robustness (evolution)

Mutational robustness (also called mutation tolerance) describes the extent to which an organism's phenotype remains constant in spite of mutation. Robustness can be empirically measured for several genomes{{cite journal|last=Sanjuán|first=R|title=Mutational fitness effects in RNA and single-stranded DNA viruses: common patterns revealed by site-directed mutagenesis studies.|journal=Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences|date=Jun 27, 2010|volume=365|issue=1548|pages=1975–82|pmid=20478892|doi=10.1098/rstb.2010.0063|pmc=2880115}}{{cite journal|last=Eyre-Walker|first=A|author2=Keightley, PD |title=The distribution of fitness effects of new mutations.|journal=Nature Reviews Genetics|date=Aug 2007|volume=8|issue=8|pages=610–8|pmid=17637733|doi=10.1038/nrg2146|s2cid=10868777}} and individual genes{{cite journal|last=Hietpas|first=RT|author2=Jensen, JD |author3=Bolon, DN |title=Experimental illumination of a fitness landscape.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=May 10, 2011|volume=108|issue=19|pages=7896–901|pmid=21464309|doi=10.1073/pnas.1016024108|pmc=3093508|bibcode=2011PNAS..108.7896H|doi-access=free}} by inducing mutations and measuring what proportion of mutants retain the same phenotype, function or fitness. More generally, robustness corresponds to the neutral band in the distribution of fitness effects of mutation (i.e. the frequencies of different fitnesses of mutants). Proteins so far investigated have shown a tolerance to mutations of roughly 66% (i.e. two thirds of mutations are neutral).{{cite journal|last=Guo|first=HH|author2=Choe, J |author3=Loeb, LA |title=Protein tolerance to random amino acid change.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Jun 22, 2004|volume=101|issue=25|pages=9205–10|pmid=15197260|doi=10.1073/pnas.0403255101|pmc=438954|bibcode=2004PNAS..101.9205G|doi-access=free}}

Conversely, measured mutational robustnesses of organisms vary widely. For example, >95% of point mutations in C. elegans have no detectable effect{{cite journal|last1=Davies|first1=E. K.|title=High Frequency of Cryptic Deleterious Mutations in Caenorhabditis elegans|journal=Science|date=10 September 1999|volume=285|issue=5434|pages=1748–1751|doi=10.1126/science.285.5434.1748|pmid=10481013|last2=Peters|first2=A. D.|last3=Keightley|first3=P. D.}} and even 90% of single gene knockouts in E. coli are non-lethal.{{cite journal|last=Baba|first=T|author2=Ara, T |author3=Hasegawa, M |author4=Takai, Y |author5=Okumura, Y |author6=Baba, M |author7=Datsenko, KA |author8=Tomita, M |author9=Wanner, BL |author10= Mori, H |title=Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection.|journal=Molecular Systems Biology|year=2006|volume=2|pages=2006.0008|pmid=16738554|doi=10.1038/msb4100050|pmc=1681482|issue=1}} Viruses, however, only tolerate 20-40% of mutations and hence are much more sensitive to mutation.

Biological processes at the molecular scale are inherently stochastic.{{Cite book|title=Stochastic processes in cell biology|last=Bressloff, Paul C.|isbn=978-3-319-08488-6|location=Cham|oclc=889941610|date = 2014-08-22}} They emerge from a combination of stochastic events that happen given the physico-chemical properties of molecules. For instance, gene expression is intrinsically noisy. This means that two cells in exactly identical regulatory states will exhibit different mRNA contents.{{Cite journal|last=Elowitz|first=M. B.|date=2002-08-16|title=Stochastic Gene Expression in a Single Cell|journal=Science|volume=297|issue=5584|pages=1183–1186|doi=10.1126/science.1070919|pmid=12183631|bibcode=2002Sci...297.1183E|s2cid=10845628|url=https://authors.library.caltech.edu/records/wsymf-b6c81/files/ElowitzSOM.pdf?download=1}}{{cite journal |last1=Blake |first1=William J. |last2=KÆrn |first2=Mads |last3=Cantor |first3=Charles R. |last4=Collins |first4=J. J. |title=Noise in eukaryotic gene expression |journal=Nature |date=April 2003 |volume=422 |issue=6932 |pages=633–637 |doi=10.1038/nature01546 |pmid=12687005 |bibcode=2003Natur.422..633B |s2cid=4347106 }} The cell population level log-normal distribution of mRNA content{{cite journal |last1=Bengtsson |first1=M. |last2=Ståhlberg |first2=A |last3=Rorsman |first3=P |last4=Kubista |first4=M |title=Gene expression profiling in single cells from the pancreatic islets of Langerhans reveals lognormal distribution of mRNA levels |journal=Genome Research |date=16 September 2005 |volume=15 |issue=10 |pages=1388–1392 |doi=10.1101/gr.3820805 |pmid=16204192 |pmc=1240081 }} follows directly from the application of the Central Limit Theorem to the multi-step nature of gene expression regulation.{{cite journal |last1=Beal |first1=Jacob |title=Biochemical complexity drives log-normal variation in genetic expression |journal=Engineering Biology |date=1 June 2017 |volume=1 |issue=1 |pages=55–60 |doi=10.1049/enb.2017.0004 |s2cid=31138796 |doi-access=free }}

