Robustness of a model systems have been developed to experimentally study robustness and its evolutionary consequences.
- Mutational robustness 1.1
- Environmental robustness 1.2
Genetic and molecular causes 2
- Organism mutational robustness 2.1
- Protein mutational robustness 2.2
Evolutionary consequences 3
- Emergent mutational robustness 3.1
- Robustness and evolvability 3.2
- Methods and model systems 4
- See also 5
- References 6
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 and individual genes by inducing mutations and measuring what proportion of mutants retain the same phenotype, function or fitness. More generally this is known as 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).
Conversely, measured mutational robustnesses of organisms vary widely. For example >95% of point mutations in C. elegans have no detectable effect and even 90% of single gene knockouts in E. coli are non-lethal. Viruses, however, only tolerate 20-40% of mutations and hence are much more sensitive to mutation.
Genetic and molecular causes
Genomes mutate by environmental damage and imperfect replication, yet they display remarkable tolerance. This comes from robustness both at the genome level and protein level.
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. 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. Similarly metabolic networks have multiple alternate pathways to produce many key metabolites.
Protein mutational robustness
Protein mutation tolerance is the product of two main features: the structure of the genetic code and protein structural robustness. Proteins are resistant to mutations because many sequences can fold into highly similar structural folds. A protein adopts a limited ensemble of native conformations because those conformers have lower energy than unfolded and mis-folded states (ΔΔG of folding). This is achieved by a distributed, internal network of cooperative interactions (hydrophobic, polar and covalent). Protein structural robustness results from few single mutations being sufficiently disruptive to compromise function. Proteins have also evolved to avoid aggregation as partially folded proteins can combine to form large, repeating, insoluble protein fibrils and masses. There is evidence that proteins show negative design features to reduce the exposure of aggregation-prone beta-sheet motifs in their structures. Additionally, there is some evidence that the genetic code itself may be optimised such that most point mutations lead to similar amino acids (conservative). Together these factors create a distribution of fitness effects of mutations that contains a high proportion of neutral and nearly-neutral mutations.
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.
Being robust may even be a favoured at the expense of total fitness as an evolutionarily stable strategy (also called survival of the flattest). 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. Mutational robustness is thought to be one driver for theoretical viral quasispecies formation.
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. 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 and microbes having large population sizes and high mutation rates. Such emergent robustness has been observed in experimental evolution of cytochrome P450s and B-lactamase. Conversely, mutational robustness may evolve as a byproduct of natural selection for robustness to environmental perturbations.
Robustness and evolvability
Mutational robustness has been thought 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. 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.
One hypothesis for how robustness promotes evolvability in asexual populations is that connected networks of fitness neutral genotypes result in mutational robustness and reduced accessibility of heritable phenotypes over short timescales. Over longer periods of time, genetic diversity spreads the population out over a larger area of genotype space, giving the population mutational access to a greater number of distinct heritable phenotypes that are reached from different points of the genetic neutral network. 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.
Another hypothesis for how robustness promotes the evolvability of proteins is that robustness takes the form of excess free energy of folding. Most mutations are destabilizing, and excess folding free energy allows them to be sufficiently tolerated for their phenotypic effects to become apparent.
In sexual populations, robustness leads to the accumulation of cryptic genetic variation with high evolutionary potential.
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.
Methods and model systems
There are many systems that have been used to study robustness. In silico models have been used to model 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.
- Distribution of fitness effects
- Neutral network (evolution)
- Evolutionary capacitance
- Fitness landscape
- Evolutionary developmental biology
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