Casandra Rodrguez y R

Dajana Blagojevic
You Ri Yang

06. Nov. 2014

Positive Selection in the Human Genome:

From Genome Scans to Biological Significance
INTRODUCTION
Human beings have evolved for better adaptation and survival since their first
appearance. This process not only allowed them to develop their own communication skills
and tools but also unique genetic makeup through various mutations, led by positive selection
(Kelley & Swanson, 2008). Comparing human genome sequences and those of closely related
primate species such as chimpanzees often reflect the evolutionary signature of human
genome. This includes copy number variations (CNVs) which are 1 kb or larger DNA
segments (Redon, et al. 2006). Some of these CNVs are present in both human and
chimpanzee genome while others are restricted to one species (Kehrer-Sawatzki & Cooper,
2008). Recent study on salivary amylase gene (AMY1) by Perry and colleagues (2007)
demonstrates the impact of copy number variation on expression differences. The signature of
positive selection also appears as a different polymorphism between and within the
population and is identified by genome-wide scans with more than millions of publicly
available SNP genotype data and various test statistics (Kelley & Swanson, 2008). Lactase
persistence of human in different groups across the continents and antigenic evolution of
influenza A (H3N2) virus are another examples of positive selection. In this paper, examples
of population and species-wide adaptation of human and viral genome under positive
selection are further discussed in detail.
Theory: positive selection and copy number variation
Positive selection
Previously, the idea that living organisms evolve for better adaptation to their
environment, thus increase their survival rate was widely accepted as a priori assumption
about the motive of positive selection (Kelley & Swanson, 2008).
However, variation of DNA polymorphism is not only caused by the increase of
beneficial DNAs but also by purifying process of disadvantageous alleles and balancing of
genetic variation within species over time and space (Harris & Meyer, 2006). When there is a
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positive selection, advantageous DNA variant increases its frequency and several methods
and test statistics are employed to detect the selection site.

Copy number variation under positive selection

Copy number variation also contributes to genetic polymorphism and diversity. It can
be formed by deletions, insertions, duplications and complex multi-site variants (Redon, et al.
2006). Kelley and Swanson (2008) explained that copy number variations and noncoding
substitutions can cause expression differences between populations by affecting the gene
transcribed so that they can take the advantage on their own fitness. Such variation influences
the amount of genes expressed and alters phenotype of the carrier. Although the presence of
selective pressure at the moment when the positive selection occurred are still vague,
variation of copy numbers across the population displays interesting insight on evolutionary
biology (Kelley & Swanson, 2008).
RESULTS & DISCUSSION
Cases of copy number variation (CNV)
Studies focus in copy number variation and level of expression in proteins, have
referred that the expression difference between populations confer different fitness
advantages which in time may be positively selected. Furthermore, positive selection act on
copy number and noncoding regions (Kelley & Swanson, 2008), suggesting that transcription
and translation pathways plays an important role in the differentiation among populations,
where transcript levels are affected. Some examples related to positive selection in humans
populations and other species are: LCT gene, FOXP2 gene, AMY1 gene and haemagglutinin
(HA1) of H3N2.
Lactase persistence
In one of the studies, lactase persistence is described as one of the most known
examples of positive selection acting in humans. Lactase persistence differs greatly between
populations and is assumed to be correlated with cattle domestication. Northern Europeans
tolerate lactase in much higher grade compared to other world populations.
Moreover, C/T- 13, 910 SNP allele frequencies in Europeans corresponds to 77%,
whereas in African Americans 14% while in Chinese population allele frequency is absent
(Bersaglieri T. et al. 2004). Thus C/T- 13, 910 allele is speculated to be a causal allele for
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lactase persistence. However, it was identified that lactase persistence is present in pastorial
areas in Africa, where European variant was absent or at very low frequency. Suggestions
were that causal variant in Europeans is different. Results revealed tree novel variants in
African population that were in association with lactase persistence in different pastorial
areas. New discovered alleles occurred on different haplotype backgrounds (Figure 1.) Most
of the alleles, related to lactase persistence took position in Oct-1 transcription factor binding
site area (Figure 1.). Anyhow, this study revealed how SNP differences affects promoter site
and expression of genes related to lactase persistence. In addition, presented study indicates
that lactase persistence has independently evolved at least twice in geographically distinct
populations.