In varying environments, perfect adaptation to one condition may come at the expense of adaptation to another. Consequently, the total selection pressure on an organism is the average selection across all environments weighted by the percentage time spent in that environment. Variable environment can therefore select for environmental robustness where organisms can function across a wide range of conditions with little change in phenotype or fitness (biology). Some organisms show adaptations to tolerate large changes in temperature, water availability, salinity or food availability. Plants, in particular, are unable to move when the environment changes and so show a range of mechanisms for achieving environmental robustness. Similarly, this can be seen in proteins as tolerance to a wide range of solvents, ion concentrations or temperatures.

File:Metabolism diagram.svg. Circles indicate metabolites and lines indicate conversions by enzymes. Many metabolites can be produced via more than one route, therefore the organism is robust to the loss of some metabolic enzymes]]

Genomes mutate by environmental damage and imperfect replication, yet they display remarkable tolerance. This comes from robustness both at many different levels.

There are many mechanisms that provide genome robustness. For example, genetic redundancy reduces the effect of mutations in any one copy of a multi-copy gene.{{cite journal|last=Gu|first=Z|author2=Steinmetz, LM |author3=Gu, X |author4=Scharfe, C |author5=Davis, RW |author6= Li, WH |title=Role of duplicate genes in genetic robustness against null mutations.|journal=Nature|date=Jan 2, 2003|volume=421|issue=6918|pages=63–6|pmid=12511954|doi=10.1038/nature01198|bibcode=2003Natur.421...63G|s2cid=4348693}} Additionally the flux through a metabolic pathway is typically limited by only a few of the steps, meaning that changes in function of many of the enzymes have little effect on fitness.{{cite journal|last=Kauffman|first=Kenneth J|author2=Prakash, Purusharth |author3=Edwards, Jeremy S |title=Advances in flux balance analysis|journal=Current Opinion in Biotechnology|date=October 2003|volume=14|issue=5|pages=491–496|doi=10.1016/j.copbio.2003.08.001|pmid=14580578}}{{cite journal|last=Nam|first=H|author2=Lewis, NE |author3=Lerman, JA |author4=Lee, DH |author5=Chang, RL |author6=Kim, D |author7= Palsson, BO |title=Network context and selection in the evolution to enzyme specificity.|journal=Science|date=Aug 31, 2012|volume=337|issue=6098|pages=1101–4|pmid=22936779|doi=10.1126/science.1216861 |pmc=3536066|bibcode=2012Sci...337.1101N}} Similarly metabolic networks have multiple alternate pathways to produce many key metabolites.{{cite journal|last=Krakauer|first=DC|author2=Plotkin, JB |title=Redundancy, antiredundancy, and the robustness of genomes.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Feb 5, 2002|volume=99|issue=3|pages=1405–9|pmid=11818563|doi=10.1073/pnas.032668599|pmc=122203|bibcode=2002PNAS...99.1405K|doi-access=free}}

