a function of environmental stress in soil fungi at \u201cEvolution Canyon,\u201d Israel","volume":"105","author":"BC Lamb","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1012066.ref049","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/1471-2148-11-158","article-title":"Mutator dynamics in sexual and asexual experimental populations of yeast","volume":"11","author":"Y Raynes","year":"2011","journal-title":"BMC Evol Biol"},{"key":"pgen.1012066.ref050","article-title":"Adaptive tuning of mutation rates allows fast response to lethal stress in Escherichia coli","author":"T Swings","year":"2017","journal-title":"eLife"},{"issue":"3","key":"pgen.1012066.ref051","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1093\/gbe\/evz031","article-title":"Evolutionary Changes after Translational Challenges Imposed by Horizontal Gene Transfer","volume":"11","author":"S Bedhomme","year":"2019","journal-title":"Genome Biol Evol"},{"issue":"2","key":"pgen.1012066.ref052","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/BF00328720","article-title":"Selection against hypermutability in Escherichia coli during long term evolution","volume":"198","author":"W Tr\u00f6bner","year":"1984","journal-title":"Mol Gen Genet"},{"issue":"13","key":"pgen.1012066.ref053","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/j.cub.2012.04.056","article-title":"The evolution of low mutation rates in experimental mutator populations of Saccharomyces cerevisiae","volume":"22","author":"MJ McDonald","year":"2012","journal-title":"Curr Biol"},{"key":"pgen.1012066.ref054","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.63910","article-title":"Phenotypic and molecular evolution across 10,000 generations in laboratory budding yeast populations","volume":"10","author":"MS Johnson","year":"2021","journal-title":"eLife"},{"issue":"1","key":"pgen.1012066.ref055","doi-asserted-by":"crossref","first-page":"5090","DOI":"10.1038\/s41598-017-05214-2","article-title":"The evolutionary advantage of heritable phenotypic heterogeneity","volume":"7","author":"O Carja","year":"2017","journal-title":"Sci Rep"},{"issue":"3","key":"pgen.1012066.ref056","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1534\/genetics.106.067678","article-title":"Beneficial mutation selection balance and the effect of linkage on positive selection","volume":"176","author":"MM Desai","year":"2007","journal-title":"Genetics"},{"issue":"3","key":"pgen.1012066.ref057","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1093\/genetics\/76.3.601","article-title":"Nautural selection for within-generation variance in offspring number","volume":"76","author":"JH Gillespie","year":"1974","journal-title":"Genetics"},{"issue":"2","key":"pgen.1012066.ref058","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/genetics\/16.2.97","article-title":"Evolution in Mendelian Populations","volume":"16","author":"S Wright","year":"1931","journal-title":"Genetics"},{"issue":"11","key":"pgen.1012066.ref059","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nrg.2016.104","article-title":"Genetic drift, selection and the evolution of the mutation rate","volume":"17","author":"M Lynch","year":"2016","journal-title":"Nat Rev Genet"},{"issue":"8","key":"pgen.1012066.ref060","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.tig.2010.05.003","article-title":"Evolution of the mutation rate","volume":"26","author":"M Lynch","year":"2010","journal-title":"Trends Genet"},{"key":"pgen.1012066.ref061","article-title":"When good mutations go bad: how population size can change the direction of natural selection","author":"Y Raynes","year":"2021","journal-title":"bioRxiv"},{"issue":"2","key":"pgen.1012066.ref062","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1534\/genetics.116.186916","article-title":"An Evolving Genetic Architecture Interacts with Hill-Robertson Interference to Determine the Benefit of Sex","volume":"203","author":"AOB Whitlock","year":"2016","journal-title":"Genetics"},{"issue":"3","key":"pgen.1012066.ref063","doi-asserted-by":"crossref","DOI":"10.1086\/731461","article-title":"(Epi)mutation Rates and the Evolution of Composite Trait Architectures","volume":"204","author":"B Polizzi","year":"2024","journal-title":"Am Nat"},{"issue":"4","key":"pgen.1012066.ref064","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1086\/394109","article-title":"The Idea of Information in Biology","volume":"74","author":"JM Smith","year":"1999","journal-title":"Quart Rev Biol"},{"issue":"5584","key":"pgen.1012066.ref065","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1126\/science.1070919","article-title":"Stochastic gene expression in a single cell","volume":"297","author":"MB Elowitz","year":"2002","journal-title":"Science"},{"issue":"1","key":"pgen.1012066.ref066","doi-asserted-by":"crossref","DOI":"10.1016\/j.cub.2017.11.058","article-title":"Stochasticity, individuality