Transcript DUPLICATIONS II. - University of KwaZulu

DUPLICATIONS I.
Small-Scale Gene Duplication
GENE 330
PEDEGREE OF GENE DUPLICATION
RESEARCH
1911 – Kowada proposed that the production of many different varieties of
maize was related to an ancient chromosome duplication.
1915 – Tischler noticed morphological differences that were correlated with
variation in chromosome number in several closely related plans.
1918 – Bridges addressed the issue of how gene duplication might
contribute to speciation and morphological innovation.
1935 – Muller produced fruit flies with a small fragment of their X
chromosome duplicated and inserted into Chromosome 2.
1936 – Bridges was able to attribute phenotypic variation in fruit fly to the
duplication – that Bar and Bar-double phenotypes (both of which have
reduced eyes) were a consequence of rare, small-scale tandem
duplication.
PEDEGREE OF GENE DUPLICATION
RESEARCH
1938 – Serebrovsky not only recognized that selection could be relaxed in
one of the genes in a duplicated pair, but also that both copies could be
modified.
1940 – Goldsmith made explicit links between organismal complexity and
gene duplication.
1947 – Metz put it, “new elements must be added”.
1951 – Stephens doubted that evolution took place by the slow
accumulation of small gene mutation. He proposed, that the only way of
achieving “evolutionary progress” would be increasing the number of
genetic loci.
1967 – Ohno stated that gene duplication was the single most important
factor in evolution.
2002 – Bailey at al. concluded that many SNPs in human genes are in fact,
variants at duplicated loci.
STUDIES AT THE PROTEIN LEVEL
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In the late 1960s, the development of starch gel electrophoresis
allowed variation to be detected in proteins themselves.
Duplicated loci produce more bands than single copy genes
Isozyme electrophoresis studies uncovered gene duplicates in
polyploids, and in species where no cytological data had predicted
their occurrence.
The discovery, that some duplicated isozymes show parallel linkage
in maize supported Kuwada’s (1911) hypothesis that this species
evolved from a tetraploid ancestor.
MECHANISMS OF GENE DUPLICATION
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Gene duplication can occur by a variety of mutational mechanisms.
The first to be observed involved chromosome-level events
including the doubling of the entire chromosome complement.
Other processes now recognized include “duplicative transposition”
and large-scale “tandem duplication” events such as those observed
in polytene chromosomes.
MEHANISMS OF GENE DUPLICATION
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Aneuploidy – at a level below entire genomes, whole
chromosomes may be duplicated (or lost) through a
process of “nondisjunction”.
Nondisjunction can occur during meiosis and involves
the failure of one or more sets of homologous
chromosomes to separate properly.
The resulting chromosome imbalance, whether involving
chromosome loss (monosomy) or gain (polysomy) often
has a clear phenotypic effect, as in Down (trisomy 21).
Partial polysomy can also be observed, as with some
individuals with Down syndrome in whom only part of
Chromosome 21 occurs in triplicate.
MECHANISMS OF GENE DUPLICATION
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Duplicative transposition involves the duplication and movement
within the genome fragments of DNA ranging in size from 1 to more
than 200kb.
Human DNA fragments created by duplicative transposition, which
were identified using FISH, have been found to contain repetitive
DNA, portions of genes (intron-exon structures), and complete genes.
Telomeres and centromeres are especially receptive to such
insertions.
The most significant evolutionary consequences of duplicative
transposition may be the large-scale pericentric chromosomal
rearrangements.
Accumulating evidence also suggests that reverse transcription plays
an important role in gene duplication (pseudogenes).
MECHANISMS OF GENE DUPLICATION
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Duplicated genes that reside next to one another are referred as local
tandem duplicates.
Unequal crossing-over (at meiosis) and possibly unequal sisterchromatid exchange (at mitosis) appear to have played roles in the
expansion of tandem arrays of gene duplicates.
Tandem duplication by unequal crossing-over was first described for
the Bar locus in fruit fly.