Protein mutation tolerance is the product of two main features: the structure of the genetic code and protein structural robustness.{{cite journal|last=Taverna|first=DM|author2=Goldstein, RA |title=Why are proteins so robust to site mutations?|journal=Journal of Molecular Biology|date=Jan 18, 2002|volume=315|issue=3|pages=479–84|pmid=11786027|doi=10.1006/jmbi.2001.5226}}{{cite journal|last=Tokuriki|first=N|author2=Tawfik, DS |title=Stability effects of mutations and protein evolvability.|journal=Current Opinion in Structural Biology|date=Oct 2009|volume=19|issue=5|pages=596–604|pmid=19765975|doi=10.1016/j.sbi.2009.08.003}} Proteins are resistant to mutations because many sequences can fold into highly similar structural folds.{{cite journal|last=Meyerguz|first=L|author2=Kleinberg, J |author3=Elber, R |title=The network of sequence flow between protein structures.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Jul 10, 2007|volume=104|issue=28|pages=11627–32|pmid=17596339|doi=10.1073/pnas.0701393104|pmc=1913895|bibcode=2007PNAS..10411627M|doi-access=free}} A protein adopts a limited ensemble of native conformations because those conformers have lower energy than unfolded and mis-folded states (ΔΔG of folding).{{cite journal|last=Karplus|first=M|title=Behind the folding funnel diagram.|journal=Nature Chemical Biology|date=Jun 17, 2011|volume=7|issue=7|pages=401–4|pmid=21685880|doi=10.1038/nchembio.565}}{{cite journal|last=Tokuriki|first=N|author2=Stricher, F |author3=Schymkowitz, J |author4=Serrano, L |author5= Tawfik, DS |title=The stability effects of protein mutations appear to be universally distributed.|journal=Journal of Molecular Biology|date=Jun 22, 2007|volume=369|issue=5|pages=1318–32|pmid=17482644|doi=10.1016/j.jmb.2007.03.069|s2cid=24638570}} This is achieved by a distributed, internal network of cooperative interactions (hydrophobic, polar and covalent).{{cite journal|last=Shakhnovich|first=BE|author2=Deeds, E |author3=Delisi, C |author4= Shakhnovich, E |title=Protein structure and evolutionary history determine sequence space topology.|journal=Genome Research|date=Mar 2005|volume=15|issue=3|pages=385–92|pmid=15741509|doi=10.1101/gr.3133605 |pmc=551565|arxiv=q-bio/0404040}} Protein structural robustness results from few single mutations being sufficiently disruptive to compromise function. Proteins have also evolved to avoid aggregation{{cite journal|last=Monsellier|first=E|author2=Chiti, F |title=Prevention of amyloid-like aggregation as a driving force of protein evolution.|journal=EMBO Reports|date=Aug 2007|volume=8|issue=8|pages=737–42|pmid=17668004|doi=10.1038/sj.embor.7401034|pmc=1978086}} as partially folded proteins can combine to form large, repeating, insoluble protein fibrils and masses.{{cite journal|last=Fink|first=AL|title=Protein aggregation: folding aggregates, inclusion bodies and amyloid.|journal=Folding & Design|year=1998|volume=3|issue=1|pages=R9–23|pmid=9502314|doi=10.1016/s1359-0278(98)00002-9|doi-access=free}} There is evidence that proteins show negative design features to reduce the exposure of aggregation-prone beta-sheet motifs in their structures.{{cite journal|last=Richardson|first=JS|author2=Richardson, DC |title=Natural beta-sheet proteins use negative design to avoid edge-to-edge aggregation.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=Mar 5, 2002|volume=99|issue=5|pages=2754–9|pmid=11880627|doi=10.1073/pnas.052706099|pmc=122420|bibcode=2002PNAS...99.2754R|doi-access=free}}

Additionally, there is some evidence that the genetic code itself may be optimised such that most point mutations lead to similar amino acids (conservative).{{cite journal|vauthors=Müller MM, Allison JR, Hongdilokkul N, Gaillon L, Kast P, van Gunsteren WF, Marlière P, Hilvert D |title=Directed evolution of a model primordial enzyme provides insights into the development of the genetic code.|journal=PLOS Genetics|year=2013|volume=9|issue=1|pages=e1003187|pmid=23300488|doi=10.1371/journal.pgen.1003187|pmc=3536711 |doi-access=free }} {{open access}}{{cite journal|last=Firnberg|first=E|author2=Ostermeier, M |title=The genetic code constrains yet facilitates Darwinian evolution.|journal=Nucleic Acids Research|date=Aug 2013|volume=41|issue=15|pages=7420–8|pmid=23754851|doi=10.1093/nar/gkt536|pmc=3753648}} Together these factors create a distribution of fitness effects of mutations that contains a high proportion of neutral and nearly-neutral mutations.

During embryonic development, gene expression must be tightly controlled in time and space in order to give rise to fully functional organs. Developing organisms must therefore deal with the random perturbations resulting from gene expression stochasticity.{{Cite journal|last1=Lagha|first1=Mounia|last2=Bothma|first2=Jacques P.|last3=Levine|first3=Michael|date=2012|title=Mechanisms of transcriptional precision in animal development|journal=Trends in Genetics|language=en|volume=28|issue=8|pages=409–416|doi=10.1016/j.tig.2012.03.006|pmc=4257495|pmid=22513408}} In bilaterians, robustness of gene expression can be achieved via enhancer redundancy. This happens when the expression of a gene under the control of several enhancers encoding the same regulatory logic (ie. displaying binding sites for the same set of transcription factors). In Drosophila melanogaster such redundant enhancers are often called shadow enhancers.{{Cite journal|last1=Perry|first1=Michael W.|last2=Boettiger|first2=Alistair N.|last3=Bothma|first3=Jacques P.|last4=Levine|first4=Michael|date=2010|title=Shadow Enhancers Foster Robustness of Drosophila Gastrulation|journal=Current Biology|language=en|volume=20|issue=17|pages=1562–1567|doi=10.1016/j.cub.2010.07.043|pmc=4257487|pmid=20797865}}

