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Positive Selection on
Genes in Humans as
Compared to
Chimpanzees
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Article Contents
. Introduction
. Positive Selection in Human
. Genome-wide Scans for Positive Selection in Human and
Chimpanzee
. Implications
Margaret A Bakewell, University of Michigan, Ann Arbor, Michigan, USA
Jianzhi Zhang, University of Michigan, Ann Arbor, Michigan, USA
Online posting date: 15th July 2008
Positive selection has been identified and extensively studied in many human genes. In
contrast, positive selection in the closest human relative, chimpanzee, has been largely
unstudied until recently. With the complete sequencing of the human and chimpanzee
genomes, a comparison of the types and numbers of genes that underwent positive
selection in the two species is possible. The types of genes under positive selection in
human and chimpanzee are different with regard to gene function, but no particular
type accounts for a large part of this difference. However, significantly more genes
experienced positive selection in the chimpanzee lineage than in the human lineage.
Synonymous and nonsynonymous mutations
Introduction
Selective forces
Positive selection occurs when an allele increases in frequency in a population because it confers a survival or
reproductive advantage to individuals who possess it. Although positive selection makes it more likely that beneficial mutations will reach high frequencies or become fixed
in a population, some advantageous mutations are lost due
to the random process of genetic drift. In contrast, many
mutations produce deleterious alleles. Those that are
strongly deleterious, conferring early death or sterility on
the individuals who carry them, are rapidly purged from a
population by the action of purifying selection. Others with
an only slightly deleterious effect may remain in a population or even increase in frequency by genetic drift or
linkage to beneficial alleles at nearby loci. However, many
mutations are neither beneficial nor deleterious. These are
said to be selectively neutral or nearly neutral. Neutral alleles increase or decrease in frequency within a population
by genetic drift. See also: Molecular Evolution: Neutral
Theory
ELS subject area: Evolution and Diversity of Life
How to cite:
Bakewell, Margaret A; and, Zhang, Jianzhi (July 2008) Positive Selection
on Genes in Humans as Compared to Chimpanzees. In: Encyclopedia of
Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0020856
Mutations that occur in protein-coding deoxyribonucleic
acid (DNA) sequences are termed synonymous if they result in no change to the amino acid sequence of the encoded
protein due to the degenerate nature of the genetic code.
Synonymous mutations are largely selectively neutral.
Nonsynonymous mutations that result in a change of
amino acid may also be neutral if the change does not affect
the function of the encoded protein. If a nonsynonymous
mutation does affect the protein function, it is most likely
deleterious and subject to purifying selection, but it may be
beneficial and therefore subject to positive selection. The
processes of mutation, drift and selection combine to determine which alleles are present in a population and which
allele will get fixed in the population. See also: Synonymous
and Nonsynonymous Rates
Statistical tests of positive selection and their
application to human and chimp
The study of molecular evolution has produced several statistical tests which can be used to identify the signature of
positive selection in DNA sequences. Generally, these tests
compare differences in DNA or protein sequences between
species (interspecific variation) and/or between individuals
or populations within a species (intraspecific variation). For
human, high-quality completed genome sequences are available. Over 99% of the human genome has been sequenced
to an accuracy of less than 1 error per 100 000 nucleotides
(International Human Genome Sequencing Consortium,
2004). In addition, intraspecific polymorphism data are
available encompassing many individuals from diverse
human populations. One major source of such data is the
ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net
1
Positive Selection on Human Genes Compared to Chimpanzees
HapMap project, which collected over 3.1 million single
nucleotide polymorphisms (SNPs) from 270 individuals
from 4 global populations, estimated to be over one quarter
of the common variation in those populations (International
HapMap Consortium, 2007). In contrast, the published
chimpanzee genome sequence was completed with a quality
level of less than 1 error per 1000 bases for only approximately 98% of the genome (Chimpanzee Sequencing and
Analysis Consortium, 2005). Additional sequencing efforts
have improved the quality of the chimpanzee genome sequence, but not to a level comparable with the human genome. Although a few polymorphism data are available for
chimpanzees, no attempt has been made to survey genomewide polymorphism in a large sample of chimpanzees.
Therefore, although the full array of tests for positive selection involving both inter- and intraspecific datasets can be
applied to human, genome-wide scans for positive selection
in chimpanzee are limited to the use of interspecific divergence data, and even these are hampered by the lower quality
of the chimp genome sequence.