Figure 1. TFBS (Transcription factor binding sites) and potential adaptive alleles upstream of LCT
(lactase) gene.
FOXP2 gene
The study in FOXP2 gene is an example of positive selection which incorporates the
analysis and understanding of polymorphisms within species and divergence data between
species (Kelley & Swanson, 2008). Mutations in human FOXP2 have revealed that
individuals affected may influence human speech, however, due to the nature of the gene
presence or absence of speech is not the only phenotype involve in these mutation.
Results found in sequence analysis comparison between humans and other mammals
revealed that only few changes in FOXP2 gene which is a transcription factor highly
conserved in mammals clade, have provided functional consequences in humans due to
intronic variations (Fig.2). Thus, comparing substitutions rates in conserved sequences, one
of the regulatory variations in humans shown to be related in the formation of
phosphorylation sites. Besides, variations suggest an adaptation along human evolution as a
recent selective sweep occurred around the emergence of anatomically modern humans
(Kelley & Swanson, 2008). Complementing their findings, human sequenced was compared
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against Neanderthal sequence where the last group sequence contained the two human
specific variations. This last finding may suggest (if results are not artifacts of the difficulty
of sampling) that this site have been segregated and fixed before the Human-Neanderthal
split.

Fig.2 In figure it is represented silent and replacement nucleotide substitutions in FOXP2 mapped
on a phylogeny of primates and mice as a less related group. Bars represent nucleotide changes
and the grey bars indicate amino acid changes (Kelley & Swanson, 2008).

AMY1 gene
Copy number variation on salivary amylase gene (AMY1) study in humans, gives the
chance to understand better how some traits depends in the number of copies as well as in the
level of expression of genes, leading to variation within human populations. The study which
have consisted in the comparison of populations with rich starch diet against populations
without a diet rich in starch demonstrated that exist a positive correlation between AMY1
gene copy number and protein expression (Fig.3).

Fig.3 The three figures (a,b & c) shows AMY1 copy number variation and salivary amylase protein exp
ression. A and b, are the diploid AMY1 gene copy number and amylase protein levels in saliva in
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pean-American individuals. Plot c shows the relationship between AMY1 diploid copy number and saliva
ry amylase protein level in the European-Americans population (Perry et al., 2007).

Thus, it was found that the mean diploid AMY1 copy number was grater in
populations with high starch diet, being 2 times greater than those with low starch diet (Perry
et al., 2007). Also this result highlight that the variation found is strongly related to diet
habits than geographic proximity due to high and low starch samples include both African
and Asian populations, which suggest that positive selection may influence AMY1 copy
number in certain populations. Consequently, the results obtained from the array based
comparative genomic hybridization analysis between Yakut (a Siberian group whose diet is
based in low starch food) and Japanese population demonstrated a differentiation between
both populations at the AMY1 locus than other copy number variable loci. This findings
support the hypothesis of positive selection among AMY1 copy number as consequence of
high starch diet (Perry et al., 2007) (Fig.4). Lastly, the comparison between humans with apes
(bonobos, chimpanzees and new world monkeys) gave a better understanding in the function
of AMY1 through different diets performed by different populations, where it was more
evident that the AMY1 copies and expression level were higher in humans than in
chimpanzees, which are mostly frugivorous and ingest small amounts of starch in comparison
with humans.
Variation in number copies and level expression found across this study compromise
mechanisms where higher salivary amylase protein levels may confer a fitness advantage for
individuals with a high-starch diet (Perry et al., 2007). The principal digestion of starch
occurs during mastication, where blood glucose levels elevates when high starch foods such
as corn, rice, and potatoes. In addition, once digestion is taking place in the stomach and
intestine, it has been observed that salivary amylase persists in those regions, augmenting the
enzymatic activity of pancreatic amylase in the small intestine (Perry et al., 2007). In
conclusion, the higher AMY1 copy number and high level of its protein expression support
the hypothesis of positive selection in recent human evolution improving the digestions
efficiency in high-starch foods which may also reduce effects of intestinal disease.

