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F u n da M e n ta l c o n c e p t s i n g e n e t i c s

Genetics and the understanding

of selection
Laurence D. Hurst
Abstract | At first sight selection is a simple notion, and some consider it the most
important evolutionary force. But how important is selection, is it really so trivial to
understand and what are the alternatives? Here I discuss how genetics is crucial for
addressing all of these questions: genetics allowed the concept of natural selection to
become viable, it contributed to our understanding of the complexities of selection and it
spurred the development of competing models of evolution. Understanding how and why
selection acts has important potential applications, from understanding the mechanisms
of disease and microbial resistance, to improving the design of transgenes and drugs.

Synonymous mutation
A nucleotide change in an
exonic DNA sequence that
does not result in a change in
the encoded amino acid. A
synonymous mutation that
reaches fixation becomes a
synonymous substitution.
Department of Biology and
Biochemistry, University of
Bath, Somerset, BA2 7AY, UK.
e‑mail: l.d.hurst@bath.ac.uk
doi:10.1038/nrg2506
Published online
2 January 2009
“How extremely stupid not to have thought of that!” was
T. H. Huxley’s famous response to the concept of natu-
ral selection. The requirements for selection also make
it seem inevitable: that there are more individuals born
than can survive and reproduce, that individuals vary in
their ability to survive and reproduce and that some of
this variation is heritable. Partly because selection can
operate under a wide range of conditions, some sup-
pose it to be the most powerful explanatory principle1
for understanding the fate of any replicating system. But
is selection inevitable? Can selection act if the selective
advantage of an allele is small? Can it even allow deleteri-
ous alleles to invade a population? What limits the action
of selection? What are the alternatives to selection?
In this Review, I discuss how understanding genetics
is key to answering all of these questions. This discus-
sion is based around three important contributions that
genetics has made to the understanding of selection.
First, Mendelian genetics enabled Darwin’s idea of natu-
ral selection to be accepted and developed by providing
a mode of inheritance in which selection can operate.
Second, a fuller appreciation of the complexities of genet-
ics allowed a more nuanced understanding of selection.
For example, it was initially thought that the fate of an
allele was determined solely by the fitness advantage it
conferred on an individual, but more developed models
of selection that consider genetics can explain why even
deleterious alleles can spread. Third, genetic observa-
tions, such as the unexpectedly high rates of evolution
and the common occurrence of polymorphisms, sug-
gested that selectionist models had limitations, and so
spurred the development of competing explanations of
evolution — the neutral and nearly neutral theories.
There are still areas of debate and uncertainty asso-
ciated with each of these developments in our under-
standing of selection that are relevant to our current
understanding of the role of selection in shaping popu-
lations and genomes. For example, recent work on gene
and genome evolution has suggested that selection might
reach further than was previously supposed, which has
practical implications. For example, if there is selection
on gene order 2, it could be important to understand
where a transgene inserts3, and showing that synonymous
mutations are under selection might suggest they cause
disease4. Therefore, understanding how and why selec-
tion acts might also improve genetic intervention5 and
our understanding of disease.
Mendelian genetics and the viability of selection
Although natural selection that favours the survival
of individuals with a fitness advantage might seem
an obvious concept, this was not the case when it was
originally proposed by Darwin. Natural selection
was initially not widely accepted owing largely to con-
fusion over how inheritance worked. It was commonly
thought that inheritance blended the traits of two indi-
viduals — for example, that the offspring that result from
a cross between a red flower and a white flower should be
pink. As blending inheritance removes variation from a
population6, it is incompatible with selection because no
individual will have an advantage over another.
The discovery and development of Mendelian genet-
ics resolved the uncertainty over Darwin’s theory of
natural selection. Under Mendelian inheritance and
with random mating, genotype frequencies after one
generation do not change. Therefore, unlike blending

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Box 1 | invasion of an allele under Mendelian and non-Mendelian inheritance
Under Mendelian inheritance, the fate of an allele that provides a fitness
advantage can be understood by the formula set out here:
Suppose that the genotype AA has a small fitness bonus (s) compared with the
genotype aa. The genotype Aa has a fitness bonus hs, in which h is a term that
captures the effects of the dominance of A over a with regard to fitness. Assuming
Hardy–Weinberg ratios, the frequency of A in the next generation (p′) is given by the
equation p′ = [p2 (1 + s) + pq (1 + hs)]/ω in which ω= p2 (1 + s) + 2 pq (1 + hs) + q2, and is
the weighted mean fitness in the population; p is the frequency of A; q = 1 – p and
is the frequency of a. Let us now suppose that all the population is type aa and a
new A allele enters. The likely fate of this allele is determined by the slope of the
line describing p′ as a function of p when p ≈ 0. If the slope is >1, the allele invades
the population. The condition for this to occur is hs >0 — that is, the heterozygote
(Aa) must have higher fitness than the aa homozygote. However, the striking thing
about this solution is what is missing. There is nothing in the solution concerning
the mode of inheritance: individual fitness is the sole determinant of the fate
of the allele.
The contrast with what is observed under non-Mendelian inheritance is striking,
as can be demonstrated by considering the invasion of a deleterious allele.
Suppose that heterozygotes transmit the A allele at a rate k and the a allele at a
rate 1 – k. For Mendelian inheritance, these rates would be equal: the unique point
k = 1 – k = 0.5. Suppose that AA has fitness 1 – t, Aa has fitness 1 – s and aa has
fitness 1. For the deleterious allele, A, to invade, the inequality 2k (1 – s)>1 must
hold105. If k is replaced with 0.5, under Mendelian inheritance, s<0 must hold, and
thus, as above, the allele is beneficial in heterozygotes. What if k = 1 — that is,
Aa × aa gives only Aa offspring? For invasion, s<0.5 must still hold. The allele can
reduce the fitness of the organism by up to 50% and still spread. Any allele for
which k>0.5, for which invasion is possible despite s<0, is one class of selfish gene
or selfish genetic element23 (not to be confused with the concept of a selfish
gene that was defined by R. Dawkins, which describes any allele that can
deterministically invade, regardless of the underlying logic). Under Mendelian
conditions, only the fitness of the individual is important, whereas under
non-Mendelian inheritance, both the rate of transmission and the fitness of the
organism determine the fate of the allele.
inheritance, Mendelian inheritance retains variation
and therefore the possibility of selection. This reten-
tion of variation applies to both discrete alleles (regard-
Hardy–Weinberg ratio less of ploidy) and continuously varying traits (such as
The binomial distribution of height)7. Importantly, under Mendelian inheritance, the
genotypes in a population, sole determinant of whether the allele will spread when
such that frequencies of the
genotypes AA, Aa and aa will
it enters a population is whether the fitness of hetero-
be p2, 2pq and q2, respectively, zygotes is greater than that of wild-type homozygotes
in which p is the frequency of (BOX 1). Basic Mendelian genetics therefore showed that
allele A and q is the frequency Darwin’s concept of natural selection is viable and also
of allele a.
suggested that only fitness, not the mode of inheritance,
Evolutionary stable needs to be considered when assessing the action of
strategy theory selection on an allele.