Interspecific divergence data can be used to compare the
rate of nonsynonymous substitution with the rate of synonymous substitution. The ratio (o) of nonsynonymous to
synonymous substitution rates is expected to equal 1 if sequences are evolving neutrally. A deficiency of nonsynonymous substitutions (o51) indicates the action of purifying
selection, where deleterious nonsynonymous mutations are
eliminated from the population. An excess of nonsynonymous substitutions (o41) indicates the action of positive
selection on favourable nonsynonymous mutations. The o
for a given gene can easily be calculated from aligned DNA
sequences of coding regions. Since positive selection may act
on only a few sites within a protein, whereas the majority of
sites are evolving neutrally or under purifying selection, the
overall signal of positive selection may be difficult to detect
with this approach. A maximum likelihood approach based
on estimation of o for different codon sites within a sequence
can be applied to detect positive selection that occurs at a
limited number of sites within the alignment. Such a test can
also be used to identify specific sites within specific branches
of a phylogenetic tree that have been subject to positive
selection. Briefly, the likelihood of the observed sequences is
found under a null model where all codon sites are evolving
either neutrally (o 5 1) or under purifying selection (o51).
The likelihood of observing the sequences is also computed
under an alternative model where some of the codons evolve
under positive selection (o41). Positive selection is inferred
if the likelihood of the observed sequences under the alternative model is significantly higher than the likelihood with
the null model. Positive selection on a particular branch
(called the foreground branch) is discovered by limiting the
sites evolving under positive selection to that branch. All
sites in the remaining branches (background branches) remain under purifying selection or neutral evolution.
The direct comparison between human and chimpanzee
sequences can identify differences between them, but to
distinguish those changes that occurred on the human
branch from those that occurred on the chimp branch it is
2
necessary to compare to an outgroup genome. The availability of additional genome sequences such as mouse (Mus
musculus) and rhesus macaque (Macaca mulatta) makes it
possible to infer ancestral states and therefore to discover
which of the differences between human and chimpanzee
occurred in the human lineage and which in the chimpanzee
lineage. See also: Neutrality and Selection in Molecular
Evolution: Statistical Tests
Positive Selection in Human
Insight into human evolution and disease
The study of positive selection in the human lineage is motivated by several factors. Many complex human-specific
traits such as advanced cognitive function and speech and
language faculties are presumably adaptive and thus may
have arisen through the action of positive selection. In this
case, identification of genes under positive selection may help
to elucidate the genetic basis for such traits and help us to
understand more about the origin of the human species.
Genes involved in these adaptive human traits may also be
implicated in disorders related to them, such as microcephaly
and speech deficits. The identification of genes involved can
therefore provide insight into the pathology of these disorders. The present environment of humans is significantly
different from that in which our ancestors lived. Therefore,
traits that were adaptive in the past may now be deleterious.
One example might be the so-called thrifty genes, very beneficial to a nutrient-limited population, but deleterious to
individuals who carry them in an environment where excess
calories are readily available and thus become susceptible to
metabolic disorders like diabetes. Genes implicated in alcoholism and hypertension have also been identified as past
targets of positive selection (Sabeti et al., 2006). Again, identification of positively selected genes (PSGs) involved in such
newly maladaptive processes can inform biomedical research
into prevention and treatment of such diseases.
Examples of positive selection in human from
the candidate gene approach
Before the availability of genome sequence, positive selection could be identified in candidate genes. Dozens of genes
were identified as having undergone positive selection in
the human lineage since its divergence from chimpanzee
(reviewed in Sabeti et al., 2006). Many of these genes are
involved in processes such as immunity and reproduction,
categories that tend to evolve quickly in many lineages. For
example, APOBEC3G, an antiviral enzyme, appears to
have evolved under positive selection in humans as well as
in other primates, presumably as a response to the evolution of viral pathogens to evade immune responses (Zhang
and Webb, 2004). An example of a reproductive gene
evolving under positive selection in humans is PRM1, a
gene involved in sperm competition (Rooney and Zhang,
1999). Indeed, functionally diverse sperm-expressed genes
ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net
Positive Selection on Human Genes Compared to Chimpanzees
including PRM1 are a group of rapidly evolving genes in
mammals (Torgerson et al., 2002). Of particular interest in
the study of human evolution are those traits that are
uniquely human, which have arisen since the divergence of
humans and our closest living relatives, the chimpanzees.
Examples of positive selection in genes involved in brain
anatomy (ASPM, Microcephalin) and speech (FOXP2)
confirm that such traits may have been shaped at least in
part by positive selection.
