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Genomewide Patterns of Substitution in Adaptively Evolving Populations of the RNA Bacteriophage MS2

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Experimental evolution of bacteriophage provides a powerful means of studying the genetics of adaptation, as every substitution contributing to adaptation can be identified and characterized. Here, I use experimental evolution of MS2, an RNA bacteriophage, to study its adaptive response to a novel environment. To this end, three lines of MS2 were adapted to rapid growth and lysis at cold temperature for a minimum of 50 phage generations and subjected to whole-genome sequencing. Using this system, I identified adaptive substitutions, monitored changes in frequency of adaptive mutations through the course of the experiment, and measured the effect on phage growth rate of each substitution. All three lines showed a substantial increase in fitness (a two- to threefold increase in growth rate) due to a modest number of substitutions (three to four). The data show some evidence that the substitutions occurring early in the experiment have larger beneficial effects than later ones, in accordance with the expected diminishing returns relationship between the fitness effects of a mutation and its order of substitution. Patterns of molecular evolution seen here-primarily a paucity of hitchhiking mutations-suggest an abundant supply of beneficial mutations in this system. Nevertheless, some beneficial mutations appear to have been lost, possibly due to accumulation of beneficial mutations on other genetic backgrounds, clonal interference, and negatively epistatic interactions with other beneficial mutations. [PUBLICATION ABSTRACT]

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									Copyright Ó 2009 by the Genetics Society of America
DOI: 10.1534/genetics.107.085837



                Genomewide Patterns of Substitution in Adaptively Evolving
                      Populations of the RNA Bacteriophage MS2

                                                             Andrea J. Betancourt1
                                       Department of Biology, University of Rochester, Rochester, New York 14627
                                                       Manuscript received December 17, 2007
                                                      Accepted for publication January 25, 2009


                                                               ABSTRACT
                 Experimental evolution of bacteriophage provides a powerful means of studying the genetics of
              adaptation, as every substitution contributing to adaptation can be identified and characterized. Here, I use
              experimental evolution of MS2, an RNA bacteriophage, to study its adaptive response to a novel
              environment. To this end, three lines of MS2 were adapted to rapid growth and lysis at cold temperature for a
              minimum of 50 phage generations and subjected to whole-genome sequencing. Using this system, I
              identified adaptive substitutions, monitored changes in frequency of adaptive mutations through the course
              of the experiment, and measured the effect on phage growth rate of each substitution. All three lines showed
              a substantial increase in fitness (a two- to threefold increase in growth rate) due to a modest number of
              substitutions (three to four). The data show some evidence that the substitutions occurring early in the
              experiment have larger beneficial effects than later ones, in accordance with the expected diminishing
              returns relationship between the fitness effects of a mutation and its order of substitution. Patterns of
              molecular evolution seen here—primarily a paucity of hitchhiking mutations—suggest an abundant supply
              of beneficial mutations in this system. Nevertheless, some beneficial mutations appear to have been lost,
              possibly due to accumulation of beneficial mutations on other genetic backgrounds, clonal interference,
              and negatively epistatic interactions with other beneficial mutations.




E    XPERIMENTAL evolution, or the study of adapta-
      tion in laboratory populations, provides a means of
following adaptation in real time and in minute detail.
                                                                               slowdown in the rate of increase in mean fitness may
                                                                               be due to one of two causes or some mixture of the two.
                                                                               First, as a population approaches an optimal phenotype,
Microbial systems, in particular, offer an opportunity to                      the supply of beneficial mutations may become ex-
rigorously test theoretical models of adaptive evolution,                      hausted, and adaptation may be limited by an increas-
as in these systems beneficial mutations can be readily                         ingly smaller mutation supply (Silander et al. 2007).
observed and their effects measured in a controlled                            Second, the rate of adaptation may slow if, as expected,
environment. Recent work in this area has addressed                            mutations with large benefits tend to be fixed earlier
such questions as whether theory can accurately predict                        than those with small benefits.
the distribution of fitness effects among beneficial alleles                        Several population genetic and physiological factors
(Sanjuan et al. 2004; Rokyta et al. 2005; Barrett et al.                       may act together to ensure that large-effect mutations
2006; Kassen and Bataillon 2006) and how interfer-                             are fixed before mutations with small effects, particu-
ence alters this distribution among fixed beneficial                             larly in large asexual populations. First, because these
alleles (Hegreness et al. 2006).                                               mutations with big benefits have shorter sweep times
   Lenski and Travisano (1994) pioneered another                               than other mutations, they will tend to be among the
kind of experimental evolution approach, which focuses                         first mutations fixed (Kimura and Ohta 1969; Gerrish
on describing patterns of evolution in evolving lines.                         and Lenski 1998; Kim and Orr 2005). This is especially
One generality that has emerged from these studies is                          true in large populations, where an abundant mutation
that evolving populations tend to increase in fitness                           supply offers opportunity for competition between bene-
rapidly upon introduction to a new environment, but                            ficial mutations (Gerrish and Lenski 1998; Kim and
more slowly later (Elena and Lenski 2003). This                                Orr 2005). Second, large-effect mutations have lower
                                                                               probabilities of stochastic loss (Haldane 1927; Gillespie
                                                                               1991; Orr 2002), and correspondingly shorter waiting
  Sequence data from this article have been deposited with the EMBL/           times until a successful mutation occurs, than small-
GenBank Data Libraries under accession nos. FJ799467–FJ99712.                  effect mutations. This may be particularly true in asexual
  1
   Address for correspondence: Institute of Evolutionary Biology, University   populations, where successful mutations may need to
of Edinburgh, King’s Bldgs., W. Mains Rd., Ashworth Labs, Room 123,
Edinburgh, EH9 3JT United Kingdom.                                             have benefits large enough to overcome the effects of
E-mail: abetanco@staffmail.ed.ac.uk                                            linked deleterious mutations ( Johnson and Barton

Genetics 181: 1535–1544 (April 2009)
1536                                                         A. J. Betancourt

2002). Third, diminishing returns epistasis may be                          Phage were grown on TOP 10 F9 E. coli cells (Invitrogen,
								
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