Furthermore, in developmental contexts were timing of gene expression in important for the phenotypic outcome, diverse mechanisms exist to ensure proper gene expression in a timely manner. Poised promoters are transcriptionally inactive promoters that display RNA polymerase II binding, ready for rapid induction.{{cite journal |last1=Zeitlinger |first1=Julia |last2=Stark |first2=Alexander |last3=Kellis |first3=Manolis |last4=Hong |first4=Joung-Woo |last5=Nechaev |first5=Sergei |last6=Adelman |first6=Karen |last7=Levine |first7=Michael |last8=Young |first8=Richard A |title=RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo |journal=Nature Genetics |date=11 November 2007 |volume=39 |issue=12 |pages=1512–1516 |doi=10.1038/ng.2007.26 |pmid=17994019 |pmc=2824921 }} In addition, because not all transcription factors can bind their target site in compacted heterochromatin, pioneer transcription factors (such as Zld or FoxA) are required to open chromatin and allow the binding of other transcription factors that can rapidly induce gene expression. Open inactive enhancers are call poised enhancers.{{cite journal |last1=Nien |first1=Chung-Yi |last2=Liang |first2=Hsiao-Lan |last3=Butcher |first3=Stephen |last4=Sun |first4=Yujia |last5=Fu |first5=Shengbo |last6=Gocha |first6=Tenzin |last7=Kirov |first7=Nikolai |last8=Manak |first8=J. Robert |last9=Rushlow |first9=Christine |last10=Barsh |first10=Gregory S. |title=Temporal Coordination of Gene Networks by Zelda in the Early Drosophila Embryo |journal=PLOS Genetics |date=20 October 2011 |volume=7 |issue=10 |pages=e1002339 |doi=10.1371/journal.pgen.1002339 |pmid=22028675 |pmc=3197689 |doi-access=free }}

Cell competition is a phenomenon first described in Drosophila{{Cite journal|last1=Morata|first1=Ginés|last2=Ripoll|first2=Pedro|date=1975|title=Minutes: Mutants of Drosophila autonomously affecting cell division rate|journal=Developmental Biology|language=en|volume=42|issue=2|pages=211–221|doi=10.1016/0012-1606(75)90330-9|pmid=1116643}} where mosaic Minute mutant cells (affecting ribosomal proteins) in a wild-type background would be eliminated. This phenomenon also happens in the early mouse embryo where cells expressing high levels of Myc actively kill their neighbors displaying low levels of Myc expression. This results in homogeneously high levels of Myc.{{cite journal |last1=Clavería |first1=Cristina |last2=Giovinazzo |first2=Giovanna |last3=Sierra |first3=Rocío |last4=Torres |first4=Miguel |title=Myc-driven endogenous cell competition in the early mammalian embryo |journal=Nature |date=10 July 2013 |volume=500 |issue=7460 |pages=39–44 |doi=10.1038/nature12389 |pmid=23842495 |bibcode=2013Natur.500...39C |s2cid=4414411 }}{{Cite journal|last1=Sancho|first1=Margarida|last2=Di-Gregorio|first2=Aida|last3=George|first3=Nancy|last4=Pozzi|first4=Sara|last5=Sánchez|first5=Juan Miguel|last6=Pernaute|first6=Barbara|last7=Rodríguez|first7=Tristan A.|date=2013|title=Competitive Interactions Eliminate Unfit Embryonic Stem Cells at the Onset of Differentiation|journal=Developmental Cell|language=en|volume=26|issue=1|pages=19–30|doi=10.1016/j.devcel.2013.06.012|pmc=3714589|pmid=23867226}}

Patterning mechanisms such as those described by the French flag model can be perturbed at many levels (production and stochasticity of the diffusion of the morphogen, production of the receptor, stochastic of the signaling cascade, etc). Patterning is therefore inherently noisy. Robustness against this noise and genetic perturbation is therefore necessary to ensure proper that cells measure accurately positional information. Studies of the zebrafish neural tube and antero-posterior patternings has shown that noisy signaling leads to imperfect cell differentiation that is later corrected by transdifferentiation, migration or cell death of the misplaced cells.{{Cite journal|last1=Xiong|first1=Fengzhu|last2=Tentner|first2=Andrea R.|last3=Huang|first3=Peng|last4=Gelas|first4=Arnaud|last5=Mosaliganti|first5=Kishore R.|last6=Souhait|first6=Lydie|last7=Rannou|first7=Nicolas|last8=Swinburne|first8=Ian A.|last9=Obholzer|first9=Nikolaus D.|last10=Cowgill|first10=Paul D.|last11=Schier|first11=Alexander F.|date=2013|title=Specified Neural Progenitors Sort to Form Sharp Domains after Noisy Shh Signaling|journal=Cell|language=en|volume=153|issue=3|pages=550–561|doi=10.1016/j.cell.2013.03.023|pmc=3674856|pmid=23622240}}{{cite journal |last1=Akieda |first1=Yuki |last2=Ogamino |first2=Shohei |last3=Furuie |first3=Hironobu |last4=Ishitani |first4=Shizuka |last5=Akiyoshi |first5=Ryutaro |last6=Nogami |first6=Jumpei |last7=Masuda |first7=Takamasa |last8=Shimizu |first8=Nobuyuki |last9=Ohkawa |first9=Yasuyuki |last10=Ishitani |first10=Tohru |title=Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo |journal=Nature Communications |date=17 October 2019 |volume=10 |issue=1 |page=4710 |doi=10.1038/s41467-019-12609-4 |pmid=31624259 |pmc=6797755 |bibcode=2019NatCo..10.4710A }}{{Cite journal|last1=Kesavan|first1=Gokul|last2=Hans|first2=Stefan|last3=Brand|first3=Michael|date=2019|title=Cell-fate plasticity, adhesion and cell sorting complementarily establish a sharp midbrain-hindbrain boundary|journal=bioRxiv|volume=147|issue=11|language=en|doi=10.1101/857870|pmid=32439756|doi-access=free|url=https://www.biorxiv.org/content/biorxiv/early/2019/11/27/857870.full.pdf}}

