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On the conservative nature of intragenic recombination

Drummond, D. Allan and Silberg, Jonathan J. and Meyer, Michelle M. and Wilke, Claus O. and Arnold, Frances H. (2005) On the conservative nature of intragenic recombination. Proceedings of the National Academy of Sciences of the United States of America, 102 (15). pp. 5380-5385. ISSN 0027-8424. PMCID PMC556249.

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Intragenic recombination rapidly creates protein sequence diversity compared with random mutation, but little is known about the relative effects of recombination and mutation on protein function. Here, we compare recombination of the distantly related beta-lactamases PSE-4 and TEM-1 to mutation of PSE-4. We show that, among beta-lactamase variants containing the same number of amino acid substitutions, variants created by recombination retain function with a significantly higher probability than those generated by random mutagenesis. We present a simple model that accurately captures the differing effects of mutation and recombination in real and simulated proteins with only four parameters: (i) the amino acid sequence distance between parents, (h) the number of substitutions, (iii) the average probability that random substitutions will preserve function, and (iv) the average probability that substitutions generated by recombination will preserve function. Our results expose a fundamental functional enrichment in regions of protein sequence space accessible by recombination and provide a framework for evaluating whether the relative rates of mutation and recombination observed in nature reflect the underlying imbalance in their effects on protein function.

Item Type:Article
Related URLs:
URLURL TypeDescription CentralArticle
Wilke, Claus O.0000-0002-7470-9261
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2005 by the National Academy of Sciences. Edited by Michael Levitt, Stanford University School of Medicine, Stanford, CA, and approved March 7, 2005 (received for review January 27, 2005). Published online before print April 4, 2005, 10.1073/pnas.0500729102. We thank Z.-G. Wang for helpful discussions. This work was supported by National Institutes of Health National Research Service Award 5 T32 MH19138 (to D.A.D.), National Institutes of Health Grant R01 GM068665-01 and Fellowship F32 GM64949-01 (to J.J.S.), and a Howard Hughes Medical Institute Predoctoral Fellowship (to M.M.M.). This paper was submitted directly (Track II) to the PNAS office.
Funding AgencyGrant Number
NIH Predoctoral Fellowship5 T32 MH19138
NIHR01 GM068665-01
NIH Postdoctoral FellowshipF32 GM64949-01
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Subject Keywords:directed evolution, mutagenesis, neutrality, lattice proteins, site-directed recombination, neisseria-meningitidis, evolutionary landscapes, protein recombiniation, directed evolution, gene, libraries, robustness, generation, mutations, tolerance
Issue or Number:15
PubMed Central ID:PMC556249
Record Number:CaltechAUTHORS:DRUpnas05a
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1415
Deposited By: Tony Diaz
Deposited On:18 Jan 2006
Last Modified:02 Oct 2019 22:43

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