Concerted Evolution
Dan Graur
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Three evolutionary models for duplicated genes
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Concerted Evolution
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Divergent (classical) evolution vs. concerted evolution
Expected
Observed
Ganley AR, Kobayashi T. 2007. Genome Res. 17:184-191.
Ribosomal RNA gene unit (in a cluster)
ITS = internally transcribed sequences
ETS = externally transcribed sequences
NTS = nontranscribed sequences
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Xenopus borealis
Xenopus laevis
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18S and 28S in X. laevis and X. borealis are identical.
NTS regions differ between the two species.
NTS regions are identical within each species.
Conclusion: NTS regions in each species have
evolved in concert, but have diverged rapidly
between species.
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(a) Stringent selection.
(b) Recent multiplication.
(c) Concerted evolution.
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(a) Stringent selection.
Refuted by the fact that the
NTS regions are as
conserved as the functional
rRNA sequences.
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(b) Recent multiplication.
Refuted by the fact that the
intraspecific homogeneity
does not decrease with
evolutionary time.
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(c) Concerted evolution.
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CONCERTED EVOLUTION
A member of a gene family does not evolve
independently of the other members of the
family.
It exchanges sequence information with
other members reciprocally or
nonreciprocally.
Through genetic interactions among its
members, a multigene family evolves in
concert as a unit.
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CONCERTED EVOLUTION
Concerted evolution
results in a homogenized
set of nonallelic
homologous sequences.
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CONCERTED EVOLUTION REQUIRES:
(1) the horizontal transfer of
mutations among the family
members (homogenization).
(2) the spread of mutations in the
population (fixation).
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Mechanisms of concerted
evolution
1. Gene conversion
2. Unequal crossing-over
3. Duplicative transposition.
4. Gene birth and death.
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gene conversion

concerted evolution
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Gene Conversion
Unbiased Gene Conversion: Sequence A has as
much chance of converting sequence B as
sequence B has of converting sequence A.
Biased Gene Conversion: The probabilities of
gene conversion between two sequences in the
two possible directions occur are unequal.
If the conversional advantage of one sequence
over the other is absolute, then one sequence is
said to the master and the other to be the slave.
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Gene conversion has been found in
all species and at all loci that were
examined in detail.
Biased gene conversion is more
common than unbiased gene
conversion.
The rate of gene conversion varies
with genomic location.
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unequal crossing-over

concerted evolution
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Unequal crossing over
Unequal crossing over
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Tomoko Ohta
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concerted evolution:
Advantages of Gene Conversion over
Unequal Crossing-Over
1. Unequal crossing-over changes
the number of repeats, and may
cause a dosage imbalance. Gene
conversion does not change repeat
number.
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normal configuration
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following unequal crossing-over
mild a-thalassemia
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concerted evolution:
Advantages of Gene Conversion over
Unequal Crossing-Over
2. Gene conversion can act on
dispersed repeats. Unequal crossingover is severely restricted when
repeats are dispersed.
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deletion
duplication
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concerted evolution:
Advantages of Gene Conversion over
Unequal Crossing-Over
3. Gene conversion can be biased.
Even a small bias can have a large
effect on the probability of fixation
of repeated mutants.
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concerted evolution:
Advantages of Unequal Crossing-Over over
Gene Conversion
1. Unequal crossing-over is faster
and more efficient in bringing about
concerted evolution.
At the mutation level, UCO occurs more
frequently than GC.
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concerted evolution:
Advantages of Unequal Crossing-Over
over Gene Conversion
2. In a gene-conversion event,
only a small region is involved.
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In yeast, an unequal crossing-over
event involves on average ~20,000
bp. A gene-conversion track cannot
exceed 1,500 bp.
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Factors affecting the rate of concerted
evolution
1. the number of repeats.
2. the arrangement of the repeats.
3. relative sizes of slowly and rapidly
evolving regions within the repeat
unit.
4. constraints on homogeneity.
5. mechanisms of concerted evolution.
6. population size.
7. dose requirements
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1. the number of repeats.
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The number of unequal
crossing-overs required for the
fixation of a variant repeat
increases roughly with n2,
where n is the number of
repeats.
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2. the arrangement of the repeats.
