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BIOCHEMISTRY
On the conservative nature of intragenic recombination

D. Allan Drummond ^* , Jonathan J. Silberg ^,  , Michelle M. Meyer ^¶, Claus O. Wilke ^* ||, and Frances H. Arnold ^, ¶, **

^*Program in Computation and Neural Systems, ^¶Biochemistry and Molecular Biophysics Option, and Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125

Edited by Michael Levitt, Stanford University School of Medicine, Stanford, CA, and approved March 7, 2005 (received for review January 27, 2005)

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 -lactamases PSE-4 and TEM-1 to mutation of PSE-4. We show that, among -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, (ii) 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.

directed evolution | mutagenesis | neutrality | lattice proteins | site-directed recombination

This paper was submitted directly (Track II) to the PNAS office.

D.A.D. and J.J.S. contributed equally to this work.

Present address: Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77005.

^|| Present address: Keck Graduate Institute, 535 Watson Drive, Claremont, CA 91711.

^** To whom correspondence should be addressed at: Division of Chemistry and ChemicalEngineering, California Institute of Technology, Mail Code 210-41, Pasadena, CA 91125. E-mail: frances{at}cheme.caltech.edu.

© 2005 by The National Academy of Sciences of the USA

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This article has been cited by other articles in HighWire Press-hosted journals:

				K. E. Griswold, Y. Kawarasaki, N. Ghoneim, S. J. Benkovic, B. L. Iverson, and G. Georgiou Evolution of highly active enzymes by homology-independent recombination PNAS, July 19, 2005; 102(29): 10082 - 10087. [Abstract] [Full Text] [PDF]

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