and behavior","volume":"28","author":"K Honegger","year":"2018","journal-title":"Curr Biol"},{"issue":"4","key":"pgen.1012066.ref067","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41576-020-00304-w","article-title":"Molecular and evolutionary processes generating variation in gene expression","volume":"22","author":"MS Hill","year":"2021","journal-title":"Nat Rev Genet"},{"issue":"1","key":"pgen.1012066.ref068","doi-asserted-by":"crossref","DOI":"10.1016\/j.devcel.2024.09.015","article-title":"Multimodal screen identifies noise-regulatory proteins","volume":"60","author":"\u00d3 Garc\u00eda-Blay","year":"2025","journal-title":"Dev Cell"},{"issue":"5","key":"pgen.1012066.ref069","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1113\/JP288218","article-title":"Multinucleation as a buffer against gene expression noise in syncytial myofibres","volume":"603","author":"K-A Hansson","year":"2025","journal-title":"J Physiol"},{"issue":"10","key":"pgen.1012066.ref070","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/nrg2662","article-title":"The evolutionary consequences of erroneous protein synthesis","volume":"10","author":"DA Drummond","year":"2009","journal-title":"Nat Rev Genet"},{"issue":"4","key":"pgen.1012066.ref071","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01018-18","article-title":"Errors during gene expression: single-cell heterogeneity, stress resistance, and microbe-host interactions","volume":"9","author":"CR Evans","year":"2018","journal-title":"mBio"},{"key":"pgen.1012066.ref072","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.sbi.2017.11.001","article-title":"Shining a light on enzyme promiscuity","volume":"47","author":"SD Copley","year":"2017","journal-title":"Curr Opin Struct Biol"},{"issue":"25","key":"pgen.1012066.ref073","doi-asserted-by":"crossref","first-page":"10036","DOI":"10.1073\/pnas.1105937108","article-title":"Evolutionary origin of a novel gene expression pattern through co-option of the latent activities of existing regulatory sequences","volume":"108","author":"M Rebeiz","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pgen.1012066.ref074","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jsbmb.2014.09.010","article-title":"Biological messiness vs. biological genius: Mechanistic aspects and roles of protein promiscuity","volume":"151","author":"WM Atkins","year":"2015","journal-title":"J Steroid Biochem Mol Biol"},{"issue":"5884","key":"pgen.1012066.ref075","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1126\/science.1158868","article-title":"Metamorphic proteins","volume":"320","author":"AG Murzin","year":"2008","journal-title":"Science"},{"issue":"23","key":"pgen.1012066.ref076","doi-asserted-by":"crossref","first-page":"5968","DOI":"10.1073\/pnas.1800168115","article-title":"Extant fold-switching proteins are widespread","volume":"115","author":"LL Porter","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pgen.1012066.ref077","doi-asserted-by":"crossref","first-page":"3177","DOI":"10.1038\/s41467-023-38519-0","article-title":"Identification of a covert evolutionary pathway between two protein folds","volume":"14","author":"D Chakravarty","year":"2023","journal-title":"Nat Commun"},{"issue":"9","key":"pgen.1012066.ref078","doi-asserted-by":"crossref","DOI":"10.1002\/bies.202300057","article-title":"Fluid protein fold space and its implications","volume":"45","author":"LL Porter","year":"2023","journal-title":"Bioessays"},{"issue":"3","key":"pgen.1012066.ref079","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.cell.2009.07.046","article-title":"Architecture-Dependent Noise Discriminates Functionally Analogous Differentiation Circuits","volume":"139","author":"T Ca\u011fatay","year":"2009","journal-title":"Cell"},{"key":"pgen.1012066.ref080","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.coisb.2018.02.010","article-title":"Living with noise: On the propagation of noise from molecules to phenotype and fitness","volume":"8","author":"FJ Bruggeman","year":"2018","journal-title":"Curr Opin Syst Biol"},{"issue":"3","key":"pgen.1012066.ref081","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.biosystems.2012.05.013","article-title":"Mechanisms of developmental robustness","volume":"109","author":"VV Gursky","year":"2012","journal-title":"Biosystems"},{"issue":"1712","key":"pgen.1012066.ref082","first-page":"1601","article-title":"Modes of response to environmental change and the elusive empirical evidence for bet hedging","volume":"278","author":"AM Simons","year":"2011","journal-title":"Proc Biol Sci"},{"key":"pgen.1012066.ref083","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-33038-9_110-1","article-title":"Developmental Plasticity and Evolution.","volume-title":"Evolutionary Developmental Biology","author":"AB