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Types of arrangement of repeated
units:
Dispersed
Clustered
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The dispersed arrangement causes
unequal crossing-over to lead to
disastrous genetic consequences.
The dispersed arrangement
reduces the frequency of gene
conversion.
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3. relative sizes of slowly and rapidly
evolving regions within the repeat unit.
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Noncoding regions evolve rapidly.
Coding regions evolve slowly.
Both unequal crossing-over and gene
conversion depend on sequence
similarity for the misalignment of
repeats.
The more coding regions there are, the
higher the rates concerted evolution will
be.
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4. constraints on homogeneity.
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Two extreme possibilities:
1. The function requires large amounts
of an invariable gene product.
rRNA and histone genes
2. The function requires a large amount
of diversity.
immunoglobulin and histocompatibility
genes
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Two extreme possibilities:
1. The function requires large amounts
of an invariable gene product.
rRNA and histone genes
2. The function requires a large amount
of diversity.
immunoglobulin and histocompatibility
genes
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5. mechanisms of concerted evolution.
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Concerted evolution under
unequal crossing-over is
quicker than that under
gene conversion.
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6. population size.
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The time required for a
variant to become fixed
in a population depends
on population size.
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7. dose requirements.
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Centripetal selection against too
many or too few repeats.
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Decreases variation
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2 loci, 3 alleles
gene conversion
2 loci, 4 alleles
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Detecting
Concerted
Evolution
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When dealing with similar
paralogous sequences, it is usually
impossible to distinguish between
two alternatives:
(1) the sequences have only recently
diverged from one another by
duplication.
(2) the sequences have evolved in
concert.
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The phylogenetic approach.
a1
a2
The two a-globin genes in humans
are almost identical. They were
initially thought to have duplicated
quite recently, so there was no
sufficient time for them to diverge in
sequence.
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The phylogenetic approach.
a1
a2
However, duplicated a-globin genes
were also discovered in distantly
related species, so most
parsimonious solution to assume
that the duplication is quite ancient,
but its antiquity is obscured by
concerted evolution.
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g
duplication
55 million years ago
Ag
Gg
speciation
5 million years ago
Ag
Gg
Ag
Gg
The orthologs
should be
closer to one
another than
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the paralogs.
Gg
A
and g
Gg
A
and g
In humans, the 5’ parts of
differ from one another at only 7
out of 1,550 nucleotide positions
(0.5%).
In contrast, the 3’ parts of
differ from one another at 145 out
of 1,550 nucleotide positions
(9.4%).
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exon 3
exons 1 and 2
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exon 3
exons 1 and 2
Expected phylogenetic tree for exons
1 and 2, if gene conversion had only
occurred in the human lineage.
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Death is not final: The resurrection of pancreatic
ribonuclease as seminal ribonuclease in Bovinae by gene
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conversion
The resurrection of pancreatic ribonuclease as seminal
ribonuclease in Bovinae through gene-conversion of a
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small region at the 5' end of the gene.
Pseudogenes may represent
reservoirs of genetic information
that participate in the evolution
of new genes, not only relics of
inactivated genes whose fate is
genomic extinction.
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21-hydroxylase (cytochrome P21) gene
In humans, the 10-exon gene is located on
chromosome 6.
The gene has a paralogous pseudogene in
the vicinity.
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21-hydroxylase (cytochrome P21) gene
Hundreds of mutations in the 21hydroxylase gene have been described.
75% of them are due to gene conversion.
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Were it not for the fact that the pseudogene is truncated, we
would be hard pressed to say which is the gene and which is the
pseudogene.
gene
pseudogene
ATGTCTCTGACCAAGGCTGAGAGGACCATGGTCGTGTCCATATGGGGCAA
ATGTCTCTGACCAAGGCTGAGAGGACCATGGTCGTGTCCATATGGGGCAA
**************************************************
gene
pseudogene
GATCTCCATGCAGGCGGATGCCGTGGGCACCGAGGCCCTGCAGAGGTGAG
GATCTCCATGCAGGCGGATGCCGTGGGCACCGAGGCCCTGCAGAG----*********************************************
gene
pseudogene
TGCCAGACAGCCTGGGACAGGTGACAGTGTCCCAGGTGACACTGGTGTAG
--------------------------------------------------
Gene
pseudogene
GTGACAGCGTGAGTTTAGTGAGGACAGGGGCCAGTGAAGAGGGGGCAATG
--------------------------------------------------
gene
pseudogene
AGGAAGCGACAGTGTGGAGGGGTAATTGTGGTGGGGAACTGTGAGGACCC...