An approach to mathematically Given that under Mendelian inheritance the likely
modelling evolution that outcome of selection can be unaffected by the mode of
defines equilibrium positions
as positions at which, if all
inheritance, many researchers (especially those working
individuals are using the same on animal behaviour) use mathematical models of selec-
strategy, invasion by rare tion that ignore the underlying genetics and concentrate
individuals who adopt a only on the effects of individual fitness. Such models (for
different strategy is impossible.
example, the evolutionary stable strategy theory and the
Optimality theory optimality theory ) have the advantage of simplifying
A quantitative evolutionary the mathematical analysis of complicated problems.
model that defines the However, although population genetics provides a
maximum or minimum fitness defence for such an approach8, it also suggests there are
values for a given trait under
specified constraints. It is often
limits to the assumption that genetics does not matter
used to investigate life-history (the ‘phenotypic gambit’ (ref. 9)). In many circumstances
evolution. there is evidence that genetics does matter. For example,
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when the heterozygote is the most fit genotype (a phe-
nomenon known as overdominance; BOX 2), models
that ignore genetics cannot explain why homozygotes
are stably maintained in the population because this is a
consequence of Mendelian segregation.
How deleterious alleles can invade
To fully appreciate the role of genetics in selection, it
is necessary to consider that there are different modes
by which selection can operate (BOX 2) . A number
of tests have been developed to distinguish these types of
selection and are introduced in BOX 3.
A demonstration of the value of genetics to under-
standing the complexities of selection is given by exam-
ining the reasons for the spread of deleterious alleles.
The basic assumption of natural selection is that
alleles that increase individual fitness invade while del-
eterious alleles are eliminated. However, this assump-
tion was challenged by cases in which deleterious alleles
did spread. Three extensions of the simple genetic
framework can explain the spread of deleterious alle-
les: non-independence between alleles in a genome
because of linkage; non-Mendelian inheritance; and
non-independence between the same alleles in dif-
ferent genomes. each of these is considered below.
The conceptual advances that underlie these insights
have provided a more nuanced understanding of how
selection operates.
Linkage, hitchhiking and background selection.
Although the simplest assumption is that each locus
within a genome is independent, this is not realistic.
linkage can result in non-independence between alle-
les, which is quantified as linkage disequilibrium, with the
fate of one allele influencing the fate of others. linkage
disequilibrium can allow deleterious alleles to spread
(hitchhiking) and can prevent advantageous alleles from
invading (thus imposing limits on selection, which is
considered in BOX 4).
Hitchhiking occurs when the spread of a positively
selected, advantageous allele carries linked alleles10 in a
selective sweep. If the inheritance is Mendelian, this phe-
nomenon can only occur if the deleterious effects of the
hitchhiking alleles are not larger than the advantageous
effects of the positively selected allele. Therefore, hitch-
hiking usually does not cause the spread of highly delete-
rious alleles. evidence of hitchhiking and its concomitant
effects of reducing variation and establishing long-range
haplotype blocks is now commonly used to identify posi-
tive selection in genomes11,12 (BOX 5; reviewed in ref.12).
For example, analysis of hitchhiking has shown that the
spread of the caspase 12 pseudogene has been driven by
positive selection in humans, probably because it confers
protection from sepsis13.
Hitchhiking is also key to understanding mutation
rates and therefore ‘evolvability’. In a sexual species,
an allele that increases the mutation rate (a modifying
allele) will generate many deleterious mutations and
should be eliminated from the population. The modi-
fying allele can only spread if it is in linkage disequilib-
rium with a new positively selected allele14. The logical
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Box 2 | Modes of selection
Selection can be subdivided into different types, depending on the evolutionary
outcome. The main concepts of the different modes of selection are described below.
Positive selection
Positive selection (also known as Darwinian selection or directional selection if it
occurs on a quantitative trait) is the spread to fixation of an allele that increases the
fitness of individuals. Numerous examples of positive selection have been observed —
for example, antibiotic resistance or the increase and decrease in the prevalence of the
melanic form of the peppered moth106. More recently, the impact of humans on positive
selection has been shown by the preference of hunters of bighorn sheep for prey with
large horns, which led to a shift in horn size and body weight107, and by the high capture
rates of cod, which led to selection for smaller fish that develop faster108. In addition to
these examples at a population level, there are also examples at a molecular level109,110.
Although Darwin initially suggested that sexual selection and natural selection are
different, sexual selection is now commonly considered a subclass of positive selection.
Sexual selection is the spread of traits that cause an individual to be more attractive to
mates and therefore have more reproductive success. However, why females chose
males and whether they gain anything more than attractive sons remains a matter of
debate111. In some cases, female choice leads to traits that are deleterious to viability
(such as large tails) but that enhance fertility by increasing attractiveness to females.
Purifying selection
Purifying selection (also known as negative or stabilizing selection) eliminates
deleterious mutations. Assuming that the outcome of evolution by natural selection
should be the production of well-adapted organisms, we expect this to be the most
common mode of selection; random tinkering with a machine that functions well is
likely to cause damage. The assumption that purifying selection is common underpins
many attempts to find conserved functional motifs in genomic sequences (known as
phylogenetic footprinting112,113). However, distinguishing purifying selection and low
mutation rates can be difficult as both processes result in little sequence change (for
example, compare ref. 88 and ref. 114).
Balancing selection
Balancing selection (also known as disruptive selection) is selection that favours
diversity. Under balancing selection, the spread of an allele never reaches fixation, and
therefore it can initially seem to be undergoing positive selection, but it then
undergoes negative selection when its frequency is too high. Thus alleles cannot be
classified as advantageous or deleterious. This type of selection can have different
forms, including frequency-dependent selection, which is central to the evolution of
mimicry115, and overdominance (see the main text). Although overdominance is rare, it
can occur when heterozygotes are resistant to a parasite — for example, in sickle-cell
anaemia and Tay–Sachs disease116.
