Robustness (evolution)

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In evolutionary biology, robustness of a biological system (also called biological or genetic robustness [1] ) is the persistence of a certain characteristic or trait in a system under perturbations or conditions of uncertainty. [2] [3] Robustness in development is known as canalization. [4] [5] According to the kind of perturbation involved, robustness can be classified as mutational, environmental, recombinational, or behavioral robustness etc. [6] [7] [8] Robustness is achieved through the combination of many genetic and molecular mechanisms and can evolve by either direct or indirect selection. Several model systems have been developed to experimentally study robustness and its evolutionary consequences.

Contents

A network of genotypes linked by mutations. Each genotype is made up of 3 genes: a, b & c. Each gene can be one of two alleles. Lines link different phenotypes by mutation. The phenotype is indicated by colour. Genotypes abc, Abc, aBc and abC lie on a neutral network since all have the same, dark phenotype. Genotype abc is robust since any single mutation retains the same phenotype. Other genotypes are less robust as mutations change the phenotype (e.g. ABc). Robustness cube annotated.svg
A network of genotypes linked by mutations. Each genotype is made up of 3 genes: a, b & c. Each gene can be one of two alleles. Lines link different phenotypes by mutation. The phenotype is indicated by colour. Genotypes abc, Abc, aBc and abC lie on a neutral network since all have the same, dark phenotype. Genotype abc is robust since any single mutation retains the same phenotype. Other genotypes are less robust as mutations change the phenotype (e.g. ABc).

Classification

Mutational robustness

Mutational robustness (also called mutation tolerance) describes the extent to which an organism's phenotype remains constant in spite of mutation. [9] Robustness can be empirically measured for several genomes [10] [11] and individual genes [12] 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). [13]

Conversely, measured mutational robustnesses of organisms vary widely. For example, >95% of point mutations in C. elegans have no detectable effect [14] and even 90% of single gene knockouts in E. coli are non-lethal. [15] Viruses, however, only tolerate 20-40% of mutations and hence are much more sensitive to mutation. [10]

Robustness to stochasticity

Biological processes at the molecular scale are inherently stochastic. [16] 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. [17] [18] The cell population level log-normal distribution of mRNA content [19] follows directly from the application of the Central Limit Theorem to the multi-step nature of gene expression regulation. [20]

Environmental robustness

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.

Genetic, molecular and cellular causes

Core eukaryotic metabolic network. 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 Metabolism diagram.svg
Core eukaryotic metabolic network. 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.

Organism mutational robustness

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. [21] 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. [22] [23] Similarly metabolic networks have multiple alternate pathways to produce many key metabolites. [24]

Protein mutational robustness

Protein mutation tolerance is the product of two main features: the structure of the genetic code and protein structural robustness. [25] [26] Proteins are resistant to mutations because many sequences can fold into highly similar structural folds. [27] A protein adopts a limited ensemble of native conformations because those conformers have lower energy than unfolded and mis-folded states (ΔΔG of folding). [28] [29] This is achieved by a distributed, internal network of cooperative interactions (hydrophobic, polar and covalent). [30] Protein structural robustness results from few single mutations being sufficiently disruptive to compromise function. Proteins have also evolved to avoid aggregation [31] as partially folded proteins can combine to form large, repeating, insoluble protein fibrils and masses. [32] There is evidence that proteins show negative design features to reduce the exposure of aggregation-prone beta-sheet motifs in their structures. [33] Additionally, there is some evidence that the genetic code itself may be optimised such that most point mutations lead to similar amino acids (conservative). [34] [35] Together these factors create a distribution of fitness effects of mutations that contains a high proportion of neutral and nearly-neutral mutations. [12]

Gene expression robustness

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. [36] 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. [37]

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. [36] Poised promoters are transcriptionally inactive promoters that display RNA polymerase II binding, ready for rapid induction. [38] 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. [39]

Cell competition is a phenomenon first described in Drosophila [40] 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 . [41] [42]

Developmental patterning robustness

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. [43] [44] [45]

Additionally, the structure (or topology) of signaling pathways has been demonstrated to play an important role in robustness to genetic perturbations. [46] Self-enhanced degradation has long been an example of robustness in System biology. [47] Similarly, robustness of dorsoventral patterning in many species emerges from the balanced shuttling-degradation mechanisms involved in BMP signaling. [48] [49] [50]

Evolutionary consequences

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. [51]

Being robust may even be a favoured at the expense of total fitness as an evolutionarily stable strategy (also called survival of the flattest). [52] 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. [53] Mutational robustness is thought to be one driver for theoretical viral quasispecies formation.

Each circle represents a functional gene variant and lines represent point mutations between them. Light grid-regions have low fitness, 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). Neutral network.png
Each circle represents a functional gene variant and lines represent point mutations between them. Light grid-regions have low fitness, 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).