-------------------------------------------------72
Were it not for the fact that the pseudogene is truncated, we
would be hard pressed to say which is the gene and which is the
pseudogene.
gene
pseudogene
ATGTCTCTGACCAAGGCTGAGAGGACCATGGTCGTGTCCATATGGGGCAA
ATGTCTCTGACCAAGGCTGAGAGGACCATGGTCGTGTCCATATGGGGCAA
**************************************************
gene
pseudogene
GATCTCCATGCAGGCGGATGCCGTGGGCACCGAGGCCCTGCAGAGGTGAG
GATCTCCATGCAGGCGGATGCCGTGGGCACCGAGGCCCTGCAGAG----*********************************************
gene
pseudogene
TGCCAGACAGCCTGGGACAGGTGACAGTGTCCCAGGTGACACTGGTGTAG
--------------------------------------------------
Gene
pseudogene
GTGACAGCGTGAGTTTAGTGAGGACAGGGGCCAGTGAAGAGGGGGCAATG
--------------------------------------------------
gene
pseudogene
AGGAAGCGACAGTGTGGAGGGGTAATTGTGGTGGGGAACTGTGAGGACCC...
-------------------------------------------------73
The birth-and-death model for the evolution of
gene families was proposed by Hughes and Nei (1989).
In this model, new copies are produced by gene duplication.
Some of the duplicate genes diverge functionally; others become
pseudogenes owing to deleterious mutations or are deleted from
the genome.
The end result of this mode of evolution is a multigene family with
a mixture of functional genes exhibiting varying degrees of
similarity to one another plus a substantial number of
pseudogenes interspersed in the mixture.
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The birth-and-death model for the evolution of
gene families
An important prediction of the birth-and-death process is that
gene-family size will vary among taxa as a result of differential
birth and death of genes among different evolutionary lineages.
Thus, an understanding of the evolutionary forces governing the
birth-and-death process is predicated upon an accurate
accounting of the number of births (duplications) and deaths
(nonfunctionalization events + deletions) in each lineage.
This “bookkeeping” turns out to be anything but a trivial
undertaking.
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Expansions/no change/contractions in the evolution of gene families
in five Saccharomyces species. Estimates of divergence times (in
millions of years) are shown in circles.
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There were 3517 gene families shared by the five species. Of these, 1254 (~37%)
have changed in size across the tree.
On each branch in the tree, the vast majority of gene family sizes remain static.
Expansions outnumbered contractions on four of the eight branches, and contractions
outnumbered expansions on the other four.
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Lineage specificity
Let us compare the number of expansions and contractions on the branches leading to
S. mikatae and S. cerevisiae from their common ancestor, approximately 22 million
years ago. On the lineage leading to S. mikatae there were 509 families that expanded
and 86 families that contracted—a ratio of 6:1. On the lineage leading to S. cerevisae
a smaller number of families changed their size, and the ratio of expanded families
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(54) to contracted ones (241) was inverted, 1:5.
Turnover Rates
Turnover = Gains + Losses
The gene turnover rate in primates is nearly twice that in nonprimate mammals (0.0024 versus 0.0014 gains and losses per gene
per million years).
A further acceleration must have occurred in the great-ape lineage,
such that humans and chimps gain and lose genes almost three times
faster (0.0039 gains and losses per gene per million years) than the
other mammals.
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BIRTH-AND-DEATH EVOLUTION:
EXAMPLES
The evolution of olfactory receptor gene
repertoires
Olfactory receptors are G-coupled proteins
that have seven α-helical transmembrane
regions. Olfactory receptor genes are
predominantly expressed in sensory neurons
of the main olfactory epithelium in the nasal
cavity. Animals use different olfactory
receptors and different combinations of
olfactory receptors to detect volatile or watersoluble chemicals.