Additionally, the structure (or topology) of signaling pathways has been demonstrated to play an important role in robustness to genetic perturbations.{{Cite journal|last1=Eldar|first1=Avigdor|last2=Rosin|first2=Dalia|last3=Shilo|first3=Ben-Zion|last4=Barkai|first4=Naama|date=2003|title=Self-Enhanced Ligand Degradation Underlies Robustness of Morphogen Gradients|journal=Developmental Cell|language=en|volume=5|issue=4|pages=635–646|doi=10.1016/S1534-5807(03)00292-2|pmid=14536064|doi-access=free}} Self-enhanced degradation has long been an example of robustness in System biology.{{cite journal |last1=Ibañes |first1=Marta |last2=Belmonte |first2=Juan Carlos Izpisúa |title=Theoretical and experimental approaches to understand morphogen gradients |journal=Molecular Systems Biology |date=25 March 2008 |volume=4 |issue=1 |pages=176 |doi=10.1038/msb.2008.14 |pmid=18364710 |pmc=2290935 }} Similarly, robustness of dorsoventral patterning in many species emerges from the balanced shuttling-degradation mechanisms involved in BMP signaling.{{cite journal |last1=Eldar |first1=Avigdor |last2=Dorfman |first2=Ruslan |last3=Weiss |first3=Daniel |last4=Ashe |first4=Hilary |last5=Shilo |first5=Ben-Zion |last6=Barkai |first6=Naama |title=Robustness of the BMP morphogen gradient in Drosophila embryonic patterning |journal=Nature |date=September 2002 |volume=419 |issue=6904 |pages=304–308 |doi=10.1038/nature01061 |pmid=12239569 |bibcode=2002Natur.419..304E |s2cid=4397746 }}{{Cite journal|last1=Genikhovich|first1=Grigory|last2=Fried|first2=Patrick|last3=Prünster|first3=M. Mandela|last4=Schinko|first4=Johannes B.|last5=Gilles|first5=Anna F.|last6=Fredman|first6=David|last7=Meier|first7=Karin|last8=Iber|first8=Dagmar|last9=Technau|first9=Ulrich|date=2015|title=Axis Patterning by BMPs: Cnidarian Network Reveals Evolutionary Constraints|journal=Cell Reports|language=en|volume=10|issue=10|pages=1646–1654|doi=10.1016/j.celrep.2015.02.035|pmc=4460265|pmid=25772352}}{{Cite journal|last1=Al Asafen|first1=Hadel|last2=Bandodkar|first2=Prasad U.|last3=Carrell-Noel|first3=Sophia|last4=Reeves|first4=Gregory T.|date=2019-08-19|title=Robustness of the Dorsal morphogen gradient with respect to morphogen dosage|language=en|doi=10.1101/739292|doi-access=free|url=https://www.biorxiv.org/content/biorxiv/early/2019/09/05/739292.full.pdf}}

Since organisms are constantly exposed to genetic and non-genetic perturbations, robustness is important to ensure the stability of phenotypes. Also, under mutation-selection balance, mutational robustness can allow cryptic genetic variation to accumulate in a population. While phenotypically neutral in a stable environment, these genetic differences can be revealed as trait differences in an environment-dependent manner (see evolutionary capacitance), thereby allowing for the expression of a greater number of heritable phenotypes in populations exposed to a variable environment.{{cite journal |doi=10.1016/j.tig.2009.07.005 |author=Masel J Siegal ML |title=Robustness: mechanisms and consequences |journal=Trends in Genetics|volume=25 |issue=9 |pages=395–403 |year=2009 |pmid=19717203 |pmc=2770586}}