Although the candidate gene approach has yielded many
interesting targets of selection, analysis of the genome-wide
distribution of the test statistics for positive selection has
revealed that some of the genes previously thought to be
positively selected may not actually be unusual compared
to the range of variation present in the entire genome. For
example, CCR5D32, a relatively common allele found in
European populations that confers significant resistance
to HIV (human immunodeficiency virus) infection was
thought to have rapidly increased in frequency due to positive selection, based on the finding of the young age of the
advantageous allele (Stephens et al., 1998). However, upon
comparison with the range of normal variation in the human genome, the sequences associated with this gene are
consistent with neutral evolution (Sabeti et al., 2005).
Hypothesis of accelerated positive selection
in human
Humans appear to have undergone much more dramatic
morphological, physiological and behavioural change than
chimpanzee since divergence from their common ancestor.
For example, fossil data show that human brain size tripled
in the last 2–3 million years. It is thus possible that more
genes have been subject to positive selection in the human
lineage than in the chimpanzee lineage. The knowledge
from candidate gene studies that many genes have evolved
under positive selection in humans and that some of these
genes are involved in the traits that are the hallmarks of our
species reinforces this belief. But, a rigorous test of the
hypothesis that either all genes or some particular categories of genes experienced heightened rates of positive
selection in the human lineage requires an unbiased comparison with a closely related species. If there has been any
general or category-specific acceleration of positive selection in the human lineage, a genome-wide scan for positive
selection in humans and chimpanzees should reveal an excess of PSGs in the human lineage.
Genome-wide Scans for Positive
Selection in Human and Chimpanzee
Pioneering genome-wide scans for positive
selection in human and chimp
The first genome-wide scan for PSGs in human and chimpanzee was performed by Clark et al. (2003), who examined
approximately 8000 orthologous genes in human and
chimpanzee, using mouse as the outgroup. The authors
used a likelihood-ratio test to detect positive selection and
ranked all the genes according to their p-value. Since genes
evolving neutrally are expected to have o values near 1, this
process potentially mixes PSGs with those under relaxed
constraint. Furthermore, the models used in this maximum
likelihood analysis have subsequently been improved to
reduce the false detection of positive selection (Zhang et al.,
2005). With these caveats, their analysis showed that genes
involved in sensory perception, especially olfaction, are
enriched in the group of genes that are likely candidates for
positive selection in human, whereas signal transduction
was the most enriched category in chimpanzee.
Another genome-wide scan for positive selection was
undertaken by Arbiza et al. (2006) using an improved
branch-site test (Zhang et al., 2005). In this study, mouse,
rat and dog were used as outgroup species. Over 9600 genes
were tested for positive selection in the human and chimp
branches. The authors identified 108 genes as positively
selected in humans and 577 in chimpanzee after multiple
testing correction. The analysis of the Gene Ontology (GO)
functions of these PSGs showed that G-protein-coupled
receptors and sensory perception were most enriched in
human PSGs, whereas cellular protein metabolism was
enriched for chimp PSGs.
Caveats for the initial comparisons
The interesting findings of these initial forays into genomewide comparison of positive selection in human and chimp
must be viewed with caution due to some deficiencies
of their design. As mentioned earlier, the first study (Clark
et al., 2003) used a test for positive selection that has been
shown to produce an unacceptably high level of false positives (Zhang, 2004). This shortcoming potentially mixes
genes that have experienced a relaxation of constraint with
those truly under positive selection.
In addition, these pioneering studies used the mouse
genome as the outgroup to distinguish human-specific
from chimpanzee-specific PSGs. Primates and rodents diverged approximately 100 million years ago, so the inference of ancestral state within primates based on rodent
sequences is potentially inaccurate. The genome of the
rhesus macaque which has subsequently become available
(Rhesus Macaque Genome Sequencing and Analysis Consortium, 2007) allows for more accurate determination of
ancestral state, as the macaque monkey diverged from humans and apes only approximately 25 million years ago.
Finally, the chimpanzee genome sequence has a lower
quality than the human genome sequence. This is of critical
importance for detection of positive selection because sequencing errors are expected to occur randomly with respect to synonymous and nonsynonymous sites. Thus, the
expected o for sequencing errors is 1. In contrast, the expected o for most sites in protein-coding DNA is 51.