Emergent mutational robustness

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. [54] 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 [55] and microbes [56] having large population sizes and high mutation rates. Such emergent robustness has been observed in experimental evolution of cytochrome P450s [57] and B-lactamase. [58] Conversely, mutational robustness may evolve as a byproduct of natural selection for robustness to environmental perturbations. [59] [60] [61] [62] [63]

Robustness and evolvability

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 ] 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. [64] [65] [66] [67]

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. [68] 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. [64] [65] [67] [69] [70] [71] [72] 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. [73]

In the case of proteins, robustness promotes evolvability in the form of an excess free energy of folding. [74] 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. [75] [76]

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. [77]

Methods and model systems

There are many systems that have been used to study robustness. In silico models have been used to model promoters, [78] [79] RNA secondary structure, protein lattice models, or gene networks. Experimental systems for individual genes include enzyme activity of cytochrome P450, [57] B-lactamase, [58] RNA polymerase, [13] and LacI [13] have all been used. Whole organism robustness has been investigated in RNA virus fitness, [10] bacterial chemotaxis, Drosophila fitness, [15] segment polarity network, neurogenic network and bone morphogenetic protein gradient, C. elegans fitness [14] and vulval development, and mammalian circadian clock. [9]

See also

Related Research Articles

<span class="mw-page-title-main">Mutation</span> Alteration in the nucleotide sequence of a genome

In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis, or meiosis or other types of damage to DNA, which then may undergo error-prone repair, cause an error during other forms of repair, or cause an error during replication. Mutations may also result from insertion or deletion of segments of DNA due to mobile genetic elements.

Junk DNA is a DNA sequence that has no relevant biological function. Most organisms have some junk DNA in their genomes - mostly pseudogenes and fragments of transposons and viruses - but it is possible that some organisms have substantial amounts of junk DNA.

Molecular evolution is the process of change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genetics to explain patterns in these changes. Major topics in molecular evolution concern the rates and impacts of single nucleotide changes, neutral evolution vs. natural selection, origins of new genes, the genetic nature of complex traits, the genetic basis of speciation, the evolution of development, and ways that evolutionary forces influence genomic and phenotypic changes.

<span class="mw-page-title-main">Neutral theory of molecular evolution</span>

The neutral theory of molecular evolution holds that most evolutionary changes occur at the molecular level, and most of the variation within and between species are due to random genetic drift of mutant alleles that are selectively neutral. The theory applies only for evolution at the molecular level, and is compatible with phenotypic evolution being shaped by natural selection as postulated by Charles Darwin.

Population genetics is a subfield of genetics that deals with genetic differences within and among populations, and is a part of evolutionary biology. Studies in this branch of biology examine such phenomena as adaptation, speciation, and population structure.

<span class="mw-page-title-main">Pseudogene</span> Functionless relative of a gene

Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by gene duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are usually identified when genome sequence analysis finds gene-like sequences that lack regulatory sequences needed for transcription or translation, or whose coding sequences are obviously defective due to frameshifts or premature stop codons. Pseudogenes are a type of junk DNA.

<span class="mw-page-title-main">Gene regulatory network</span> Collection of molecular regulators

A generegulatory network (GRN) is a collection of molecular regulators that interact with each other and with other substances in the cell to govern the gene expression levels of mRNA and proteins which, in turn, determine the function of the cell. GRN also play a central role in morphogenesis, the creation of body structures, which in turn is central to evolutionary developmental biology (evo-devo).

Evolvability is defined as the capacity of a system for adaptive evolution. Evolvability is the ability of a population of organisms to not merely generate genetic diversity, but to generate adaptive genetic diversity, and thereby evolve through natural selection.

Evolutionary capacitance is the storage and release of variation, just as electric capacitors store and release charge. Living systems are robust to mutations. This means that living systems accumulate genetic variation without the variation having a phenotypic effect. But when the system is disturbed, robustness breaks down, and the variation has phenotypic effects and is subject to the full force of natural selection. An evolutionary capacitor is a molecular switch mechanism that can "toggle" genetic variation between hidden and revealed states. If some subset of newly revealed variation is adaptive, it becomes fixed by genetic assimilation. After that, the rest of variation, most of which is presumably deleterious, can be switched off, leaving the population with a newly evolved advantageous trait, but no long-term handicap. For evolutionary capacitance to increase evolvability in this way, the switching rate should not be faster than the timescale of genetic assimilation.

<span class="mw-page-title-main">Canalisation (genetics)</span> Measure of the ability of a population to produce the same phenotype

Canalisation is a measure of the ability of a population to produce the same phenotype regardless of variability of its environment or genotype. It is a form of evolutionary robustness. The term was coined in 1942 by C. H. Waddington to capture the fact that "developmental reactions, as they occur in organisms submitted to natural selection...are adjusted so as to bring about one definite end-result regardless of minor variations in conditions during the course of the reaction". He used this word rather than robustness to consider that biological systems are not robust in quite the same way as, for example, engineered systems.

