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The Role of Transient Hypermutators in Adaptive Mutation in Escherichia Coli

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The Role of Transient Hypermutators in Adaptive Mutation in Escherichia Coli Proc. Natl. Acad. Sci. USA Vol. 96, pp. 6862–6867, June 1999 Genetics The role of transient hypermutators in adaptive mutation in Escherichia coli WILLIAM A. ROSCHE† AND PATRICIA L. FOSTER†‡, WITH APPENDIX BY JOHN CAIRNS§ †Department of Environmental Health, Boston University School of Public Health, Boston University School of Medicine, Boston, MA 02118; and §Clinical Trial Service Unit, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom Communicated by Philip Hanawalt, Stanford University, Stanford, CA, April 23, 1999 (received for review January 10, 1999) ABSTRACT Microbial populations under nonlethal se- that bear adaptive mutations than among cells that do not (3). lection can give rise to mutations that relieve the selective In four cases in which this has been tested, the prediction has pressure, a phenomenon that has come to be called ‘‘adaptive been confirmed (3–6). However, it is not possible to determine mutation.’’ One explanation for adaptive mutation is that a from those results what proportion of the mutations that occur small proportion of the cells experience a period of transient during selection arise from hypermutating cells—that will hypermutation, and that these hypermutators account for the depend on the proportion of cells that are in the hypermutable mutations that appear. The experiments reported here inves- state and the degree to which their mutation rate is elevated tigated the contribution that hypermutators make to the (7, 8). Two independent measurements are needed to solve for mutations occurring in a Lac2 strain of Escherichia coli during these two unknowns. selection for lactose utilization. A broad mutational screen, In the experiments reported here, we used a broad muta- loss of motility, was used to compare the frequency of non- tional screen, loss of motility, to compare the frequency of selected mutations in starved Lac2 cells, in Lac1 revertants, nonselected mutations in starved Lac2 cells, in selected Lac1 and in Lac1 revertants carrying yet another nonselected revertants, and in those few Lac1 revertants that carried an mutation. These frequencies allowed us to calculate that the additional mutation. This procedure allowed us to solve the hypermutating subpopulation makes up '0.06% of the pop- equations given in the Appendix and thereby to estimate both ulation and that its mutation rate is elevated '200-fold. From the size of the hypermutating subpopulation, p, and the these numbers we conclude that the hypermutators are re- magnitude of its increase in mutation rate, M. Our results show sponsible for nearly all multiple mutations but produce only that, even though the hypermutating minority is responsible '10% of the adaptive Lac1 mutations. for nearly all of the multiple mutations, it makes only a small contribution to the adaptive Lac1 mutations occurring during Although spontaneous mutations occur at random while cells lactose selection in E. coli strain FC40. are proliferating, apparently static microbial populations un- der nonlethal selective pressure also accumulate mutations. In MATERIALS AND METHODS some cases, these mutations appear to be confined to genes that give an adaptive phenotype, and for this reason the Bacterial Strains. E. coli strain FC722 is a rifampicin- R 2 D phenomenon has come to be called directed or adaptive resistant (Rif ) derivative of P90C [F ara (lac proB)X111 thi 9 mutation (1). Most models for adaptive mutation invoke a (9)] that carries the F 128 episome with a mutant lac allele, F S genomewide process that produces genetic variants at random (lacI33-lacZ) (10), and a tetracycline-sensitive (Tet ) defec- but postulate that these variants are transitory unless the cell tive Tn10 element (4). FC722 is isogenic to strain FC40 (11) S achieves a mutation that relieves the selective pressure (2). The except for the episomal Tet element. FC1259 is FC722 but mutL::Kan [allele from strain GM4250 (12)] and was con- most extreme of these ‘‘trial-and-error’’ models is the ‘‘hyper- 2 mutable state’’ proposed by Hall (3). According to this model, structed by P1vir transduction. Strain FC691 is F but carries F most cells in a population under selection do not mutate, but the (lacI33-lacZ) allele on its chromosome. FC691 is a a minority transiently experience a high mutation rate and derivative of GM4270 (obtained from M. G. Marinus, Uni- soon die unless a useful mutation occurs. versity of Massachusetts Medical School) created by curing its Escherichia coli strain FC40 is unable to catabolize lactose episome with acridine orange (see ref. 13). FC29 is rifampicin- S 2 (Lac2) but reverts to lactose utilization (Lac1) when lactose is sensitive (Rif ) and carries a nonrevertible Lac allele on its its sole carbon and energy source. Although this reversion has episome (11). been considered an example of adaptive mutation, during Media. M9 minimal medium (14) was supplemented with lactose selection nonselected mutations in a nearby gene 0.1% lactose (Lac), maltose (Mal) (both from Difco), glycerol accumulate in the Lac2 population at about the same rate as (Gly), or D-galacturonic acid (GA) (both from Sigma). When 1 m do Lac mutations (4). Thus, the mutational process in FC40 required, antibiotics were added at 100 g/ml rifampicin (Rif), m m does not meet the original definition of adaptive mutation, 10 g/ml tetracycline (Tet), 22.5 g/ml kanamycin (Kan), or 10 m which specified that only adaptive mutations should appear. g/ml spectinomycin (Spc) (all from Sigma). Resistances to 1 5-fluorocytosine (5FC) and 5-fluorouracil (5FU) were However, we continue here to call the Lac mutations ap- m pearing during lactose selection ‘‘adaptive’’ simply to distin- screened on M9-Gly medium supplemented with 20 g/ml 5FC 1 m guish them from the Lac mutations occurring during nonse- or 10 g/ml 5FU (both from Sigma). Mutators were screened lective growth and from nonselected mutations occurring on MacConkey Base Agar (Difco) supplemented with 1.0% during lactose selection. arabinose (Mac-Ara) or salicin (Mac-Sal). Motility was A specific prediction of the hypermutable-state model is that screened on LB medium (14) solidified with 0.35% Bacto Agar nonselected mutations occur at a higher frequency among cells (Difco). The publication costs of this article were defrayed in part by page charge Abbreviations: Lac, lactose; Rif, rifampicin; Tet, tetracycline; Mal, maltose; Gly, glycerol; 5FC, 5-fluorocytosine; 5FU, 5-fluorouracil; payment. This article must therefore be hereby marked ‘‘advertisement’’ in MMR, mismatch repair; Mac, MacConkey agar. accordance with 18 U.S.C. §1734 solely to indicate this fact. ‡To whom reprint requests should be addressed. e-mail: pfoster@ PNAS is available online at www.pnas.org. bu.edu. 6862 Downloaded by guest on October 1, 2021 Genetics: Rosche and Foster Proc. Natl. Acad. Sci. USA 96 (1999) 6863 Experimental Techniques. Lac1 revertants were selected on the episome (strain FC722) or on the chromosome (strain M9-Lac plates as described (11). About 107 FC722 cells, 106 FC691) (Fig. 1). However, when the Lac2 allele is on the FC1259 cells (each with 109 FC29 scavengers), or 109 FC691 chromosome, adaptive mutation to Lac1 has different genetic cells (without scavengers) were plated on each of 60, 48, and requirements and occurs at an .100-fold lower rate (ref. 13, 80 M9-Lac plates, respectively. Each plate received cells from and unpublished results; Fig. 1). In contrast, loss of methyl- an independent culture grown to saturation in M9-Gly me- directed mismatch repair (MMR) (16) increases the rate of 1 dium. Each day for 5 days after plating, new Lac colonies adaptive mutation to Lac1 100-fold (17). Strain FC1259 is were counted, and their positions were marked. The plates isogenic to FC722 but defective in mutL, which encodes a were incubated at 37°C for an additional day to allow the component of the MMR system (18). We tested for nonse- colonies that appeared on day 5 to grow to the same size as lected mutations in Lac1 revertants and starved Lac2 cells of earlier arising colonies. Plates were then stored at 4°C. Each each of these three strains. colony was assigned an identification number specifying its Mutations in as many as 55 genes, '1% of the E. coli position and day of appearance, and then some of its cells were genome, could affect motility (15, 19). Because motility is a transferred (patched) with a sterile wooden toothpick to a novel mutational screen, we tested our assay for reproducibility rectangular Nunc Omni tray containing 50 ml of solid M9-Lac (see Materials and Methods). Of the five mutant motility 1 Rif medium for strains FC722 and FC1259 or M9-Lac phenotypes identified (here collectively called Mot*), Mot2 medium for strain FC691. The cells were patched in a pattern (no swimming) was the most reproducible, and so it is the only corresponding to the array of a standard 96-well microplate. phenotype given in Tables 1 and 3 and Fig. 2. Eighty-five After transfer, the Omni trays were incubated at 37°C for 48 percent of the Lac1 clones grew vigorously on lactose; of these hours. 1 2 2 strongly Lac clones, 2% had an apparent Mot phenotype in Starved Lac cells were obtained by taking plugs from the the initial screen, and 70% of these were confirmed to be lactose plates each day (11) and plating an appropriate dilution composed entirely of motility-defective cells on retesting (see on M9-Gly plates (plus Rif for strains FC722 and FC1259), below for the characteristics of the remaining clones). If the which were then incubated at 37°C for the duration of the cells were only weakly Lac1, this value dropped to 15%; poor experiment. These colonies were also assigned identification growth on the lactose medium used for the initial gridding numbers and then patched to Omni trays containing M9-Gly 1 results in fewer cells being transferred to the motility-screening Rif medium for strains FC722 and FC1259 or M9-Gly medium, giving an apparent motility deficiency.
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