Neutral network (evolution)

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Not to be confused with 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 an be though 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]

References[edit]

  1. ^ a b van Nimwegen, E; Crutchfield, JP; Huynen, M (Aug 17, 1999). "Neutral evolution of mutational robustness.". Proceedings of the National Academy of Sciences of the United States of America 96 (17): 9716–20. doi:10.1073/pnas.96.17.9716. PMC 22276. PMID 10449760. 
  2. ^ Taverna, DM; Goldstein, RA (Jan 18, 2002). "Why are proteins so robust to site mutations?". Journal of Molecular Biology 315 (3): 479–84. doi:10.1006/jmbi.2001.5226. PMID 11786027. 
  3. ^ Tokuriki, N; Tawfik, DS (Oct 2009). "Stability effects of mutations and protein evolvability.". Current opinion in structural biology 19 (5): 596–604. doi:10.1016/j.sbi.2009.08.003. PMID 19765975. 
  4. ^ Meyerguz, L; Kleinberg, J; Elber, R (Jul 10, 2007). "The network of sequence flow between protein structures.". Proceedings of the National Academy of Sciences of the United States of America 104 (28): 11627–32. doi:10.1073/pnas.0701393104. PMID 17596339. 
  5. ^ Karplus, M (Jun 17, 2011). "Behind the folding funnel diagram.". Nature chemical biology 7 (7): 401–4. doi:10.1038/nchembio.565. PMID 21685880. 
  6. ^ Tokuriki, N; Stricher, F; Schymkowitz, J; Serrano, L; Tawfik, DS (Jun 22, 2007). "The stability effects of protein mutations appear to be universally distributed.". Journal of Molecular Biology 369 (5): 1318–32. doi:10.1016/j.jmb.2007.03.069. PMID 17482644. 
  7. ^ Shakhnovich, BE; Deeds, E; Delisi, C; Shakhnovich, E (Mar 2005). "Protein structure and evolutionary history determine sequence space topology.". Genome Research 15 (3): 385–92. doi:10.1101/gr.3133605. PMID 15741509. 
  8. ^ Monsellier, E; Chiti, F (Aug 2007). "Prevention of amyloid-like aggregation as a driving force of protein evolution.". EMBO Reports 8 (8): 737–42. doi:10.1038/sj.embor.7401034. PMID 17668004. 
  9. ^ Fink, AL (1998). "Protein aggregation: folding aggregates, inclusion bodies and amyloid.". Folding & design 3 (1): R9–23. doi:10.1016/s1359-0278(98)00002-9. PMID 9502314. 
  10. ^ Richardson, JS; Richardson, DC (Mar 5, 2002). "Natural beta-sheet proteins use negative design to avoid edge-to-edge aggregation.". Proceedings of the National Academy of Sciences of the United States of America 99 (5): 2754–9. doi:10.1073/pnas.052706099. PMC 122420. PMID 11880627. 
  11. ^ Müller, MM; Allison, JR; Hongdilokkul, N; Gaillon, L; Kast, P; van Gunsteren, WF; Marlière, P; Hilvert, D (2013). "Directed evolution of a model primordial enzyme provides insights into the development of the genetic code.". PLoS genetics 9 (1): e1003187. doi:10.1371/journal.pgen.1003187. PMID 23300488. 
  12. ^ Firnberg, E; Ostermeier, M (Aug 2013). "The genetic code constrains yet facilitates Darwinian evolution.". Nucleic Acids Research 41 (15): 7420–8. doi:10.1093/nar/gkt536. PMID 23754851. 
  13. ^ Hietpas, RT; Jensen, JD; Bolon, DN (May 10, 2011). "Experimental illumination of a fitness landscape.". Proceedings of the National Academy of Sciences of the United States of America 108 (19): 7896–901. doi:10.1073/pnas.1016024108. PMC 3093508. PMID 21464309. 
  14. ^ Kimura, Motoo. (1983). The neutral theory of molecular evolution. Cambridge
  15. ^ Kimura M. (1968). Evolutionary Rate at the Molecular Level. Nature 217:624-6.
  16. ^ Proulx, SR; Adler, FR (Jul 2010). "The standard of neutrality: still flapping in the breeze?". Journal of evolutionary biology 23 (7): 1339–50. doi:10.1111/j.1420-9101.2010.02006.x. PMID 20492093. 
  17. ^ van Nimwegen E.,Crutchfield J. P., Huynen M. (1999). "Neutral evolution of mutational robustness". PNAS 96 (17): 9716–9720. doi:10.1073/pnas.96.17.9716. 
  18. ^ Bloom, JD; Lu, Z; Chen, D; Raval, A; Venturelli, OS; Arnold, FH (Jul 17, 2007). "Evolution favors protein mutational robustness in sufficiently large populations.". BMC biology 5: 29. doi:10.1186/1741-7007-5-29. PMID 17640347. 
  19. ^ Bershtein, Shimon; Goldin, Korina; Tawfik, Dan S. (June 2008). "Intense Neutral Drifts Yield Robust and Evolvable Consensus Proteins". Journal of Molecular Biology 379 (5): 1029–1044. doi:10.1016/j.jmb.2008.04.024. PMID 18495157. 
  20. ^ Wright, Sewel (1932). "The roles of mutation, inbreeding, crossbreeding and selection in evolution". Proceedings of the sixth international congress of genetics: 356–366. 
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  23. ^ Masel, J (Mar 2006). "Cryptic genetic variation is enriched for potential adaptations.". Genetics 172 (3): 1985–91. doi:10.1534/genetics.105.051649. PMC 1456269. PMID 16387877. 
  24. ^ Hayden, EJ; Ferrada, E; Wagner, A (Jun 2, 2011). "Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme.". Nature 474 (7349): 92–5. doi:10.1038/nature10083. PMID 21637259. 
  25. ^ Bornberg-Bauer, E; Huylmans, AK; Sikosek, T (Jun 2010). "How do new proteins arise?". Current opinion in structural biology 20 (3): 390–6. doi:10.1016/j.sbi.2010.02.005. PMID 20347587. 
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