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Neutral genetic drift can alter promiscuous protein functions, potentially aiding functional evolution

Bloom, Jesse D. and Romero, Philip A. and Lu, Zhongyi and Arnold, Frances H. (2007) Neutral genetic drift can alter promiscuous protein functions, potentially aiding functional evolution. Biology Direct, 2 . Art. No. 17. ISSN 1745-6150. PMCID PMC1914045.

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[img] Plain Text (Additional file 1: Mutations in neutrally evolved P450s) - Supplemental Material
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[img] Plain Text (Additional file 3: Raw activity and sequence data) - Supplemental Material
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Background: Many of the mutations accumulated by naturally evolving proteins are neutral in the sense that they do not significantly alter a protein's ability to perform its primary biological function. However, new protein functions evolve when selection begins to favor other, "promiscuous" functions that are incidental to a protein's original biological role. If mutations that are neutral with respect to a protein's primary biological function cause substantial changes in promiscuous functions, these mutations could enable future functional evolution. Results: Here we investigate this possibility experimentally by examining how cytochrome P450 enzymes that have evolved neutrally with respect to activity on a single substrate have changed in their abilities to catalyze reactions on five other substrates. We find that the enzymes have sometimes changed as much as four-fold in the promiscuous activities. The changes in promiscuous activities tend to increase with the number of mutations, and can be largely rationalized in terms of the chemical structures of the substrates. The activities on chemically similar substrates tend to change in a coordinated fashion, potentially providing a route for systematically predicting the change in one activity based on the measurement of several others. Conclusion: Our work suggests that initially neutral genetic drift can lead to substantial changes in protein functions that are not currently under selection, in effect poising the proteins to more readily undergo functional evolution should selection favor new functions in the future.

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URLURL TypeDescription CentralArticle
Bloom, Jesse D.0000-0003-1267-3408
Romero, Philip A.0000-0002-2586-7263
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2007 Bloom et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Received 18 June 2007; Accepted 28 June 2007; Published 28 June 2007. We thank Andrew Sawayama and Sabine Bastian for helpful comments. JDB was supported by a Howard Hughes Medical Institute predoctoral fellowship. ZL was supported by a summer undergraduate research fellowship from the California Institute of Technology. Authors' contributions: JDB, PR, and FHA designed the study. JDB, PR, and ZL performed the experiments. JDB and PR analyzed the data. JDB and FHA wrote the paper.
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Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Caltech Summer Undergraduate Research Fellowship (SURF)UNSPECIFIED
PubMed Central ID:PMC1914045
Record Number:CaltechAUTHORS:BLObd07
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ID Code:8001
Deposited By: Archive Administrator
Deposited On:16 Jul 2007
Last Modified:26 Nov 2019 20:04

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