Diversity might also be selected for in cyclical host–parasite co-evolution (‘Red
Queen’ selection117), in which there is constant change, with hosts under selection for
resistance and parasites under selection to counteradapt. However, the relevance of
Red Queen cyclical dynamics is debatable: because there is little evidence to support
cyclicity and co-evolution118, it has been suggested that it may be only a theoretical
nicety119. It has conversely been argued that Red Queen selection is hard to prove and
that there is some evidence that supports the theory120; for example, from archives of
past gene pools in lake sediments121. By contrast, in vitro studies have reported the
presence of stable polymorphisms rather than cyclicity in host–parasite systems122.
Balancing selection is often suggested to be unusual, a theory that is partly supported
by the failure of genome scans to detect balancing selection123. However, this failure
might reflect a statistical weakness of such scans. With the recent increase in SNP data,
locus-specific analyses are producing more examples than might have been
expected124–127. However, current examples are largely associated with immune
functions (as expected from the Red Queen model) and might therefore be
unrepresentative of the genome as a whole.
Linkage disequilibrium consequence of this should be that it is easier for dif-
A measure of genetic ferent mutation rates to be evolved by asexual species,
associations between alleles which lack recombination and therefore link together all
at different loci that indicates
whether certain allelic
alleles, than by sexual species, in which recombination
combinations are more or less limits hitchhiking 14; however, this theoretical prediction
common than expected. remains to be tested.
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The converse effect to hitchhiking 15 is background
selection, in which selective elimination of a deleterious
allele from the population leads to the loss of other alle-
les in linkage disequilibrium (BOX 4). Both hitchhiking
and background selection can cause reduced variation
in genomic domains with low rates of recombination16–18.
However, these phenomena may not completely explain
the relationship between genetic variation and recombi-
nation rate. For example, at least in mammals, there is
evidence that recombination might itself be mutagenic
owing to errors introduced during double-strand break
repair 19–21. This is consistent with the positive correlation
between the rate of recombination and the rate of sub-
stitutions19–21 that is observed, for example, at the mam-
malian pseudoautosomal region, which has a high rate of
recombination19.
Despite the effects of linkage, single-locus models can
be defended. Because of recombination, any given allele
is exposed on average to many genetic backgrounds,
and therefore the average fitness effect of the allele is
what matters, not its current neighbours. More gener-
ally, an allele that is not itself subject to selection but that
has consequences at other loci (for example, an allele
that changes the rate of recombination) will, under a
wide range of conditions and in the absence of linkage
disequilibrium, evolve as if to maximize mean fitness22.
Non-Mendelian inheritance and selfish elements.
Although hitchhiking is normally limited to weak del-
eterious alleles, relaxing the assumption of Mendelian
inheritance provides the possibility of the spread of
highly deleterious alleles (‘selfish genetic elements’).
These alleles deterministically invade the population
and simultaneously create the conditions for the spread
of other alleles at different loci that suppress the selfish
element 23. For example, male flies that are heterozygous
for the segregation distorter (Sd+/–) transmit the drive
allele (Sd+) almost exclusively 24. This phenomenon in
which one allele is transmitted to more than half the off-
spring of a heterozygous parent is known as meiotic drive,
and it can allow a strongly deleterious allele to invade
(BOX 1) and permits the spread of unlinked suppressors of
meiotic drive.
Uniparental inheritance of cytoplasmic factors also
allows selfish elements to spread. Cytoplasmic sex-ratio
distorters are transmitted exclusively by females and distort
the sex ratio by favouring females. For example, they kill
males, feminize males and make females asexual, thereby
leaving only daughters25,26. The male-killing element can
spread if this process redistributes resources to surviving
sisters, which contain a clonal relative of the killing
allele27. The same logic underpins cytoplasmic male
sterility in plants28.
A further example of how deleterious factors can
spread is provided by the cytoplasmic incompatibility caused
by Wolbachia infection in insects29. In males, Wolbachia
cause the death of zygotes that lack Wolbachia. In effect,
Wolbachia transfer a toxic substance into sperm that is
neutralized by an antidote produced by the same bacte-
ria when the bacteria are maternally transmitted to the
zygote. The death of all of the progeny when the female
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Box 3 | diagnosis of the mode of selection from substitution data
1.7
1.6
1.5
1.4
1.3
1.2
1.1
KA/KS
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Frequency
Several tests have been developed to determine the mode of selection by | Genetics
Nature Reviews
comparing genome sequences from different species, and the principles of these
tests are introduced here. If a protein is evolving neutrally, then a mutation that
alters an amino acid should have the same chance of fixation as a synonymous
mutation. By comparing orthologous genes between any two species, we can
partition changes into non-synonymous and synonymous ones. Adjusting for the
fact that most mutations will have been non-synonymous (and for the possibility of
multiple hidden changes), we can then compare the number of non-synonymous
changes per non-synonymous site (KA) with the corresponding number of
synonymous changes per synonymous site (KS). The KA/KS ratio is then a diagnostic
of how a gene evolves. If this ratio is equal to one, we cannot infer the action of
selection; if it is greater than one we infer positive selection; and if KA/KS << 1 we
infer purifying selection. An example of this type of analysis is shown in the figure: a
histogram and box plot of the distribution of the KA/KS ratios for 5,057 mouse–human
orthologues. These data indicate that few genes have KA/KS >1 , but that most have
KA/KS<<1, which is indicative of the importance of purifying selection. In general,
many examples of genes with KA/KS > 1 are probably driven by host–parasite
coevolution109.
Applied across a whole gene in a pairwise comparison, the KA/KS ratio is a crude
tool, as positive selection might be present in just one lineage or in just a few
codons. The inference of positive selection can also be undermined — for example,
by purifying selection on synonymous mutations128. The use of multiple species
alignments allows the form of selection to be resolved129.
An extension of this between-species analysis is the McDonald–Kreitman test130,
which analyses both between- and within-species differences. If the substitutions in
a protein are due to positive selection, we should see a higher ratio of
non-synonymous to synonymous differences between species than within species. If
the assumption of neutrality of synonymous mutations is correct, then it is possible
to test whether adaptive evolution has occurred and estimate the proportion of
substitutions that are a consequence of positive adaptive evolution. However, this
method is biased by rare weakly deleterious alleles, and the failure to allow for
this limitation might have led to serious underestimation of the proportion of adaptive
changes in both flies and bacteria73. An additional method is the Hudson–Kreitman–
Aguadé test131. In the strict sense, this is a test to reject neutrality that compares the
rate of polymorphism to divergence for multiple genes. If the ratio varies more among
genes than is expected from null neutral assumptions, neutrality is rejected.