Today, one of the most spectacular examples of tamdemly duplicated
genes known is provided by those encoding rRNAs, which occur in
long tandem arrays of up to thousands of copies in some eukaryotic
genomes.
It is also now clear that tandem duplication is an important process in
protein-coding gene duplication
THE LIFE AND DEATH OF GENE
DUPLICATES IN THE GENOME
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In well-known analysis (Lynch and Conery in 2000) was the
estimate that a gene is as likely to be duplicated as a single
nucleotide is to experience a substitution.
Lynch and Conery also found that humans and nematodes make
new genes faster than Drosophila.
Nembaware et al.(2002) proposed that the probability of a gene
being duplicated is correlated with its length.
Gene exhibiting low rates of molecular evolution appear more
likely to be retained in duplicate
In yeast, the slowly evolving genes that had been preferentially
retained in duplicate appeared to be the genes that were most
highly expressed.
THE EVOLUTION OF GENE FAMILIES
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By the process of duplication and divergence, certain genes may
come to exist as “families” of repeated copies.
In some cases, these are of obvious importance for organismal
fitness.
Two well-known examples from human medicine include the
hemoglobin and immunoglobulin gene families.
Hemoglobin
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Hemoglobin , is made up of four peptides; two α-globins and two βglobins. There are several different types of α-globins and β-globins
(each encoded by a different paralogous gene), and at different
periods of human development hemoglobin is comprised of different
combinations of these globins.
In humans they originated from a single gene, the α-globin genes all
occur on Chromosome 16 and the β-globin genes occur on
Chromosome 11.
These genes are distantly related to a single myoglobin gene on
chromosome 22, showing that a diversity of duplication events led to
the structure of this globin superfamily.
Immunoglobulins
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Humans are able to make antibodies against millions of potential
antigens.
Gene duplication plays an important role in this almost unlimited
antigen response.
In the human genome has been found between 149 and 168 functional
immunoglobulin genes in four classes; variable sequences (V), leader
(orD) sequences, joiner sequences (J), and constant sequences (C).
In mammalian genomes, the V, D, and J genes are linked, with
multiple V genes next to multiple D genes next to multiple J genes.
These sets of linked genes are rearranged and assembled by a
process called “somatic recombination” in order to produce an
enormous number of different antibodies.
THE CONTRIBUTION OF GENE
DUPLICATION TO GENOME STRUCTURE
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Genome duplication events have contributed to gene family
expansion and to genome evolution in a great diversity of species.
In Mycobacterium tuberculosis, more than 33% of genome is
comprised of recently duplicated genes.
In Plasmodium falciparum, duplication events have produced unlinked
duplicated sets of rRNA genes – to be different ribosomes for different
environments.
During the sequencing of human genome, each nucleotide was
sequences approximately five times. This study identified 8595
duplicated regions (defined as sequences having >94% sequence
identity over 5000bp) and concluded that 130.5 Mb of the Human
genome had been recently duplicated.
WHAT HAPPENS TO DUPLICATED
GENES?
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Nonfunctionalization – most duplicates become nonfunctional (i.e.
pseudogenes).
While “junk DNA” (pseudogenes) strictly defined, does not account
for the massive variation in genome size among eukaryote species,
pseudogenes are well represented in many genomes.
Recent estimate based on Chromosomes 21 and 22 suggests that
the Human genome may contain about 9000 processed (a
reinserted, intronless mRNA sequence) and 10.000 classical
pseudogenes (lost of function).
Interestingly, a large portion of the pseudogenes on these
chromosomes are located in “pseudogenic hotspots” near the
centromeres.
WHAT HAPPENS TO DUPLICATED
GENES?
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The duplicated regions of the human genome were defined by size, not
gene content.
Looked at the genes within the recently duplicated blocks, has been found
that some genes were more likely to be duplicated than others,
Gene associated with immunity, membrane surface interactions, drug
detoxification, growth and development were particularly common within the
recently duplicated segments
Genes involved in signaling and related cellular processes tend to be
commonly found as duplicates in various eukaryotes, whereas genes with
poorly characterized functions are much more likely to be present in only
one copy.