Being robust may even be a favoured at the expense of total fitness as an evolutionarily stable strategy (also called survival of the flattest).{{cite journal|last=Wilke|first=CO|author2=Wang, JL |author3=Ofria, C |author4=Lenski, RE |author5= Adami, C |title=Evolution of digital organisms at high mutation rates leads to survival of the flattest.|journal=Nature|date=Jul 19, 2001|volume=412|issue=6844|pages=331–3|pmid=11460163|doi=10.1038/35085569|bibcode=2001Natur.412..331W|s2cid=1482925|url=https://authors.library.caltech.edu/records/br5zq-k4b57/files/412331a0_S1.pdf?download=1}} A high but narrow peak of a fitness landscape confers high fitness but low robustness as most mutations lead to massive loss of fitness. High mutation rates may favour population of lower, but broader fitness peaks. More critical biological systems may also have greater selection for robustness as reductions in function are more damaging to fitness.{{cite journal | author = Van Dijk | title = Mutational Robustness of Gene Regulatory Networks | journal = PLOS ONE | year = 2012 | volume = 7 | issue = 1 | pages = e30591 | doi = 10.1371/journal.pone.0030591 | pmid = 22295094 | last2 = Van Mourik | first2 = Simon | last3 = Van Ham | first3 = Roeland C. H. J. | pmc=3266278|display-authors=etal| bibcode = 2012PLoSO...730591V | doi-access = free }} {{open access}} Mutational robustness is thought to be one driver for theoretical viral quasispecies formation.File:Neutral network.png, dark regions have high fitness. (a) White circles have few neutral neighbours, black circles have many. Light grid-regions contain no circles because those sequences have low fitness. (b) Within a neutral network, the population is predicted to evolve towards the centre and away from 'fitness cliffs' (dark arrows).]]

{{see also|Neutral network (evolution)}}

Natural selection can select directly or indirectly for robustness. When mutation rates are high and population sizes are large, populations are predicted to move to more densely connected regions of neutral network as less robust variants have fewer surviving mutant descendants.{{cite journal | vauthors=van Nimwegen E, Crutchfield JP, Huynen M | title = Neutral evolution of mutational robustness | journal = PNAS | year = 1999| volume = 96 | issue = 17 | pages = 9716–9720| pmid = 10449760 | pmc = 22276 | doi=10.1073/pnas.96.17.9716| bibcode =1999PNAS...96.9716V| arxiv =adap-org/9903006| doi-access = free }} The conditions under which selection could act to directly increase mutational robustness in this way are restrictive, and therefore such selection is thought to be limited to only a few viruses{{cite journal |vauthors=Montville R, Froissart R, Remold SK, Tenaillon O, Turner PE | title = Evolution of mutational robustness in an RNA virus | journal = PLOS Biology | year = 2005 | volume = 3| issue = 11| pages = 1939–1945 | doi=10.1371/journal.pbio.0030381| pmid = 16248678 | pmc = 1275523 | doi-access = free }} {{open access}} and microbes{{cite journal | author = Masel J, Maughan H| title = Mutations Leading to Loss of Sporulation Ability in Bacillus subtilis Are Sufficiently Frequent to Favor Genetic Canalization | journal = Genetics | year = 2007 | volume = 175| issue = 1 | pages = 453–457 | doi=10.1534/genetics.106.065201| pmid = 17110488 | last2 = Maughan | pmc = 1775008 }} having large population sizes and high mutation rates. Such emergent robustness has been observed in experimental evolution of cytochrome P450s{{cite journal|last=Bloom|first=JD|author2=Lu, Z |author3=Chen, D |author4=Raval, A |author5=Venturelli, OS |author6= Arnold, FH |title=Evolution favors protein mutational robustness in sufficiently large populations.|journal=BMC Biology|date=Jul 17, 2007|volume=5|pages=29|pmid=17640347|doi=10.1186/1741-7007-5-29 |pmc=1995189|bibcode=2007arXiv0704.1885B|arxiv=0704.1885 |doi-access=free }} {{open access}} and B-lactamase.{{cite journal|last=Bershtein|first=Shimon|author2=Goldin, Korina |author3=Tawfik, Dan S. |title=Intense Neutral Drifts Yield Robust and Evolvable Consensus Proteins|journal=Journal of Molecular Biology|date=June 2008|volume=379|issue=5|pages=1029–1044|doi=10.1016/j.jmb.2008.04.024|pmid=18495157}} Conversely, mutational robustness may evolve as a byproduct of natural selection for robustness to environmental perturbations.{{cite journal |vauthors=Meiklejohn CD, Hartl DL |title=A single mode of canalization|journal=Trends in Ecology & Evolution|volume=17 |issue=10|pages=468–473 |year=2002 |doi=10.1016/s0169-5347(02)02596-x}}{{cite journal |doi=10.1002/1097-010X(20001015)288:3<242::AID-JEZ5>3.0.CO;2-O |vauthors=Ancel LW, Fontana W |title=Plasticity, evolvability, and modularity in RNA|journal=Journal of Experimental Zoology|volume=288 |issue=3 |pages=242–283 |year=2000 |pmid=11069142|citeseerx=10.1.1.43.6910 }}{{cite journal |doi=10.1093/molbev/msp008 |vauthors=Szöllősi GJ, Derényi I |title=Congruent Evolution of Genetic and Environmental Robustness in Micro-RNA|journal=Molecular Biology and Evolution|volume=26 |issue=4 |pages=867–874 |year=2009 |pmid=19168567 |arxiv=0810.2658 |s2cid=8935948 }}{{cite journal |doi=10.2307/2411105 |pmid=28565347 |vauthors=Wagner GP, Booth G, Bagheri-Chaichian H | title=A population genetic theory of canalization | journal=Evolution|volume=51 |issue=2 |pages=329–347|year=1997 |jstor=2411105}}{{cite journal |author=Lehner B |title=Genes Confer Similar Robustness to Environmental, Stochastic, and Genetic Perturbations in Yeast|journal=PLOS ONE |volume=5 |issue=2 |pages=468–473 |year=2010 |pmid=20140261 |pmc=2815791 |doi=10.1371/journal.pone.0009035 |bibcode=2010PLoSO...5.9035L|doi-access=free}} {{open access}}