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is not infected with Wolbachia ensures an increase in the
frequency of Wolbachia-infected individuals30. Such a
cytoplasmic incompatibility factor is currently spread-
ing in Californian fruit flies31 and many 32, if not most 33,
species of insect are probably infected with Wolbachia or
another cytoplasmic bacterium, although the proportion
of these bacteria that manipulate their hosts is unknown.
Although selfish elements are important in demon-
strating how non-Mendelian inheritance can allow the
spread of deleterious alleles, their relevance in organisms
remains unclear. A wide range of phenomena have been
suggested to be explained by selfish elements23, includ-
ing the evolution of sexes, genomic imprinting, polyan-
dry 34, sex determination and hybrid sterility. Although
the importance of selfish elements in these examples is
unresolved, selfish elements do explain the otherwise
paradoxical persistence of sterile individuals in some
populations; for example, in the cases of segregation dis-
torters in flies and the T complex in mice35, homozygotes
are sterile but are maintained in the population because
of meiotic drive in heterozygotes. Whether selfish
genetic elements are an intellectual curiosity or whether
they drive the evolution of genetic systems or speciation
remains to be resolved; it will be important to investigate
how common they are to determine their role.
Relatedness, kin selection and inclusive fitness. A fur-
ther explanation for how deleterious alleles can spread is
gained from considering that an allele in one individual
can affect the fortune of the same allele in other indi-
viduals. This has led to the understanding that traits can
spread not because they are beneficial to the individual,
but because they promote the fitness of other bearers
of the same allele (relatives). Perhaps the most obvious
traits that are bad for individual fitness are acts of self-
sacrifice — dramatic examples include the existence of
sterile castes in social insects and termites that explode.
To understand the evolution of such traits, the normal
genetic framework needs to be expanded to consider
the impact of an allele on other individuals. In the con-
text of social evolution, we need to consider the fitness
of the organism that acts on other alleles (the ‘actor’)
and its relatives that share the same allele (inclusive fit-
ness), rather than the fitness of the actor alone. Selection
does not need to be good for the individual36, but an
individual can promote its own alleles by helping a rela-
tive if b/c>1/r, in which b is the benefit gained by the
receiver, c is the cost to the altruist and r is the relat-
edness between the two (Hamilton’s rule). This princi-
ple, termed kin selection, has robust explanatory power,
and can be used to predict the course of experimental
evolution in microorganisms37.
A deeper understanding of kin selection and selfish
elements is provided by asking whether a rare allele will
invade (BOX 1), rather than whether the allele is ‘good for
the individual’ or ‘good for the group’. This concept is
illustrated by sex-ratio evolution: in a species in which
only females invest in the next generation, making males
is a form of altruism. For example, Fisher 38 identified
that a sex ratio of 1 to 1 is a stable investment ratio,
although it does not maximize population fitness, and
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Box 4 | linkage and the limits of selection
As well as providing an explanation for how deleterious alleles spread, linkage also
imposes limits on positive selection. Hill and Robertson examined linked alleles in a
sexual species and showed that selection at one locus can interfere with selection at
a second, beneficial mutation and reduce the probability of its fixation132. This is now
known as Hill–Robertson interference. Crucially, the degree of interference increases
with genetic linkage between the loci under selection. Generally, this means that
linkage between sites under selection will reduce the overall effectiveness of
selection in natural populations. Domains of low recombination, and hence
longer-range linkage disequilibrium, are expected to be those in which the strength
of both positive selection (Hill–Robertson interference) and purifying selection
(background selection, see the main text) are limited.
The importance of Hill–Robertson interference is still debated132, and interpretation
of the results is made difficult by a lack of understanding of the confounding
variables. For example, the Hill–Robertson model predicts that the extremities of
exons should be better adapted than cores owing to less interference from introns;
this is suggested to be a possible selective advantage for long introns133. However, in
Drosophila melanogaster, the differences in adaptation between the interior and
exterior of exons is due to the location of splice enhancers, and not necessarily to the
different selection strengths84. Likewise, although the rates of evolution are
correlated with the local recombination rate as predicted by the Hill–Robertson
model134,135, in yeast (Saccharomyces cerevisiae) this is at least in part due to different
classes of gene being located in different genomic recombination domains134.
Possibly the most important role of Hill–Robertson interference that has been
proposed is in enabling the selection of alleles that affect the recombination rate.
These alleles spread by weakening the degree of interference between linked sites136.
This is because background selection against deleterious mutant alleles (see the main
text) provides a stochastic advantage to recombination, an advantage that increases
with population size. With low levels of recombination, selection at other loci
reduces the effective population size and genetic variance in fitness at a focal locus.
As a consequence, the population is less able to respond to selection and to rid itself
of deleterious mutations. Recombination, by contrast, combines chromosomes of
intermediate fitness to create chromosomes that are free from deleterious
mutations. However, this hypothetical role of Hill–Robertson interference remains to
be rigorously tested.
Haplotype block Hamilton39 recognized special conditions for biased sex
A chromosomal region in which ratios (for a review see ref. 40). These examples can all
groups of alleles at different
genetic loci are inherited
be explained by asking whether an allele will invade. The
together more often than kin-selection framework is valid for assessing sex ratios41,
expected by chance. but this framework is not a dynamic model, which might
reduce its power 42. In addition, the relationship between
Pseudoautosomal region
kin selection and the classical multilocus approach is still
Any section on a telomeric end
of an X or Y chromosome that debated43, and because it can be difficult to precisely esti-
undergoes recombination in mate the core parameters (b, c and r) of Hamilton’s rule it
the heterogametic (XY) sex. is difficult to quantitatively test kin selection.
Meiotic drive
The three concepts of linkage, non-Mendelian inher-
A distortion of meiotic itance and kin selection described here show that an
inheritance such that one understanding of genetics allows selection to explain
allele at a heterozygous site is why deleterious alleles can spread. each of these mech-
recovered in more than half of
anisms is also linked to new questions as to how they
the gametes (in contrast to the
expected 50:50 Mendelian shape evolution in practice, and they provide insights
segregation) owing to effects into the reach and role of selection.
that occur before zygote
formation. alternatives to selection
Cytoplasmic factor The explanations for the spread of deleterious alleles
A gene present in host show how understanding genetics is important to our
organelles, such as understanding of how selection might explain otherwise
mitochondria, or in intracellular unexpected phenomena. However, other genetic discov-
parasites, such as Wolbachia,
that is typically passed from
eries highlighted limitations to models of selection. A
mother to offspring through major limitation of deterministic selectionist models of
the cytoplasm. evolution is that they miss the possibility that alleles can
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change frequency owing to chance alone (genetic drift).