Therefore, high rates of sequencing error, as seen in the
chimpanzee genome compared to the human genome,
ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net
3
Positive Selection on Human Genes Compared to Chimpanzees
inflate o and can lead to false detection of positive selection. This prevented the previous studies from making a
robust quantitative comparison of the prevalence of positive selection in human and chimpanzee.
examined (6.1%). The proportion of human PSGs associated with human diseases is also greater than the fraction of chimp PSGs underlying human diseases, whereas
the proportion of chimp PSGs and chimp non-PSGs
associated with human disease are not different.
Population size affects the strength of
selection
Unbiased comparison finds more PSGs in
chimpanzee than in human
To address the caveats noted and to make an impartial
comparison of positive selection in human and chimpanzee, Bakewell et al. (2007) performed a scan of nearly 14 000
genes (greater than 50% of the genes in the primate genome) using the improved branch-site test of positive selection (Zhang et al., 2005). Rhesus macaque was used as
the outgroup. To ensure that chimpanzee sequence quality
did not affect the results, codons containing low-quality
bases in the chimp sequence were eliminated.
The results of this study show that significantly more
genes evolved under positive selection in chimpanzee than
in human (Table 1), contrary to the common belief that an
enhancement of positive selection in the human lineage led
to our dramatic phenotypic differentiation from the human–chimp common ancestor. The excess of PSGs in
chimpanzee is true at the nominal significance level of 5%
as well as after multiple testing corrections.
Seven genes are PSGs in both human and chimpanzee,
more than would be expected by chance, indicating some
common targets of selection in the two lineages. A randomization test revealed that there are significant differences in the distribution of unshared human and chimp
PSGs among biological process and molecular function
categories as annotated in the PANTHER database.
However, the categories contributing most to the difference are categories such as protein metabolism and ion
transport that are not obviously linked to the major
phenotypic differences between human and chimp
(Figure 1). An analysis of tissue group of highest expression reveals no significant differences of PSG distribution
between human and chimp. Human PSGs are more
likely than non-PSGs to be associated with human genetic disease: 9.7% of human PSGs are disease-associated, significantly greater than that among the non-PSGs
Although chimpanzee has more PSGs than human, the
overall o in human is greater for the entire dataset as well as
for the 13 508 non-PSGs. Most of these genes are under
negative selection as shown by their o551. The higher
overall o in human therefore reflects weaker purifying selection. Population genetic data indicate that the long-term
effective population size of humans is 3–5-fold smaller than
that of chimpanzees. The last common ancestor of human
and chimp had an effective population size comparable to
that of the chimpanzee lineage. Population genetic theories
predict that both purifying selection and positive selection
are less effective in a smaller population. Both the greater
number of PSGs in chimp and the overall higher o in human are consistent with this prediction. See also: Effective
Population Size; Human and Chimpanzee Nucleotide
Diversity
Implications
Patterns of evolution and laws of population
genetics apply to human evolution
Genes found to be under positive selection in humans by
candidate gene approaches are often involved in processes
that are also under positive selection in other lineages, such
as immunity and reproduction. This demonstrates that
humans have been subject to some of the same evolutionary
pressures as other taxa. The finding that fewer genes
have undergone positive selection in the human lineage
than in the chimpanzee lineage while more nonsynonymous changes have been tolerated in human genes is
consistent with the population genetic theory, which predicts weaker natural selection in smaller populations. This
Table 1 Genic positive selection in human and chimp lineages since their split
Comparison
Chimp
Human
Chimp/human
ratio
p-value
Number of PSGs
Number of PSGs after Bonferroni correction
Number of PSGs at 5% false discovery rate
Number of synonymous changes in all genes
Number of nonsynonymous changes in all genes
Mean o of all genes
Mean o of 13 508 non-PSGs
233
21
59
29 644
17 701
0.245
0.238
154
2
2
30 083
19 000
0.259
0.252
1.51
10.5
29.5
0.985
.0932
0.946
0.944
50.0001
50.0001
50.0001
40.05
50.0001
50.0001
50.0001
Source: Reproduced from Bakewell et al. (2007).
