Why have sex? It seems that genetic studies in the normally non-sexualE. coli may have the key

Visser, J.A.G.M., de

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PLoS Biology  |  www.plosbiology.org 1844 September 2007  |  Volume 5  |  Issue 9  |  e245
Primer
“Why sex?” is a question that has occupied the minds of evolutionary biologists for more than a century. The evolution of organisms that mix 
their genes during reproduction is considered one of the 
major transitions in evolution [1], because it fundamentally 
changed how genes are transmitted to the next generation. 
In asexual reproduction, offspring inherit a more or less 
unaltered genome from the parent. In sexual reproduction, 
genetic material is ﬁ rst reduced in the gametes (sperm or 
ovaries) and then fused with that of another individual, 
before new offspring may develop. Sexual reproduction 
has led to the evolution of males and females with different 
and sometimes even opposing reproductive interests and 
behavior. The consequence of sex, which many evolutionary 
biologists think explains its existence, is the production of 
genetic variation by mixing genes from different individuals.
Nineteenth-century German biologist August Weismann 
[2] was the ﬁ rst to realize that sex can produce variation 
and that variation allows organisms to better respond 
to selection. Three models have since been proposed as 
general explanations for the advantages of sex by elaborating 
Weismann’s idea: (i) sex facilitates adaptation to a novel 
environment by combining beneﬁ cial gene variants, or 
alleles, from different genomes (Fisher-Muller (FM) model 
[3,4]); (ii) sex helps organisms stay adapted to existing 
environmental conditions by combining and efﬁ ciently 
removing deleterious alleles (mutational deterministic (MD) 
model [5]); or—a combination of these two ideas—(iii) sex 
helps to liberate beneﬁ cial alleles from linked deleterious 
alleles in the genome in which they arose (mutational load 
(ML) model [6,7]).
Several recent laboratory evolution experiments have 
found support for Weismann’s proposal that sex facilitates 
the response to selection [8]. However, distinguishing 
between the different models remains a challenge. In 
particular, it has been difﬁ cult to alter recombination without 
changing other variables that might confer a sex advantage, 
such as environmental conditions or non-neutral genetic 
markers. In one attempt to overcome these problems, Rice 
and Chippindale [7] smartly used genetic tools to construct 
synthetic chromosomes of the fruit ﬂ y Drosophila melanogaster 
that could not recombine and hence evolved asexually. This 
trick allowed the authors to study the effect of recombination 
on the fate of an introduced beneﬁ cial mutation without 
the obscuring effects of differences in initial ﬁ tness or 
environmental conditions used to induce sex in some 
populations. In another recent attempt, Goddard et al. [9] 
constructed asexual yeast strains by deleting genes involved 
in the production of gametes. This also allowed them and 
others [10] to compare the evolution of sexual and asexual 
yeast populations under the same conditions. However, 
none of these studies has been able to relate observed ﬁ tness 
changes to the genetic changes responsible, a connection 
that provides a useful handle for distinguishing between the 
relative contributions of beneﬁ cial and deleterious mutations 
to any observed sex advantage, and hence for distinguishing 
among the three competing models explaining sex.
In this issue of PLoS Biology, Tim Cooper [11] takes the 
art of testing sex hypotheses to a new level of experimental 
rigor. Instead of using constructed asexual variants of a sexual 
species, Cooper used Escherichia coli—which, like all bacteria, 
reproduce asexually—to test the relative contribution of the 
models mentioned above. The choice of E. coli may seem 
Bacterial Solutions to the Problem of Sex
J. Arjan G. M. de Visser
Citation: de Visser JAGM (2007) Bacterial solutions to the problem of sex. PLoS Biol 
5(9): e245. doi:10.1371/journal.pbio.0050245
Copyright: © 2007 J. Arjan G. M. de Visser. 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 author and source are credited.
Abbreviations: FM, Fisher–Muller; MD, mutational deterministic; ML, mutational 
load
J. Arjan G. M. de Visser is Assistant Professor at the Laboratory of Genetics, 
Wageningen University, Wageningen, The Netherlands. E-mail: Arjan.deVisser@
wur.nl
doi:10.1371/journal.pbio.0050245.g001
 Figure 1. Predictions from the FM and ML Models about the Fitness 
of a Focal Beneﬁ cial Mutation during Its Increase in Frequency in the 
Population
The advantage of recombination, according to the FM model, derives 
from combining beneﬁ cial mutations; the advantage predicted by the 
ML model results from the liberation of the focal beneﬁ cial mutation 
from linked deleterious mutations in the genome in which it originated.  
(A) Fitness of the focal beneﬁ cial mutation in a recombining (rec+, solid 
line) and nonrecombining (rec−, dashed line) population measured 
relative to the ancestor. (B) Fitness of the same mutation relative to that 
of contemporary clones from the same population.  It is assumed that 
the focal mutant in the rec− populations does not accumulate further 
beneﬁ cial mutations.
Primers provide a concise introduction into an important aspect of biology 
highlighted by a current PLoS Biology research article.
PLoS Biology  |  www.plosbiology.org 1845 September 2007  |  Volume 5  |  Issue 9  |  e245
odd but is an excellent one for several reasons. First, by 
introducing the F plasmid carrying the genes for conjugation 
(the bacterial equivalent of sex), Cooper could study the 
consequence of sex—i.e., genetic recombination—while 
excluding obscuring effects from changed conditions or 
ﬁ tness. Second, by manipulating the mutation rate, he 
could create conditions where competition among different 
beneﬁ cial mutations is known to limit the rate of adaptation 
[12], a prerequisite for the advantage of recombination 
according to the FM model. Third, by using the same strains 
and conditions that have been used in a previous long-term 
evolution experiment [13], Cooper knew which beneﬁ cial 
mutations were to be expected and could study the dynamics 
of a major adaptive mutation in order to distinguish between 
the FM and ML models.
