title: Evolution favors protein mutational robustness in sufficiently large populations.
abstract: BACKGROUND
  An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties.
  
  
  RESULTS
  Here, we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by mathematical theory, and can be quantitatively related to the way that the proteins occupy their neutral network.
  
  
  CONCLUSIONS
  Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon could contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA. jesse.bloom@gmail.com
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Bloom
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Lu
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.forename: Alpan
authors.initials: A
authors.lastname: Raval
authors.forename: Ophelia S
authors.initials: OS
authors.lastname: Venturelli
authors.forename: Frances H
authors.initials: FH
authors.lastname: Arnold
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004795:Enzyme Stability; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D019143:Evolution, Molecular; D008962:Models, Theoretical; D009154:Mutation; D011110:Polymorphism, Genetic; D011156:Population Density; D011506:Proteins / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D011506:Proteins; D003577:Cytochrome P-450 Enzyme System