It is important to note that it is not only the type of gene that can be influence
the preponderance of duplication, but also the species in which a given gene
family finds itself.
NEOFUNCTIONALIZATION
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The number of examples of the evolution of new, potentially adaptive
functions in duplicated genes is still quite small.
An interesting example of neofunctionalization is the duplication of the
ribonuclease (RNAse1) gene in a leaf-eating colobine monkey (CM). CMs
eat leaves, which are fermented in their foregut, which, when digested,
serve as a source of nutrition. CMs have two RNAse1 genes; RNAse1a,
which digests double-stranded RNA, and RNAse1b, which has
undergone several radical amino acid substitutions that appear to allow it
to digest bacterial RNA in the acidic foregut.
In this sense, duplication and divergence of RNAse1 genes can be taken
to represent an adaptation of these monkeys to a new nutritional niche.
Another striking example from primates involves the evolution of
trichromatic (tree-color) vision (SW, MW and LW opsin gene).
SUBFUNCTIONALIZATION
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In 1999, Force at al. introduced the “duplication-degenerationcomplementation” (DDC) model.
In this model, degenerative mutations in regulatory elements
controlling the expression of two duplicated genes lead to
complementary expression patterns.
As a hypothetical example, if the original gene was expressed in
both arms and legs, the degeneration of the elements controlling
arm expression in one duplicate and the complementary
degeneration of the elements controlling leg expression in the other
would lead to a partitioning of gene functions between duplicates.
REVERSION
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In 1972, Koch proposed a multistep model of enzyme evolution
involving gene duplication.
According to this model, the evolutionary improvement of
enzymatic function by 0ne-step-at-a-time substitutions reaches a
plateau, and than only very rare multiple simultaneous mutations
or locus duplication can improve enzyme function.
Koch model posits that if evolution takes the duplication route, at
some point in the future the advantage of having two genes for
one enzyme will diminish.
Than one copy is free to experience nonselective mutational
changes.
Reversion occurs, when duplicate is revived, i.e., codes for a
better enzyme, which will take over in the population.
HOX GENE DUPLICATION
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Homeobox genes encode transcription factors that regulate the
expression of a diversity of genes early in development.
Mutations in some of these genes lead to so-called “homeotic
transformations’, in which one body structure is replaced by another.
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In vertebrates these genes are called Hox genes, and typically occur
in one or more clusters of up to 13 genes.
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Hox genes are expressed in different regions of the developing
embryo.
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The order of genes within the clusters reflects their order of
expression along the interior to posterior axis.
HOX GENE DUPLICATION
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The evolution of these clusters has been driven by a complex history
of duplication and divergence that has now been characterized
through phylogenetic analyses.
Analyses suggest that tandem duplication of protoHox gene
produced a four-gene cluster and that this entire cluster was
duplicated producing a four-gene Hox cluster and, on a different
chromosome, a four-gene ParaHox cluster.
The observation, that Amphioxus possesses one Hox gene cluster,
whereas amphibians, reptiles, birds, and mammals have four, is
consistent with the hypothesis that there were two whole-genome
duplication events early in vertebrate evolution.
IMPORTANCE OF GENE DUPLICATION
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It is becoming apparent that duplications arise at a rapid rate and that
many gene duplicates are retained.
Very important genes related to physiology, immunity and development
exist as families of duplicates.
Gene family expansion is an ongoing phenomenon and involves a great
diversity of mutations.
Vertebrates have more Hox genes than invertebrates.
Gene duplication is a common occurrence, that the rate of duplication
varies among species.
Whether or not a duplicate is retained depends on its function, its mode
of duplication, the species in which it occurs, and its expression rate.
Duplication leads to an increase in evolutionary rate in some cases but
not in others.
Change in mutation rate might not be correlated with functional
divergence.