<span class="mw-page-title-main">Gene</span> Sequence of DNA or RNA that codes for an RNA or protein product

In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA, that is transcribed to produce a functional RNA. There are two types of molecular genes: protein-coding genes and non-coding genes.

<span class="mw-page-title-main">Directed evolution</span> Protein engineering method

Directed evolution (DE) is a method used in protein engineering that mimics the process of natural selection to steer proteins or nucleic acids toward a user-defined goal. It consists of subjecting a gene to iterative rounds of mutagenesis, selection and amplification. It can be performed in vivo, or in vitro. Directed evolution is used both for protein engineering as an alternative to rationally designing modified proteins, as well as for experimental evolution studies of fundamental evolutionary principles in a controlled, laboratory environment.

Neutral mutations are changes in DNA sequence that are neither beneficial nor detrimental to the ability of an organism to survive and reproduce. In population genetics, mutations in which natural selection does not affect the spread of the mutation in a species are termed neutral mutations. Neutral mutations that are inheritable and not linked to any genes under selection will be lost or will replace all other alleles of the gene. That loss or fixation of the gene proceeds based on random sampling known as genetic drift. A neutral mutation that is in linkage disequilibrium with other alleles that are under selection may proceed to loss or fixation via genetic hitchhiking and/or background selection.

Enquiry into the evolution of ageing, or aging, aims to explain why a detrimental process such as ageing would evolve, and why there is so much variability in the lifespans of organisms. The classical theories of evolution suggest that environmental factors, such as predation, accidents, disease, and/or starvation, ensure that most organisms living in natural settings will not live until old age, and so there will be very little pressure to conserve genetic changes that increase longevity. Natural selection will instead strongly favor genes which ensure early maturation and rapid reproduction, and the selection for genetic traits which promote molecular and cellular self-maintenance will decline with age for most organisms.

<span class="mw-page-title-main">Genome evolution</span> Process by which a genome changes in structure or size over time

Genome evolution is the process by which a genome changes in structure (sequence) or size over time. The study of genome evolution involves multiple fields such as structural analysis of the genome, the study of genomic parasites, gene and ancient genome duplications, polyploidy, and comparative genomics. Genome evolution is a constantly changing and evolving field due to the steadily growing number of sequenced genomes, both prokaryotic and eukaryotic, available to the scientific community and the public at large.

A neutral network is a set of genes all related by point mutations that have equivalent function or fitness. Each node represents a gene sequence and each line represents the mutation connecting two sequences. Neutral networks can be thought of as high, flat plateaus in a fitness landscape. During neutral evolution, genes can randomly move through neutral networks and traverse regions of sequence space which may have consequences for robustness and evolvability.

<i>Homeotic protein bicoid</i> Protein-coding gene in the species Drosophila melanogaster

Homeotic protein bicoid is encoded by the bcd maternal effect gene in Drosophilia. Homeotic protein bicoid concentration gradient patterns the anterior-posterior (A-P) axis during Drosophila embryogenesis. Bicoid was the first protein demonstrated to act as a morphogen. Although bicoid is important for the development of Drosophila and other higher dipterans, it is absent from most other insects, where its role is accomplished by other genes.

<span class="mw-page-title-main">Epistasis</span> Dependence of a gene mutations phenotype on mutations in other genes

Epistasis is a phenomenon in genetics in which the effect of a gene mutation is dependent on the presence or absence of mutations in one or more other genes, respectively termed modifier genes. In other words, the effect of the mutation is dependent on the genetic background in which it appears. Epistatic mutations therefore have different effects on their own than when they occur together. Originally, the term epistasis specifically meant that the effect of a gene variant is masked by that of different gene.

<i>De novo</i> gene birth Evolution of novel genes from non-genic DNA sequence

De novo gene birth is the process by which new genes evolve from non-coding DNA. De novo genes represent a subset of novel genes, and may be protein-coding or instead act as RNA genes. The processes that govern de novo gene birth are not well understood, although several models exist that describe possible mechanisms by which de novo gene birth may occur.

Constructive neutral evolution(CNE) is a theory that seeks to explain how complex systems can evolve through neutral transitions and spread through a population by chance fixation (genetic drift). Constructive neutral evolution is a competitor for both adaptationist explanations for the emergence of complex traits and hypotheses positing that a complex trait emerged as a response to a deleterious development in an organism. Constructive neutral evolution often leads to irreversible or "irremediable" complexity and produces systems which, instead of being finely adapted for performing a task, represent an excess complexity that has been described with terms such as "runaway bureaucracy" or even a "Rube Goldberg machine".

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