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Published online on November 2, 2006, 10.1073/pnas.0608309103 OPEN ACCESS ARTICLE


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Genetics
Multiple pathways of selected gene amplification during adaptive mutation

( gene duplication | genetic adaptation | natural selection | genome instability | mutation under selection )

Elisabeth Kugelberg *, Eric Kofoid *, Andrew B. Reams *, Dan I. Andersson {dagger}, and John R. Roth *{ddagger}

*Section of Microbiology, College of Biological Sciences, University of California, Davis, CA 95616; and {dagger}Department of Medical Biochemistry and Microbiology, S-751-23 Uppsala University, Uppsala, Sweden

Contributed by John R. Roth, September 21, 2006 (sent for review August 8, 2006)

In a phenomenon referred to as "adaptive mutation," a population of bacterial cells with a mutation in the lac operon (lac-) accumulates Lac+ revertants during prolonged exposure to selective growth conditions (lactose). Evidence was provided that selective conditions do not increase the mutation rate but instead favor the growth of rare cells with a duplication of the leaky lac allele. A further increase in copy number (amplification) improves growth and increases the likelihood of a sequence change by adding more mutational targets to the clone (cells and lac copies per cell). These duplications and amplifications are described here. Before selection, cells with large (134-kb) lac duplications and long junction sequences (>1 kb) were common (0.2%). The same large repeats were found after selection in cells with a low-copy-number lac amplification. Surprisingly, smaller repeats (average, 34 kb) were found in high-copy-number amplifications. The small-repeat duplications form when deletions modify a preexisting large-repeat duplication. The shorter repeat size allowed higher lac amplification and better growth on lactose. Thus, selection favors a succession of gene-amplification types that make sequence changes more probable by adding targets. These findings are relevant to genetic adaptation in any biological systems in which fitness can be increased by adding gene copies (e.g., cancer and bacterial drug resistance).

Author contributions: E. Kugelberg, E. Kofoid, A.B.R., D.I.A., and J.R.R. designed research; E. Kugelberg, E. Kofoid, and A.B.R. performed research; E. Kugelberg and E. Kofoid contributed new reagents/analytic tools; E. Kugelberg, E. Kofoid, D.I.A., and J.R.R. analyzed data; and E. Kugelberg, D.I.A., and J.R.R. wrote the paper.

The authors declare no conflict of interest.

Freely available online through the PNAS open access option.

{ddagger}To whom correspondence should be addressed.

John R. Roth, E-mail: jrroth{at}ucdavis.edu

www.pnas.org/cgi/doi/10.1073/pnas.0608309103
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