Recognition of this limitation led to the development of
new models. The first of these was neutral theory, which
provided an explanation for evolution that, at least at a
molecular level, offered serious competition to natural
selection. However, as outlined below, this model also
has many limitations and led to the suggestion of an
alternative, the nearly neutral theory.
Two potential limitations of selection were high-
lighted by two predictions made by the population
genetics of selection developed by the modern synthesis.
The first prediction was that polymorphism should be
rare. It is difficult to find theoretical conditions in which
alleles should be polymorphic, assuming that balancing
selection (BOX 2) occurs rarely. However, protein elec-
trophoresis and, later, genomic sequencing showed that
polymorphism is unexpectedly common44–46. The second
prediction, called Haldane’s dilemma47, is that rates of
adaptive evolution would be limited by population size.
Haldane argued that for each selective substitution event
there has to be selective death. As many selective events
require many deaths, the rate of evolution should have
an upper limit that is determined by the population size.
Nevertheless, analysis of the rate of evolution of several
proteins suggested that the rate was too high for all of the
observed evolution to have occurred through selection48.
These two apparent problems with selection helped to
prompt the development of the alternative models based
on evolution by genetic drift.
The rise and fall of the neutral theory. The first alterna-
tive model based on drift was neutral theory. In strict
neutral theory, alleles are modelled as neutrally buoyant
diffusing particles of gas that can go up or down with
equal probability by chance. In this framework, polymor-
phism is expected to be common and to scale with the
population size according to equation 1, in which H is
heterozygosity, Ne is the effective population size and
µ is the mutation rate (fIG. 1).
4Ne µ
H= (1)
1 + 4Ne µ
Although this model is qualitatively correct 49, strict
neutral theory has little quantitative explanatory power.
For example, the theory predicts large differences in
heterozygosity between humans (Ne~104) and fruit flies
(Ne~106), but the observed difference is modest 50–52
(fIG. 1). Neutral theory is therefore a useful null hypoth-
esis because it makes strong quantitative predictions, but
it is a poor model as these expectations are rarely met 53.
Further evidence against the strict neutral theory
comes from analysis of the rates of evolution between
lineages. If molecular evolution is neutral, then we expect
that, on average, lineages with the same mutation rate will
evolve at the same rate. owing to chance, we expect some
lineages to evolve at different rates. The neutral theory
predicts that the variation in rates (V) between lineages
should be equal to the mean rate (M), as the process has
a Poisson distribution. Consequently, dispersion (D), which
is equal to V/M, should equal one. Most early analyses
suggested that D does not equal one for synonymous or
volUMe 10 | FeBRUARy 2009 | 87
REVIEWS
Cytoplasmic sex-ratio non-synonymous changes49,54. Therefore, neutral theory
distorter became less prominent and is no longer adhered to,
A factor inherited in the although its value as a null hypothesis remains.
cytoplasm (for example, It is also worth noting that Haldane’s dilemma, which
mitochondria or heritable
bacteria) that modifies the
was originally cited as a reason for needing alternative
sex ratio, typically causing a models to selection, is now mostly considered not to be
female bias. a problem55. Therefore, the cost of substitution suggested
by Haldane cannot be used as a defence of neutral theory.
Cytoplasmic incompatibility
Haldane’s calculations assume hard selection56, which is
A sperm–egg incompatibility
that is usually associated with
selection that increases the total number of deaths, and
Wolbachia infection. Wolbachia also assume that the effects of multiple mutations are
modify the host sperm in the additive. However, selection can operate such that an
testes, and the same strain of advantageous genotype occupies a higher proportion of
Wolbachia must be present in
the egg to rescue this
limited niches (soft selection), in which case the amount
modification. Absence of of death is unaffected. Fixation of a selectively advan-
rescue results in incompatibility tageous mutation therefore need not involve selective
and zygotic lethality. mortality 56. Assuming that each extra mutation has non-
additive effects can also mitigate Haldane’s dilemma57.
However, given that positive selection can potentially
affect non-coding sequences58 and proteins, reexamination
of Haldane’s dilemma might be warranted.
Box 5 | application of intrapopulation data to assay the role of selection
Selection leaves its mark not only on the divergence between species (BOX 3), but also
on the patterns within a species. These various footprints of selection have been used
to devise tests for selection that rely on different aspects of the effects of selection.
tests based on population differentiation
If a selective sweep has started in one subpopulation but is yet to reach others, then
we should observe extreme levels of population differentiation. The Lewontin–
Krakauer137 test takes advantage of this fact and has recently been resurrected in
multiple forms138, including genome scans for selection139,140. This approach has been
bolstered by the development of a rigorous statistical framework to identify outlier
loci141. Further modifications to this test, which aim to discover alleles that have been
nearly fixed within a population by a selective sweep, have identified more than 300
strong candidate regions in humans142.
tests based on frequency spectra
The neutral theory predicts how common, on average, the most common variant will
be and, more generally, the relative proportions of all variants. This allows us to
determine the level of homozygosity143 if we know the number of variants. Different
deviations from neutral expectations are expected for different modes of selection:
purifying selection will tend to increase the fraction of mutations segregating at
low frequencies and positive selection will increase the number of alleles seen at high
frequencies. The central test for examining the expectation of neutrality is Tajima’s D144.
In this test, the average number of nucleotide differences between pairs of sequences
is compared with the total number of SNPs. Fu and Li’s test145 extends Tajima’s D by
considering other species so as to polarize the changes (ancestral versus derived
alleles). These tests and subsequent refinements146,147 are probably the most commonly
applied tests for neutrality and deviation from neutrality.
tests based on linkage disequilibrium and haplotype structure
Variants that are positively selected shortly after spreading, or alleles under balancing
selection, will drag linked alleles with them. This causes an increase in linkage
disequilibrium and extends the span of haplotypes further than expected by
chance148. Indeed, two alleles (glucose-6-phosphate dehydrogenase and CD40L)
associated with malaria resistance show such an extended haplotype148. Several tests
have been proposed to formalize this approach to detecting selection (reviewed in
ref. 149), and recent genome-wide scans that used high-density SNPs have identified
numerous possible candidates of selection in humans100,150.
A concern with all of these tests, unlike the KA/KS and McDonald–Kreitman tests
(BOX 3), is that inference of selection or rejection of neutrality tends to be sensitive to
assumptions concerning demography101,149, and extensive simulation of alternative
possible demographies (see, for example, ref. 100) is necessary to ensure some degree
of confidence in the result.