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BIRTH-AND-DEATH EVOLUTION:
EXAMPLES
The evolution of olfactory receptor gene repertoires
Tetrapods have 400-2,100 olfactory receptor sequences, but 20-60% are pseudogenes.
These numbers are small in comparison to the number of odorants, but olfactory
receptors function in a combinatorial manner, whereby a single receptor may detect
multiple odorants, and a single odorant may be detected by multiple receptors.
Functional olfactory receptor genes (red)
Pseudogenes (blue)
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BIRTH-AND-DEATH EVOLUTION:
EXAMPLES
The evolution of olfactory receptor gene repertoires
Vertebrate olfactory receptors genes are classified into at least nine subfamiles (a, b, g,
d, e, z, h, q, and k), each of which originated from one or a few ancestral genes in the
most recent common ancestor of vertebrates. There was an enormous expansion in the
number of a and g genes in non-amphibian tetrapods. The remaining gene families are
present primarily in fish and amphibian genomes. This observation suggests that a and
g mostly detect airborne odorants, while the function of the other gene families is to
detect water-soluble odorants.
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BIRTH-AND-DEATH EVOLUTION:
EXAMPLES
The evolution of olfactory receptor gene repertoires
Primates generally have a smaller number of functional olfactory receptor genes than
rodents and a higher proportion of pseudogenes.
1063 genes, 328 pseudogenes (24%)
388 genes, 414 pseudogenes (52%)
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BIRTH-AND-DEATH EVOLUTION:
EXAMPLES
Color
Vision
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Color vision in primates is mediated in the eye by up to three types
of photoreceptor cells (cones), which transduce photic energy into
electrical potentials.
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Each type of color-sensitive cone expresses one type of colorsensitive pigment (photopigment). Each photopigment consists of
two components: a transmembrane protein called opsin, and either
of two lipid derivatives of vitamin A, 11-cis-retinal or 11-cis-3,4dehydroretinal. Variation in spectral sensitivity, i.e., color
specificity is determined by the sensitivity maximum of the
opsins.
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John Dalton. 1794. “Extraordinary Facts
Relating to the Vision of Colours.”
Memoirs of the Manchester Literary &
Philosophical Society.
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Ishihara Plates
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Opsins
Long wavelength (red)
Medium wavelength (green)
Short wavelength (blue)
Suggested flag for Mars
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• Routine trichromacy = all individuals regardless of sex can achieve
trichromacy.
• Dichromacy (in humans, referred to as color blindness):
protanopia (L-deficiency),
deuteranopia (M-deficiency),
tritanopia (S-deficiency).
• Because of X-linkage, protanopia and deuteranopia are considerably more
common in males than in females.
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•Monochromacy can occur if both L and M photopigments are faulty.
Most prosiminas (Strepsirrhini) and New World monkeys (Platyrhhini) carry only one
X-linked pigment gene, and are, therefore, dichromatic. The ancestral X-linked opsin
is thought to resemble the M-opsin, and indeed most prosimians and New World
monkeys are protanopic.
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However, because shifts in the maximal sensitivity of opsins can be achieved quite
easily by missense mutations in as few as 3-5 codons, in a few diurnal taxa of
prosimians, L-alleles have been produced. In some lineages, the L-allele became fixed
in the population at the expense of the M-alleles. In consequence, these taxa are
deuteranopic.
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In other cases, a polymorphic state consisting of two or more alleles is maintained in
the population. As an example, in white-faced capuchin monkeys (Cebus capucinus),
there exist two alleles at the X-linked opsin locus, the maximal-sensitivity peaks of
which being similar to those of human L and M opsins, respectively. For this reason,
while males and homozygous females are dichromatic, heterozygous females are
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trichromatic (Figure 6a.8). This type of trichromacy is called allelic trichromacy.
Saimiri sciureus
Squirrel monkey
New-World monkeys possess only two opsin loci, one autosomal and
one X-linked. However, the X-linked opsin locus is highly
polymorphic. Two of these alleles have maximal-sensitivity peaks
similar to those of human red and green opsin, while the third allele has
an intermediate peak. A heterozygous female will be trichromatic,
while males and homozygous females are dichromatic.
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