Paaby","year":"2018"},{"issue":"3","key":"pgen.1012066.ref084","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/brv.12476","article-title":"A long winter for the Red Queen: rethinking the evolution of seasonal migration","volume":"94","author":"BM Winger","year":"2019","journal-title":"Biol Rev Camb Philos Soc"},{"issue":"1","key":"pgen.1012066.ref085","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1093\/genetics\/74.1.171","article-title":"Selection of Migration Modification","volume":"74","author":"BJ Balkau","year":"1973","journal-title":"Genetics"},{"issue":"6844","key":"pgen.1012066.ref086","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/35085569","article-title":"Evolution of digital organisms at high mutation rates leads to survival of the flattest","volume":"412","author":"CO Wilke","year":"2001","journal-title":"Nature"},{"issue":"4","key":"pgen.1012066.ref087","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1111\/j.1420-9101.2009.01697.x","article-title":"Survival of the steepest: hypersensitivity to mutations as an adaptation to soft selection","volume":"22","author":"M Archetti","year":"2009","journal-title":"J Evol Biol"},{"issue":"51","key":"pgen.1012066.ref088","doi-asserted-by":"crossref","first-page":"19402","DOI":"10.1073\/pnas.0608569103","article-title":"Evolutionary theory for modifiers of epistasis using a general symmetric model","volume":"103","author":"U Liberman","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"679","key":"pgen.1012066.ref089","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1086\/280193","article-title":"The Possible Modification of the Response of the Wild Type to Recurrent Mutations","volume":"62","author":"RA Fisher","year":"1928","journal-title":"Am Natur"},{"issue":"2","key":"pgen.1012066.ref090","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1558-5646.2007.00303.x","article-title":"Evolution of evolvability in a developmental model","volume":"62","author":"J Draghi","year":"2008","journal-title":"Evolution"},{"issue":"1713","key":"pgen.1012066.ref091","first-page":"1903","article-title":"Evolution of adaptive phenotypic variation patterns by direct selection for evolvability","volume":"278","author":"M Pavlicev","year":"2011","journal-title":"Proc Biol Sci"},{"issue":"2","key":"pgen.1012066.ref092","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/molbev\/msl172","article-title":"The conversion of 3\u2019 UTRs into coding regions","volume":"24","author":"MG Giacomelli","year":"2007","journal-title":"Mol Biol Evol"},{"issue":"1","key":"pgen.1012066.ref093","doi-asserted-by":"crossref","first-page":"3754","DOI":"10.1093\/gbe\/evz275","article-title":"High Transcriptional Error Rates Vary as a Function of Gene Expression Level","volume":"12","author":"KM Meer","year":"2020","journal-title":"Genome Biol Evol"},{"key":"pgen.1012066.ref094","first-page":"2023","article-title":"A narrow range of transcript-error rates across the tree of life","author":"W Li","year":"2023","journal-title":"bioRxiv"},{"issue":"1","key":"pgen.1012066.ref095","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1186\/s13059-017-1344-6","article-title":"The fitness cost of mis-splicing is the main determinant of alternative splicing patterns","volume":"18","author":"B Saudemont","year":"2017","journal-title":"Genome Biol"},{"issue":"1","key":"pgen.1012066.ref096","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1146\/annurev-ecolsys-110218-024613","article-title":"An integrative framework for understanding the mechanisms and multigenerational consequences of transgenerational plasticity","volume":"50","author":"AM Bell","year":"2019","journal-title":"Annu Rev Ecol Evol Syst"},{"issue":"4","key":"pgen.1012066.ref097","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.tpb.2007.08.006","article-title":"The evolution of bet-hedging adaptations to rare scenarios","volume":"72","author":"OD King","year":"2007","journal-title":"Theor Popul Biol"},{"key":"pgen.1012066.ref098","doi-asserted-by":"crossref","first-page":"111270","DOI":"10.1016\/j.jtbi.2022.111270","article-title":"Effect of compositional fluctuation on the survival of bet-hedging species","volume":"553","author":"X Zhou","year":"2022","journal-title":"J Theor Biol"},{"issue":"6","key":"pgen.1012066.ref099","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1086\/735690","article-title":"Beyond the (Geometric) Mean: Stochastic Models Undermine Deterministic Predictions of Bet Hedger Evolution","volume":"205","author":"M Weissman","year":"2025","journal-title":"Am Nat"},{"issue":"2","key":"pgen.1012066.ref100","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/BF00312603","article-title":"Translational accuracy and sexual differentiation in Chlamydomonas reinhardtii","volume":"18","author":"L Bult\u00e9","year":"1990","journal-title":"Curr