Neutral network (evolution)

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Not to be confused with Neural network or Network-neutral data center.

A neutral network is a set of genes all related by point mutations that have equivalent function or fitness.[1] 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.

Genetic and molecular causes[edit]

Neutral networks exist in fitness landscapes since proteins are robust to mutations. This leads to extended networks of genes of equivalent function, linked by neutral mutations.[2][3] Proteins are resistant to mutations because many sequences can fold into highly similar structural folds.[4] A protein adopts a limited ensemble of native conformations because those conformers have lower energy than unfolded and mis-folded states (ΔΔG of folding).[5][6] This is achieved by a distributed, internal network of cooperative interactions (hydrophobic, polar and covalent).[7] Protein structural robustness results from few single mutations being sufficiently disruptive to compromise function. Proteins have also evolved to avoid aggregation[8] as partially folded proteins can combine to form large, repeating, insoluble protein fibrils and masses.[9] There is evidence that proteins show negative design features to reduce the exposure of aggregation-prone beta-sheet motifs in their structures.[10] Additionally, there is some evidence that the genetic code itself may be optimised such that most point mutations lead to similar amino acids (conservative).[11][12] Together these factors create a distribution of fitness effects of mutations that contains a high proportion of neutral and nearly-neutral mutations.[13]

Neutral networks and evolution[edit]

Neutral networks are a subset of the sequences in sequence space that have equivalent function, and so form a wide, flat plateau in a fitness landscape. Neutral evolution can therefore be visualised as a population diffusing from one set of sequence nodes, through the neutral network, to another cluster of sequence nodes. Since the majority of evolution is thought to be neutral,[14][15] a large proportion of gene change is the movement though expansive neutral networks.

Neutral networks and robustness[edit]

Each circle represents a functional gene variant and lines represents 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).

The more neutral neighbours a sequence has, the more robust to mutations it is since mutations are more likely to simply neutrally convert it into an equally functional sequence.[1] Indeed, if there are large differences between the number of neutral neighbours of different sequences within a neutral network, the population is predicted to evolve towards these robust sequences. This is sometimes called circum-neutrality and represents the movement of populations away from cliffs in the fitness landscape.[16]

In addition to in silico models,[17] these processes are beginning to be confirmed by experimental evolution of cytochrome P450s[18] and B-lactamase.[19]

Neutral networks and evolvability[edit]

See also: Evolvability

Interest in the interplay between genetic drift and selection has been around since the 1930s when the shifting-balance theory proposed that in some situations, genetic drift could facilitate later adaptive evolution.[20] Although the specifics of the theory were largely discredited,[21] it drew attention to the possibility that drift could generate cryptic variation that, though neutral to current function, may affect selection for new functions (evolvability).[22]

By definition, all genes in a neutral network have equivalent function, however some may exhibit promiscuous activities which could serve as starting points for adaptive evolution towards new functions.[23][24] In terms of sequence space, current theories predict that if the neutral networks for two different activities overlap, a neutrally evolving population may diffuse to regions of the neutral network of the first activity that allow it to access the second.[25] This would only be the case when the distance between activities is smaller than the distance that a neutrally evolving population can cover. The degree of interpenetration of the two networks will determine how common cryptic variation for the promiscuous activity is in sequence space.[26]


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