88 | FeBRUARy 2009 | volUMe 10
© 2009 Macmillan Publishers Limited. All rights reserved
The nearly neutral theory. The quantitative limitations
of the neutral theory led to the development of a more
accurate model of drift. This model, known as the nearly
neutral theory, is more than a minor modification of
the neutral theory, not least because the two make
different predictions.
Strict neutral theory considers mutations with no
selective effect. This is improbable as all mutations are
likely to have some, albeit potentially small, effect. To
address this weakness, the nearly neutral theory 49,59
considers mutations that have a small effect by using
diffusion equations to evaluate the possibility that
particles might not be neutrally buoyant. Some parti-
cles can be slightly buoyant (weakly advantageous) or
slightly more dense (weakly deleterious), but both types
can be fixed. In this regard, the nearly neutral model
focuses on the concept that adaptation may be due not to
strong selection of rare variants with large effects, but
to weak selection of common variants.
The neutral and nearly neutral theories make differ-
ent predictions. Strict neutral theory predicts that rates
of evolution should be independent of population size
and simply equal to the mutation rate. By contrast, an
important consequence of the nearly neutral model
is that population size can matter. The nearly neutral
model recognizes three classes of deleterious mutations:
those that are effectively neutral (s<<1/2Ne), those that
are slightly deleterious (s~1/2Ne) and those that are del-
eterious (s>>1/2Ne), in which s is the fitness cost (fIG. 2).
Mutations that are effectively neutral have a substitution
rate equal to that of neutral mutations. The probability
of fixation of slightly deleterious mutations is appreci-
able, but it is lower than that of neutral mutations. For a
given small value of s, the important prediction of this
model is that the rate of evolution should increase as the
population size decreases (more mutations will be in
the effectively neutral or slightly deleterious class). Hence
we expect that in large populations (for example, bacte-
ria populations), purifying selection is efficient and few
deleterious mutations fit in the two classes that can lead
to fixation. This model correctly predicts that purifying
selection should be weaker in species with long generation
times because these species have small populations60.
The nearly neutral versus selectionist debate. owing to
the weakness of the strict neutral model, the neutralist
versus selectionist debate was abandoned and replaced
by the nearly neutral versus selectionist debate. In this
debate, the two positions are often hard to discriminate as
they make many similar predictions. For example, both
the nearly neutral and the selectionist model can explain
an approximately constant rate of protein evolution49,61,
and both models also claim to explain the insensitivity
of protein polymorphism levels to population size10,49–51.
Both selection and nearly neutral evolution are also
consistent with high dispersion values (D)62, but the
explanations they offer for this observation are differ-
ent. Advocates of selection note that high dispersion
occurs when positive selection on a given protein occurs
down some lineages but not others (episodic evolution).
By contrast, nearly neutral models note that if lineages
www.nature.com/reviews/genetics

T complex
A region on chromosome 17 in
the mouse that is subject to
meiotic drive. The complex
contains four inversions and
occupies approximately half
of the chromosome.
Kin selection
Selection that allows an
individual to increase its fitness
by increasing the number of
copies of its genes in the
population by provisioning
benefits to relatives.
Modern synthesis
The prevailing theoretical
framework of evolution that
resulted from a combination of
genetics, systematics,
comparative morphology and
palaeontology in the 1930s
and 1940s. It is also known as
evolutionary synthesis or the
synthetic theory.
Effective population size
(Ne). The size of a population
measured by the expected
effect (through genetic drift) of
the population size on genetic
variability. It is related to, but
never exceeds, the true
population size (N).
Poisson distribution
A discrete frequency
distribution of the number of
independent events per time
interval, for which the mean
value is equal to the variance.
Dispersion
The ratio of the variance to
the mean rate of evolution
observed when orthologous
sequences from at least three
different taxa are compared.
NATURe RevIeWS | Genetics
differ in Ne (possibly owing to speciation bottlenecks),
dispersion should be high. However, the selectionist the-
ory predicts that the lineages down which selection acts
are not necessarily the same for different proteins. But if
a species-wide reduction in Ne causes high dispersion, as
suggested by the nearly neutral model, we expect accel-
erated rates to be a property of the lineage. In the case of
Heterozygosity (H)
three genes that are involved in circadian clocks, careful
analysis63 showed that selection explains the data better.
However, the debate between selection and nearly neu-
tral evolution has recently been reopened by the find-
ings that D might often be equal to one and that prior
analyses were distorted by unrepresentative genes64.
Given the frustrations in attempting to discrimi-
nate between the two models, the field has moved on
to address a more direct question: what proportion
of all substitutions are adaptive? This question can be
answered by an extension of the MacDonald–Kreitman
test (BOX 3), under the assumption that positive selec-
tion leaves an excess of non-synonymous substitutions
compared with non-synonymous polymorphisms65–67.
Genome-wide application of this method to protein-
coding genes in humans suggests that 9% of genes
might be subject to positive selection68. Unfortunately
such estimates are sensitive to methodological details,
with estimates in flies ranging between 20% and 95%69–71.
optimization of methods to estimate the proportion of
substitutions owing to selection, including controlling
for confounding effects of demography 72 and rare weakly
deleterious alleles73, is an active area of research. In addi-
tion, the importance of the assumption of neutrality of
synonymous mutations has yet to be evaluated.
the reach and role of selection
As the discussion of linkage and weakly selected variants
suggests, selection has limits. For example, selection is
impeded in domains of low recombination (effectively,
domains of low Ne), in species with low Ne, when the
fitness benefit of a mutation is small and when herit-
able variation is absent. But in practice what do these
limits mean? The roles of selection in domains of low
recombination, in species with low Ne and when the
fitness benefit is small are currently being explored in
evolutionary genomics, and evolutionary developmental
biology (evo-devo) asks whether the scope of realizable
heritable variation might determine what phenotypic
space is unexplored.
Does heritable variation limit adaptation? Population
genetics focuses on the fate of mutations. However, evo-
devo researchers emphasize the role of ‘developmental
constraint’ in shaping variation. In its strict form, devel-
opmental constraint means that there is no heritable vari-
ation for certain developmental traits, as genetic variation
that affects these crucial aspects of development will
result in non-viable individuals or may not be possible.