The results provide clear support for the FM model. After 
1,000 generations of laboratory evolution, all lines showed 
greater ﬁ tness—refuting the effect of deleterious mutations 
(MD model) as primary explanation, and recombining 
(rec+) lines (that is, those with sex) had improved more 
than nonrecombining (rec−) lines. To distinguish between 
the explanations offered by the FM model (sex combines 
beneﬁ cial mutations) and the ML model (sex liberates 
beneﬁ cial mutations from deleterious genetic backgrounds), 
Cooper looked at the competitive dynamics of a focal 
beneﬁ cial mutation (in regulatory gene spoT), which was 
found in rec+ and rec− lines alike. This allowed him to test 
two speciﬁ c predictions of the FM model. First, competition 
with other clones carrying beneﬁ cial mutations should slow 
down the ﬁ xation of the focal mutation in rec− lines, but not 
in rec+ lines. Second, this same interference should lower 
the ﬁ tness of clones carrying the focal mutation relative to 
contemporary clones in rec− lines, but not in rec+ lines, once 
competing clones reach appreciable frequencies (Figure 1). 
As a control for the possible effects of deleterious mutations 
(and hence the ML model), the ﬁ tness of these clones 
relative to their ancestors should not decrease during the 
same time interval. Both predictions were supported by the 
data. By using a simple experimental system, which allowed 
an unprecedented level of control of evolutionary variables 
and detailed information on the genetics and population 
dynamics underlying the evolutionary changes, this study 
provides the most speciﬁ c support found so far for the FM 
model.
How strongly do these data reject alternate explanations for 
the evolutionary maintenance of sex? Parasites or otherwise-
ﬂ uctuating environmental conditions can be ruled out from 
the experimental conditions set during evolution. Similarly, 
the faster removal of deleterious mutations, proposed by the 
MD model, is unlikely to have been very important, because 
both of its prerequisites—a rate of deleterious mutations 
of at least one per genome per generation and prevailing 
synergistic interactions among mutations—are not met by 
E. coli. However, it is more difﬁ cult to refute any effect from 
deleterious mutations, because they are likely also the most 
frequent type of mutations in these bacterial populations. 
Although they are not the primary explanation, sex beneﬁ ts 
from liberating occasional beneﬁ cial mutations from linked 
deleterious mutations (ML model) and from the more 
efﬁ cient removal of multiple deleterious mutations (MD 
model) may have contributed to the higher ﬁ tness of the 
rec+ populations. Another complicating factor is that the 
support for the FM model based on the dynamics of the 
focal mutation depends on the assumption that beneﬁ cial 
mutations go to ﬁ xation one-by-one in the rec− populations. 
A recent study of asexual adaptation in yeast [14] indicates 
that when beneﬁ cial mutations are sufﬁ ciently common to 
cause clonal interference, additional beneﬁ cial mutations 
may occur on the background of a focal beneﬁ cial mutation 
that will then collectively go to ﬁ xation. Although in such 
a scenario clonal interference will still occur—only some 
of it will be between clones carrying multiple beneﬁ cial 
mutations—it will alter the competitive dynamics of beneﬁ cial 
mutations in sexual and asexual populations in ways yet to 
be explored [15]. A systematic comparison over time of the 
ﬁ tness of clones carrying spoT mutations from rec− and rec+ 
populations relative to the ancestor and to contemporary 
clones (along the lines suggested in Figure 1) would be one 
way to see whether and how recombination affects adaptation 
when multiple beneﬁ cial mutations go to ﬁ xation together.
How relevant are these bacterial results for understanding 
the evolutionary maintenance of sex in higher organisms? 
In other words, does the bacterial support for the FM model 
mean that recombination between beneﬁ cial mutations 
is the universally best explanation for the existence of sex 
and recombination? Not necessarily. The beneﬁ ts of sex 
depend on factors that are likely to differ among species, 
including the variability of environmental conditions, the 
population size, and the rate, ﬁ tness effects, and interactions 
of mutations. We are gathering information on some of these 
factors for micro-organisms, but they are hardly known for 
higher organisms. Only the patient collection of such data 
from a variety of different organisms may ultimately reveal 
whether organisms share general unifying principles that 
allow a universal explanation for sex, or alternatively whether 
different explanations are required for different species 
[16]. Possibly unifying principles may be found in shared 
genetic architectures. For instance, the way genes interact to 
cause the structures and functions necessary for survival and 
reproduction is one source of evolutionary constraint that 
allows sex to be beneﬁ cial [8,17].
Undoubtedly, the study by Cooper [11] will stimulate 
further studies of the evolution of recombination using 
simple experimental systems. Only by manipulating 
single evolutionary variables at a time, while removing 
the confounding effects of other variables, can the 
contribution of the different models explaining sex be 
tested in unambiguous ways. To reach the desired level of 
experimental control, the subject of study must be isolated 
from its natural environment and stripped from all its 
nonessential attributes. While such reductionism holds the 
danger of changing the “natural behavior” of the subject 
of study, it is arguably the most efﬁ cient way forward. Most 
importantly, as the study by Cooper shows, simple systems 
beneﬁ t from the detailed information they can provide on 
the evolutionary dynamics of genetic change and how this 
differs between sexual and asexual populations. One can only 
hope that new genetic technologies will soon allow similar 
experimental rigor in studies with other organisms. 
Acknowledgements
I thank Duur Aanen, Fons Debets, and Danny Rozen for useful 
comments, and the Netherlands Organization for Scientiﬁ c Research 
for funding.
PLoS Biology  |  www.plosbiology.org 1846 September 2007  |  Volume 5  |  Issue 9  |  e245
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