{{see also|Evolvability|Canalisation (genetics)}}

Mutational robustness has been thought to have a negative impact on evolvability because it reduces the mutational accessibility of distinct heritable phenotypes for a single genotype and reduces selective differences within a genetically diverse population.{{Citation needed|date=March 2014}} Counter-intuitively however, it has been hypothesized that phenotypic robustness towards mutations may actually increase the pace of heritable phenotypic adaptation when viewed over longer periods of time.{{cite journal |doi=10.1038/nature08694 |title=Mutational robustness can facilitate adaptation |year=2010 |last1=Draghi |first1=Jeremy A. |last2=Parsons |first2=Todd L. |last3=Wagner |first3=Günter P. |last4=Plotkin |first4=Joshua B. |journal=Nature |volume=463 |issue=7279 |pages=353–5 |pmid=20090752 |pmc=3071712|bibcode = 2010Natur.463..353D }}{{cite journal |doi=10.1098/rspb.2007.1137 |title=Robustness and evolvability: A paradox resolved |year=2008 |last1=Wagner |first1=A. |journal=Proceedings of the Royal Society B: Biological Sciences |volume=275 |issue=1630 |pages=91–100 |pmid=17971325 |pmc=2562401 |jstor=25249473}}{{cite journal |doi=10.1016/j.tig.2010.06.002 |vauthors=Masel J, Trotter MV |title=Robustness and evolvability |journal=Trends in Genetics|volume=26 |issue=9 |pages=406–414 |year=2010 |pmid=20598394 |pmc=3198833}}{{cite journal | author = Aldana | title = Robustness and evolvability in genetic regulatory networks | journal = Journal of Theoretical Biology | year = 2007 | volume = 245 | issue = 3 | pages = 433–448 | pmid = 17188715 | author2 = Balleza, E | author3 = Kauffman, S | author4 = Resendiz, O | doi = 10.1016/j.jtbi.2006.10.027 | bibcode = 2007JThBi.245..433A |display-authors=etal}}

One hypothesis for how robustness promotes evolvability in asexual populations is that connected networks of fitness-neutral genotypes result in mutational robustness which, while reducing accessibility of new heritable phenotypes over short timescales, over longer time periods, neutral mutation and genetic drift cause the population to spread out over a larger neutral network in genotype space.{{cite journal |author1=Ebner, Marc |author2=Shackleton, Mark |author3=Shipman, Rob |title=How neutral networks influence evolvability |journal=Complexity |date=2001 |volume=7 |issue=2 |pages=19–33 |doi=10.1002/cplx.10021 |bibcode=2001Cmplx...7b..19E }} This genetic diversity gives the population mutational access to a greater number of distinct heritable phenotypes that can be reached from different points of the neutral network.{{cite journal | author = Babajide | title = Neutral networks in protein space: A computational study based on knowledge-based potentials of mean force | journal = Folding & Design | year = 1997 | volume = 2 | issue = 5 | pages = 261–269 | pmid = 9261065 | author2 = Hofacker, I. L. | author3 = Sippl, M. J. | author4 = Stadler, P. F. | doi=10.1016/s1359-0278(97)00037-0|display-authors=etal| doi-access = free }}{{cite journal | author = van Nimwegen and Crutchfield | title = Metastable evolutionary dynamics: Crossing fitness barriers or escaping via neutral paths? | journal = Bulletin of Mathematical Biology | year = 2000 | volume = 62 | issue = 5 | pages = 799–848 | pmid = 11016086 | doi = 10.1006/bulm.2000.0180 | arxiv = adap-org/9907002 | s2cid = 17930325 }}{{cite journal | author = Ciliberti| title = Innovation and robustness in complex regulatory gene networks | journal = Proceedings of the National Academy of Sciences, USA | year = 2007 | volume = 104 | issue = 34 | pages = 13591–13596 | doi=10.1073/pnas.0705396104| pmid = 17690244 | pmc = 1959426 |display-authors=etal|bibcode =2007PNAS..10413591C| doi-access = free }}{{cite journal | author = Andreas Wagner | title = Neutralism and selectionism: a network-based reconciliation | journal = Nature Reviews Genetics | year = 2008 | volume = 9 | pages=965–974 |doi=10.1038/nrg2473 | issue=12 | pmid=18957969| s2cid = 10651547 | url = https://www.zora.uzh.ch/id/eprint/6535/2/Wagner_NRG_2008.pdf }} However, this mechanism may be limited to phenotypes dependent on a single genetic locus; for polygenic traits, genetic diversity in asexual populations does not significantly increase evolvability.{{cite journal|last=Rajon|first=E.|author2=Masel, J. |title=Compensatory Evolution and the Origins of Innovations|journal=Genetics|date=18 January 2013|volume=193|issue=4|pages=1209–1220|doi=10.1534/genetics.112.148627|pmid=23335336|pmc=3606098}}