Such strict constraints are suggested to determine unex-
plored morphological space74. For example, deleterious
effects (such as embryonic cancer) of mutations that alter
the morphology of neck vertebrae75 might explain why
most mammals have seven of these vertebrae. However,
© 2009 Macmillan Publishers Limited. All rights reserved
REVIEWS
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.185
0.1
0.056
0
0.001 0.001 0.01 0.1 1 10 100 1,000
0.01483 0.0567 Ne µ
Figure 1 | Heterozygosity predicted by the neutral
Nature Reviews | Genetics
hypothesis. A plot of heterozygosity (H) predicted by the
neutral hypothesis as a function of the product of the
effective population size (Ne) and the mutation rate (µ).
The basis for this pattern is explained in the main text. The
shaded area indicates the range of heterozygosities
observed in various animals, including humans, mice and
flies. If the neutral theory could explain the observed
heterozygosities, there would be little difference in Ne µ
between these taxa. However, this is not the case, and
so the absurdity of this prediction is accepted as a
rejection of the neutral hypothesis52. Figure is modified,
with permission, from ref. 52  (1974) Columbia
University Press.
few examples of strict developmental constraint exist
and the evolutionary relevance of laboratory-based
identification of potential constraints is also uncertain.
For example, although artificial breeding experiments
provide little evidence of heritable variation in sex
ratios76, sex ratios naturally evolve — social spiders with
heteromorphic sex chromosomes have independently
evolved biased sex ratios at least five times77.
A less strict concept of developmental constraint
supposes that the profile of phenotypes is skewed by
the way that development works. To test this hypothesis,
artificial selection experiments can be used to find how
easy it would be for a given trait to evolve78. However,
there have been few experimental analyses compared
with the number of theoretical studies of developmental
constraints. one instructive example is butterfly wing
patterning. Analyses of patterning show that, despite
the potential for constraint owing to a developmen-
tal coupling between different eyespots, independent
change can occur. This flexibility is consistent with the
diversity of wing patterns across species and argues that
natural selection has a dominant role in shaping existing
variation79.
volUMe 10 | FeBRUARy 2009 | 89
 REVIEWS

1,000 µ specify the most abundant tRNAs — this effect increases

the accuracy and/or rate of translation81. Consequently,
synonymous mutations can be opposed by purifying selec-
s >0 10–4
10–5 tion81. In mammals, evidence for such selection is limited4,
100 µ
but recent evidence from mammals and Drosophila spp.
10–6 shows that selection frequently acts on synonymous muta-
tions that affect exonic splice enhancers82 and that this alters
10 µ 10–7 codon usage83,84. The effect of splicing-associated selection
Fixation rate

is shown by the association of synonymous mutations that

10–8
alter splicing with human disease4. Many other mecha-
nisms by which synonymous mutations affect fitness have
µ s=0
also been identified: they affect mRNA stability 85, miRNA
–10–8 binding 86, protein folding 87 and nucleosome formation88.
The hypothesis that synonymous mutations must be neu-
µ
–10–7 tral therefore lacks an understanding of the complexities
10
of gene expression.
s <0 –10–6
However, explaining how isochores have evolved
requires a more subtle role for selection. Currently, the
µ
100 best explanation for the approximately homogeneous
103 104 105 106 107 108
nucleotide content of these genomic blocks is that iso-
Population size (Ne) chores evolved as a consequence of mutation bias coupled
Figure 2 | effective population size and fixation in the nearly neutral
Nature model.
Reviews The
| Genetics with drift favouring GC to AT mutations. These processes
relationship between effective population size (Ne) and the rate of fixation under are countered in domains of high recombination by biased
the nearly neutral model for differing values of the fitness effect (s). s = 0 for strictly gene conversion that favours GC pairs over AT pairs dur-
neutral alleles; s<0 for deleterious alleles; and s>0 for positively selected alleles. ing the resolution of heteroduplexes89,90. Biased gene
For s = 0, the classic result is derived — the substitution rate is the same as the conversion is similar to meiotic drive because it is a form
mutation rate and is independent of Ne. For deleterious mutations, the important
of selection at the gene level. Such a process can cause
point is that we can divide the plot into the three for any given value of s. First, for
small values of s, there is a domain in which the fixation rate is indistinguishable from genome-wide effects with no substitutional cost, as no
the rate that neutral mutations are fixed. This is the zone of effective neutrality. death of individuals occurs in the process, just ‘death’ (con-
Second, there is a zone around s = 1/2Ne in which fixation is possible but the rate is version) of alleles. Although it is difficult to distinguish
lower than the neutral rate. Third, there is a zone at s>1/2Ne in which fixation is rare biased gene conversion from selection on GC content,
(strongly deleterious alleles). These deleterious alleles can persist in a population the effects of biased gene conversion have only recently
owing to mutation–selection equilibrium, but are unlikely to become fixed variations. begun to be appreciated. Biased gene conversion may even
Figure is modified, with permission, from ref. 151  (1986) W.H. Freeman and Co. give false positive signals of positive selection in protein
coding sequences. This is because non-synonymous
sites tend to be less GC-rich than synonymous sites,
More generally, the history of artificial selection exper- so when biased gene conversion acts it predominantly
iments, practiced by plant and animal breeders, has been accelerates rates of evolution at non-synonymous sites,
important for understanding the relationship between producing a KA/KS ratio (BOX 3) that is greater than one91.
heritable variation and selection. These experiments allow However, genome evolution studies also suggest that,
heritability to be estimated and have driven developments broadly, the nearly neutral theory has great explana-
in quantitative genetics that have been combined with the tory power. lynch and colleagues considered whether
statistical methods currently used to estimate parameters intron size and, more generally, genome size increase as
of selection in the wild80. In general, heritability studies Ne decreases92,93, and found that the predictions of the
have shown that most traits are selectable most of the nearly neutral hypothesis fit the evidence. According
time, so the level of heritable variation does not impose to the nearly neutral model, species with small popula-
Exonic splice enhancer limits on selection. tions (for example, humans) are unable to eliminate
A short (approximately 6 insertions that are mildly deleterious; however, the same
nucleotide) motif that Selection and the genome. The population genetics the- insertion in yeast is easily opposed by purifying selection
is present in exons. It is
necessary for the binding of
ory has shown that there are limitations to the role of (s is <1/2Ne for humans and >1/2Ne for yeast). This model
serine–arginine proteins selection; however, studies of gene and genome evolution suggests that yeast and Escherichia coli have better adapted
that are involved in defining have also shown that selection can occur in unexpected genomes than humans. The same model correctly predicts
exon ends. situations. Genomic research has therefore allowed fur- little variation in 5′ UTR length between species94 but also
ther evaluation of the relative merits of selectionist and predicts greater 5′ UTR length variation as a function of
Isochore
A chromosomal block of nearly neutral models. local GC content within species, which is not observed95.
approximately uniform GC one aspect of genomic research that suggests selection For gene-order evolution in yeast, a simple strictly neutral
nucleotide content. This is may be more widespread than previously thought is the null model96,97 correctly predicts that whether two genes
shown, for example, by a study of synonymous mutations. It has commonly been stay physically linked depends on the size of the intergenic
correlation in nucleotide
content between genes
supposed that synonymous mutations are effectively neu- spacer between them. Nonetheless, there are examples of
when comparing introns tral46, especially in humans (in which Ne is low). However, genes that are grouped2 either as co-expression clusters97,98
and synonymous sites. in many species, highly expressed genes use codons that or as clusters of essential genes99.