4
ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net
0.03
0.03
0.02
0.02
Frequency
Frequency
Positive Selection on Human Genes Compared to Chimpanzees
Observed
0.01
0
Observed
0.01
0
90
130
170
210
2
(a)
90
250
170
130
210
250
2
(b)
# of PSGs
PANTHER category
Biological Process
Protein metabolism and modification
mRNA transcription
Anion transport
Phosphate transport
# of genes
Human
Chimp
2
2815
9
40
9.09
1144
171
5
6
25
1
6.50
6.29
80
4
0
6.15
Proteolysis
938
2
16
6.04
Ectoderm development
mRNA transcription regulation
604
891
8
3
3
17
5.11
4.99
Stress response
Fatty acid metabolism
780
169
2
3
14
0
4.85
4.61
Ion transport
G-protein mediated signaling
578
682
12
14
7
9
4.49
4.44
Molecular function
Lyase
153
6
0
9.22
Phosphatase
Nucleic acid binding
194
2597
5
13
0
46
7.69
7.46
Nuclease
2285
12
42
6.68
Transferase
Other transporters
1296
208
5
6
25
2
6.50
4.24
(c)
Figure 1 Functional differences between human and chimp unshared positively selected genes (PSGs). Human and chimp PSGs show a significantly larger
difference in distribution across (a) biological process groups and (b) molecular function groups than by chance (P 5 0.84% and 0.26%, respectively; one-tail
randomization test). The 373 unshared human and chimp PSGs were randomly divided into 147 human PSGs and 226 chimp PSGs and w2 was computed. This
procedure was repeated 10 000 times to obtain the null distribution of w2. The bars show the frequency distribution of the w2 values in the random divisions and
the arrows show the observed w2 values. Here the randomization test is superior to the standard w2 test because the functional groups are not independent from
one another and a single gene may belong to more than one group. Similar results are obtained when the seven shared PSGs are included. (c) Biological process
and molecular function groups show the greatest differences between human and chimp unshared PSGs, as ranked by individual w2 values. Shown here are the
groups that each contributes at least 2% of the total w2 of all groups. Groups with a higher frequency of human PSGs than chimp PSGs are in red, whereas those
with a higher frequency of chimp PSGs than human PSGs are in blue. Reproduced from Bakewell et al. (2007).
finding demonstrates that the laws of population genetics
apply equally to humans despite the dramatic morphological and behavioural changes that have occurred in the
human lineage.
Many adaptive traits may be unrecognized
The biological categories in which human and chimpanzee PSGs differ do not match up well with the expected
categories based on the most well-known differences between human and chimpanzee, such as brain size. This
suggests that there are adaptive differences between the
two species of which we are not aware, or that the genetic basis for the known differences may involve unexpected processes. This is especially true for chimpanzee
where the adaptive traits and differences since the human–chimp common ancestor have not been well studied. Indeed, a comprehensive catalogue of differences in
ENCYCLOPEDIA OF LIFE SCIENCES & 2008, John Wiley & Sons, Ltd. www.els.net
5
Positive Selection on Human Genes Compared to Chimpanzees
development, anatomy, behaviour, physiology and disease susceptibility between humans and the great apes is
a goal, the achievement of which would greatly enhance
our ability to robustly define ‘humanness’ (Varki and
Altheide, 2005). Given that chimpanzees have more
PSGs than humans, it is probably true that they have
many unknown adaptations.
The catalogue of positive selection is
incomplete
Genome-wide studies of positive selection using tests that
depend only on interspecific divergence data are limited in
their power to detect recent or ongoing selection. Proper
investigation of selection in these time frames requires the
use of polymorphism data. Beneficial alleles in human
populations during and after the out-of-Africa migration
as they moved into new environments and encountered
new pathogens may still have to be fixed and thus be undetectable by studies such as the ones described earlier.
See also: Human Evolution: Radiations in the Last 300 000
Years; Modern Human Origins: The ‘Out of Africa’
Debate
There is not necessarily a direct correspondence between
the amount of molecular change and the amount of
phenotypic change. A single nucleotide change can produce pleiotropic effects, as for example with the sickle-cell
mutation. The effects of single or few mutations can produce phenotypes with very different fitnesses and be acted
on by natural selection, yet are undetectable to a test of
positive selection based on o due to their minor impact to
the overall substitution rate of the gene. Single genes can
have large effects, and it may be that the seemingly large
phenotypic changes in modern humans are due to a few
changes of large effect rather than an overall acceleration of
positive selection.
This article focuses on positive selection in genes, but
positive selection can also act on regulatory regions of the
genome. Because of the very high level of identity (approximately 99%) between human and chimpanzee coding sequences, King and Wilson (1975) proposed that the
important differences between human and chimp are likely
to be in gene expression rather than in protein sequence.
The study of the noncoding regions of the genome will
identify many additional candidates for positive selection
in human and in chimpanzee (Haygood et al., 2007).
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Positive Selection on Human Genes Compared to Chimpanzees
complemented by fossil evidence. Molecular Phylogenetics and
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