Positive selection acting continuously on hemagluthinin (HA1) of H3N2

Previously studies measured antigenic distances between HA1 and H3N2 from
various years by use of HA inhibition assay and revealed that isolates formed different
antigenic clusters.

Thus, it was proposed that antigenic evolution of HA1 for H3N2

occurred punctuated. On the other hand, evolution of nucleotide and amino acid sequences of
Fig.4
In graph
a, itais continuous
shown the diet
and AMY1
copy number variation.
Where
it is compared
thedoubts
AMY1 diploid
HA1
showed
pattern.
As consequence,
population
genetics
analysis
copy number frequency distributions between populations with diets that incorporate high starch food and
occurred with
whether
positive
selection
onstarch.
HA1 The
occurred
punctuated
for theofCcumulative
branchesdistribution
or
populations
diets that
include
little or no
plot b is
the representation
of continuously.
diploid AMY1 By
copyuse
number
for each population
studied selection
(Perry et was
al., 2007).
of molecular
analysis positive
detected in NC-T branches.

In addition, positive selection was also detected for the C-T branches and value was > 1 for
epitopes A and B (Y. Suzuki 2008.). Moreover, figure 2 shows that T branches (red colored)
are presented as set of branches connecting the root of the human sequences and the cluster of
the latest isolates. Based on these results, it seems like positive selection acted throughout
trunk branches (C-T and NC-T). According to Fitch et al.1991. positive selection was
detected for epitopes A-E on the T branches. Table 1 indeed shows that > 1 for epitopes A,
B and E for the T branches. In addition positive selection was detected for epitope A. Thus
positive selection operated mainly in E-SE Asia or the tropics. NC-NT branches in contrast
did not show any positive selection. Suggestions were that NC-NT branches were mainly
neutral.
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Figure 3. Phylogenetic tree reperesenting HA1s of 209 H3N2 human influenza A viruses and
1 duck virus, based on NJ method. Isolates are associates with antigenic clusters by different
colors. Red colors refer to T branches, while thick branches indicate to C branches.
Accordingly: C-T: thick red, C-NT: thick black, NC-T: thin red and NC-NT: thin black
branches.

Table 1. Estimation of values from different sites and branches for the phylogentic tree,
based on Neighbour Joining (NJ) method from figure 3.

REFERENCES
Enard, W., Przeworski, M., Fisher, S. E., Lai, C. S., Wiebe, V., Kitano, T.,& Pbo, S.
(2002). Molecular evolution of FOXP2, a gene involved in speech and language. Nature,
418(6900), 869-872.
Harris E., Meyer D. (2006). The Molecular Signature of Selection Underlying Human
Adaptations. Yearbook of Physical Anthropology. 49:89-130.
Kelly, J., Swanson W. (2008). Positive Selection in the Human Genome: From Genome
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Scans to Biological Significnce. Annual Review of Genomics and Human Genetics.

9:143-60.
Kehrer-Sawatzki H., Cooper D. (2008). Comparative analysis of copy number variation
in primate genomes. Cytogenetic and Genome Research. 123:288-296.
Perry, G. H., Dominy, N. J., Claw, K. G., Lee, A. S., Fiegler, H., Redon, R., ... & Stone,
A. C. (2007). Diet and the evolution of human amylase gene copy number variation.
Nature genetics, 39(10), 1256-1260.
Redon, R., et al. (2006). Global variation in copy number in the human genome. Nature.
444:444454.