Genet"},{"issue":"1","key":"pgen.1012066.ref101","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.tree.2023.08.014","article-title":"Beyond reaction norms: the temporal dynamics of phenotypic plasticity","volume":"39","author":"L Dupont","year":"2024","journal-title":"Trends Ecol Evol"},{"issue":"6","key":"pgen.1012066.ref102","doi-asserted-by":"crossref","DOI":"10.1093\/femsre\/fuae029","article-title":"Why HPV16? Why, now, HPV42? How the discovery of HPV42 in rare cancers provides an opportunity to challenge our understanding about the transition between health and disease for common members of the healthy microbiota","volume":"48","author":"IG Bravo","year":"2024","journal-title":"FEMS Microbiol Rev"},{"issue":"7","key":"pgen.1012066.ref103","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1010833","article-title":"Characterizing the landscape of gene expression variance in humans","volume":"19","author":"S Wolf","year":"2023","journal-title":"PLoS Genet"},{"issue":"3","key":"pgen.1012066.ref104","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1111\/j.1558-5646.1996.tb02339.x","article-title":"Perspective: complex adaptations and the evolution of evolvability","volume":"50","author":"GP Wagner","year":"1996","journal-title":"Evolution"},{"issue":"6796","key":"pgen.1012066.ref105","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/35020564","article-title":"Evolvability of an RNA virus is determined by its mutational neighbourhood","volume":"406","author":"CL Burch","year":"2000","journal-title":"Nature"},{"issue":"19","key":"pgen.1012066.ref106","doi-asserted-by":"crossref","DOI":"10.1016\/j.cub.2006.08.080","article-title":"Evolvability","volume":"16","author":"PD Sniegowski","year":"2006","journal-title":"Curr Biol"},{"issue":"9","key":"pgen.1012066.ref107","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.tig.2010.06.002","article-title":"Robustness and evolvability","volume":"26","author":"J Masel","year":"2010","journal-title":"Trends Genet"},{"key":"pgen.1012066.ref108","doi-asserted-by":"crossref","first-page":"8597","DOI":"10.1073\/pnas.0702207104","article-title":"The frailty of adaptive hypotheses for the origins of organismal complexity","volume":"104","author":"M Lynch","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pgen.1012066.ref109","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/BF00127472","article-title":"Evolutionary plasticity in prokaryotes: A panglossian view: Evolutionary plasticity in prokaryotes","volume":"11","author":"M Weber","year":"1996","journal-title":"Biol Philos"},{"issue":"1","key":"pgen.1012066.ref110","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nrg2278","article-title":"Is evolvability evolvable?","volume":"9","author":"M Pigliucci","year":"2008","journal-title":"Nat Rev Genet"},{"issue":"2","key":"pgen.1012066.ref111","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.tree.2015.11.009","article-title":"How can evolution learn?","volume":"31","author":"RA Watson","year":"2016","journal-title":"Trends in Ecology & Evolution"},{"issue":"6","key":"pgen.1012066.ref112","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/evlett\/qrad048","article-title":"The evolution of genetic covariance and modularity as a result of multigenerational environmental fluctuation","volume":"7","author":"I do O","year":"2023","journal-title":"Evol Lett"},{"issue":"1","key":"pgen.1012066.ref113","doi-asserted-by":"crossref","first-page":"9364","DOI":"10.1038\/s41598-017-06574-5","article-title":"Evolution of risk preference is determined by reproduction dynamics, life history, and population size","volume":"7","author":"O Kolodny","year":"2017","journal-title":"Sci Rep"},{"key":"pgen.1012066.ref114","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jtbi.2019.01.023","article-title":"The impact of truncation selection and diffusion on cooperation in spatial games","volume":"466","author":"B Morsky","year":"2019","journal-title":"J Theor Biol"},{"issue":"9","key":"pgen.1012066.ref115","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s00439-017-1809-4","article-title":"Deep intronic mutations and human disease","volume":"136","author":"R Vaz-Drago","year":"2017","journal-title":"Hum Genet"}],"updated-by":[{"DOI":"10.1371\/journal.pgen.1012066","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000}}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1012066","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T17:45:52Z","timestamp":1773942352000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1012066"}},"subtitle":[],"editor":[{"given":"Justin C.","family":"Fay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,13]]},"references-count":115,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1012066","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,13]]}}}