Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 15, Pages 5380-5385Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0500729102
Keywords
directed evolution; mutagenesis; neutrality; lattice proteins; site-directed recombination
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Funding
- NIGMS NIH HHS [F32 GM064949, F32 GM 64949-01, R01 GM068665, R01 GM 068665-01] Funding Source: Medline
- NIMH NIH HHS [5T32 MH 19138, T32 MH019138] Funding Source: Medline
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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.
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