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© 2009 Macmillan Publishers Limited. All rights reserved


How important is selection to gene and genome evolu-
tion? The examples discussed here show that the answer
depends on whether the cases in which the assumption
that selection must be irrelevant is wrong (as with selection
on synonymous mutations) are highlighted, or the cases in
which the nearly neutral model is valid (as with genome
size or intron size) are highlighted. However, the exam-
ples of isochores and gene order also show that there are
circumstances in which neither a basic model of selection
nor the nearly neutral model provide the full picture.
Questions and directions
This discussion has shown how an understanding
of genetics transformed the understanding of selection:
genetics rescued selection as a concept, then explained
how seemingly counterintuitive observations make sense
and provided a rigorous framework to understand selec-
tion and alternative evolutionary models. These events led
to the current age in which the development of statistical
methods and the availability of new data sets provide an
improving appreciation of the way in which genes and
genomes evolve.
This Review has largely concentrated on the history
of conceptual advances. However, the current genomic
age is likely to lead to a discovery mode of research, and
the development of new genome scans100,101 and other
tools will be important. For example, advances in the
analysis of selective sweeps using SNP data will help to
locate genomic domains under selection. However, the
conservative and error-prone nature of many current
high-throughput statistical approaches and the difficul-
ties of dealing with demography cannot be understated.
Indeed, tests for selection on synonymous mutations that
begin with a mechanism (for example, binding of splic-
ing factors to exonic splice enhancer motifs) have been
successful in resolving the action of selection; however,
statistical tests that are not based on a mechanism (for
example, comparing rates of synonymous site and intronic
evolution) have proved unhelpful and unconvincing4. The
proliferation of genomic scans based on statistical tests
irrespective of mechanism is probably inevitable, and
these scans can suggest candidate regions of selection for
further scrutiny. However, a fuller understanding of how
genes, proteins and genomes work will be needed to more
precisely resolve what selection is doing and the under-
lying mechanisms, as well as to eliminate the possibility
that any signal of selection is not an artefact. Achieving a
thorough and convincing demonstration of the activity of
selection will require ever closer integration of molecular
biology and molecular evolution.
In addition to these methodological hurdles, many
conceptual questions remain unanswered — for exam-
ple: why does the recombination rate positively corre-
late with diversity; and if recombination is mutagenic,
what is the mechanism responsible and does it occur in
all species? The relative importance of drift and selec-
tion also remains unclear: for example, why do species
with a large Ne not have high rates of polymorphism and
what proportion of all substitutions is the result of selec-
tion? Developing robust methods to address these issues
remains challenging.
NATURe RevIeWS | Genetics
© 2009 Macmillan Publishers Limited. All rights reserved
REVIEWS
Perhaps the most profound conceptual issues have
come from recent genomic discoveries. Genomic
features either suggest that genomes are not greatly
shaped by selection or, as in the case of selection on
synonymous mutations, they have shown that there are
underexplored complexities of how genomes work. A
number of questions remain unanswered — for exam-
ple: are we still missing the regulatory importance of
some transcribed but untranslated sequences; what
proportion of alternative splicing is functional; and is
transcriptional noise a failure of selection or an adapta-
tion to environmental variability? These questions can
all be approached by both comparative and experimen-
tal studies, and the answers have implications for our
understanding of genomic evolution. For example, if
many alternative transcripts and non-coding transcripts
are transcriptional noise, they need not be evolution-
arily conserved or have repeatable expression profiles,
and exons that are unique to unnecessary isoforms
should evolve free from purifying selection. If levels of
transcriptional noise are adaptive, engineered strains
of yeast in which genes that are subject to high levels of
transcriptional noise are made less noisy (or vice versa)
should be at a growth disadvantage. Again, integration
between molecular biology and molecular evolution is
expected to lead the way.
Why is it important to understand selection? There are
some important practical reasons: what we call purifying
selection in the formal literature is disease when the muta-
tion affects humans. Hence, looking for genomic regions
that are under purifying selection and understanding
the mutations that are subject to purifying selection,
even beyond those that alter proteins, are important for
identifying disease-causing mutations4 and understand-
ing mechanisms of pathogenesis. In addition, identifying
sites of positive selection in the genome can help us to
understand our interactions with pathogens and how they
evade our defences102.
Understanding selection can help us to not only
understand disease but also disease prevention or cures.
For example, knowing whether gene order and synony-
mous sites are under selection is also important to opti-
mize the benefits and minimize the risks of altering genes
and genomes, whether for genetically modified crops,
transgenic models of human disease or gene therapy. The
hypothesis that synonymous sites matter has already led
to new strategies to develop attenuated viruses5. Current
results also suggest a need for caution: if neighbouring
genes can affect each others’ activity and be preserved as a
pair over a long period of evolutionary time, is it likely that
transgenes will affect the expression of genes near their
insertion site? Understanding selection might also help
the introduction of genes into a population: the prospect
of spreading, by hitchhiking, genes that can block trans-
mission of insect-borne pathogens103, such as Wolbachia,
using the strong selection of selfish elements has
potentially far-reaching consequences.
More generally, where and how selection operates
tells us how genes, genomes and organisms work. Indeed,
although evolutionary genetics was once effectively dis-
tinct from molecular genetics, it is now hard to separate
volUMe 10 | FeBRUARy 2009 | 91
REVIEWS
the two. For example, multisequence alignments, looking
for conserved domains and constructing the duplication
history of a gene by phylogenetic analysis are fast becom-
ing standard parts of the analytical tool kit of molecular
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Acknowledgements
The author is a Royal Society Wolfson Research Merit Award
holder.
FuRtHeR inFoRMation
Laurence Hurst’s webpage:
http://www.bath.ac.uk/bio-sci/research/profiles/hurst-l.html
All links Are Active in tHe online Pdf
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