In the case of proteins, robustness promotes evolvability in the form of an excess free energy of folding.{{cite journal | author = Bloom| title = Protein stability promotes evolvability | journal = Proceedings of the National Academy of Sciences | year = 2006 | volume = 103 | issue = 15 | pages = 5869–74 | doi=10.1073/pnas.0510098103 | pmid=16581913 | pmc=1458665|display-authors=etal| bibcode=2006PNAS..103.5869B| doi-access = free }} Since most mutations reduce stability, an excess folding free energy allows toleration of mutations that are beneficial to activity but would otherwise destabilise the protein.

In sexual populations, robustness leads to the accumulation of cryptic genetic variation with high evolutionary potential.{{cite book|author=Waddington CH |title=The strategy of the genes |year=1957 |publisher=George Allen & Unwin}}{{cite journal|last=Masel|first=J.|title=Cryptic Genetic Variation Is Enriched for Potential Adaptations|journal=Genetics|date=30 December 2005|volume=172|issue=3|pages=1985–1991|doi=10.1534/genetics.105.051649|pmid=16387877|pmc=1456269}}

Evolvability may be high when robustness is reversible, with evolutionary capacitance allowing a switch between high robustness in most circumstances and low robustness at times of stress.{{cite journal|last=Masel|first=J|title=Q&A: Evolutionary capacitance.|journal=BMC Biology|date=Sep 30, 2013|volume=11|pages=103|doi=10.1186/1741-7007-11-103|pmid=24228631|pmc=3849687|doi-access=free}} {{open access}}

There are many systems that have been used to study robustness. In silico models have been used to model promoters,{{cite journal | last=Bianco | first=Simone | title=Artificial Intelligence: Bioengineers' Ultimate Best Friend | journal=GEN Biotechnology | publisher=Mary Ann Liebert | volume=1 | issue=2 | date=2022-04-01 | issn=2768-1572 | doi=10.1089/genbio.2022.29027.sbi | pages=140–141 | s2cid=248313305}}{{cite journal | vauthors = Vaishnav ED, de Boer CG, Molinet J, Yassour M, Fan L, Adiconis X, Thompson DA, Levine JZ, Cubillos FA, Regev A | title = The evolution, evolvability and engineering of gene regulatory DNA | journal = Nature | volume = 603 | issue = 7901 | pages = 455–463 | date = March 2022 | pmid = 35264797 | doi = 10.1038/s41586-022-04506-6| pmc = 8934302 | bibcode = 2022Natur.603..455V }} RNA secondary structure, protein lattice models, or gene networks. Experimental systems for individual genes include enzyme activity of cytochrome P450, B-lactamase, RNA polymerase, and LacI have all been used. Whole organism robustness has been investigated in RNA virus fitness, bacterial chemotaxis, Drosophila fitness, segment polarity network, neurogenic network and bone morphogenetic protein gradient, C. elegans fitness and vulval development, and mammalian circadian clock.{{cite book |author=Wagner A |title=Robustness and evolvability in living systems |publisher = Princeton University Press |series=Princeton Studies in Complexity |year=2005 |isbn=0-691-12240-7}}{{page needed|date=July 2013}}

• Distribution of fitness effects
• Evolvability
• Canalization
• Neutral network (evolution)
• Epistasis
• Evolutionary capacitance
• Fitness landscape
• Evolutionary developmental biology

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Category:Evolutionary biology

Category:Genetics