29/3/2022: Evolution and Development: Lecture 7: Cis and Trans regulatory evolution
2 types of regulatory evolution:
- Trans regulation: the regulation of a gene by proteins such as transcription factors. The
evolution of the protein sequence of transcription factors influences the set of genes to
which they bind.
- Cis regulation: The regulation of a gene by its adjacent to the gene, these are
regulatory regions such as transcription factor binding sites, enhancers, etc. The
evolution of the nucleotide sequence of transcription factor binding sites influences the
set of transcription factors to which they bind.
Cis: directly active on the gene itself.
Trans: act on the gene, but is mediated by proteins that are established by different genes
Which regulation is most important? → it is generally held that cis-regulatory evolution is most
important for evolution:
- Coding differences between species are rare (i.e. 96% identity between humans and
chimps)
- Most mutations are neutral (or nearly neutral)
- Transcription factors between diverse species are functionally equivalent (i.e. mouse
eyeless hox gene can trigger eye development in fruit fly after 800 million years of
divergence, and vice versa)
Because of this, we would think that cis-regulation is most powerful.
Mechanism:
- Cis-regulatory regions have to activate or suppress binding sites for many different
transcription factors that allow the expression of the gene to be finely matched to specific
tissues and times in development.
- Consequence: Gain or loss of enhancer regions will thus only affect the expression of a
gene in specific tissues or times but not globally – it will still be expressed appropriately
elsewhere in the body.
- This contrasts with the evolution of transcription factors themselves (trans-regulatory
evolution) in which the effect of the TF will be modified globally throughout the body.
Proteins do not change → hox genes are the same in every animal → expression is different →
therefore it results in different phenotypes.
As different transcription factors binding sites (A5/A6) get lost, different phenotypes occur.
The Colour pattern of the abdomen in fruitflies → different transcription factors result in no color
or dark color → results in different patterns.
Cis regulation evolution can make use of existing genetic components to generate novelty.
These components have a spatial and temporal expression of transcription factors. (?)
, Top: The expression pattern of nine transcription factors in the
developing wing. These are not “pigmentation control genes”.
Many of them are highly conserved elements of the arthropod
body plan, i.e. in green is “engrailed” a hox gene specifying the
anterior/posterior axis in the wing.
Middle: By gaining/losing binding sites for transcription factors
that already set up a conserved “regulatory landscape” across
Drosophila species, pigmentation proteins can come to be
regulated in different parts of the wing
Bottom: end result, divergent pigmentation patterns
The orange color pattern is formed by combining red and green
landscape → green is blocking red → results in orange form → therefore the black dot can be
formed on the wing of the fruit fly.
Since there are 9 different transcription factors, many possible wing colorations are due to
cis-regulatory evolution.
The idea is that transcription factors change and can accumulate over time → resulting in
large-scale differentiations to the body plan.
What is the mechanism for the gain of cis-regulatory elements across several different genes all
involved in the same basic pathway or functional cluster of genes?
Trans regulatory evolution:
The conservation of transcription factors function may have been exaggerated. We saw some
examples in which the function of transcription factors varies across different species.
Changes in protein structure are commonly observed due to natural selection T
The cis model of regulatory evolution ignores the fact that transcription factors do not
necessarily have to bind directly to DNA binding sites in order to influence gene expression –
co-regulators operate through protein-protein interaction (PPI).
The evolutionary model:
We start with transcription factor A → regulates a set of genes (TG-1, TG-2, and TG-3 → when
there is a mutation in protein B that is not involved in the transcription → if it yields higher
fitness, evolution will tend to fix B into the transcription of DNA so that B works as a transcription
factor → protein-protein interactions between A and B → evolve together.
This allows B to become a regulator of the target genes in a modular manner. This means that
tissues / developmental time windows are already regulated by A rather than in a haphazard
way. This could potentially allow the complete replacement of A by B for a set of genes another
reason why trans-regulatory change may be more meanable for evolution.
2 types of regulatory evolution:
- Trans regulation: the regulation of a gene by proteins such as transcription factors. The
evolution of the protein sequence of transcription factors influences the set of genes to
which they bind.
- Cis regulation: The regulation of a gene by its adjacent to the gene, these are
regulatory regions such as transcription factor binding sites, enhancers, etc. The
evolution of the nucleotide sequence of transcription factor binding sites influences the
set of transcription factors to which they bind.
Cis: directly active on the gene itself.
Trans: act on the gene, but is mediated by proteins that are established by different genes
Which regulation is most important? → it is generally held that cis-regulatory evolution is most
important for evolution:
- Coding differences between species are rare (i.e. 96% identity between humans and
chimps)
- Most mutations are neutral (or nearly neutral)
- Transcription factors between diverse species are functionally equivalent (i.e. mouse
eyeless hox gene can trigger eye development in fruit fly after 800 million years of
divergence, and vice versa)
Because of this, we would think that cis-regulation is most powerful.
Mechanism:
- Cis-regulatory regions have to activate or suppress binding sites for many different
transcription factors that allow the expression of the gene to be finely matched to specific
tissues and times in development.
- Consequence: Gain or loss of enhancer regions will thus only affect the expression of a
gene in specific tissues or times but not globally – it will still be expressed appropriately
elsewhere in the body.
- This contrasts with the evolution of transcription factors themselves (trans-regulatory
evolution) in which the effect of the TF will be modified globally throughout the body.
Proteins do not change → hox genes are the same in every animal → expression is different →
therefore it results in different phenotypes.
As different transcription factors binding sites (A5/A6) get lost, different phenotypes occur.
The Colour pattern of the abdomen in fruitflies → different transcription factors result in no color
or dark color → results in different patterns.
Cis regulation evolution can make use of existing genetic components to generate novelty.
These components have a spatial and temporal expression of transcription factors. (?)
, Top: The expression pattern of nine transcription factors in the
developing wing. These are not “pigmentation control genes”.
Many of them are highly conserved elements of the arthropod
body plan, i.e. in green is “engrailed” a hox gene specifying the
anterior/posterior axis in the wing.
Middle: By gaining/losing binding sites for transcription factors
that already set up a conserved “regulatory landscape” across
Drosophila species, pigmentation proteins can come to be
regulated in different parts of the wing
Bottom: end result, divergent pigmentation patterns
The orange color pattern is formed by combining red and green
landscape → green is blocking red → results in orange form → therefore the black dot can be
formed on the wing of the fruit fly.
Since there are 9 different transcription factors, many possible wing colorations are due to
cis-regulatory evolution.
The idea is that transcription factors change and can accumulate over time → resulting in
large-scale differentiations to the body plan.
What is the mechanism for the gain of cis-regulatory elements across several different genes all
involved in the same basic pathway or functional cluster of genes?
Trans regulatory evolution:
The conservation of transcription factors function may have been exaggerated. We saw some
examples in which the function of transcription factors varies across different species.
Changes in protein structure are commonly observed due to natural selection T
The cis model of regulatory evolution ignores the fact that transcription factors do not
necessarily have to bind directly to DNA binding sites in order to influence gene expression –
co-regulators operate through protein-protein interaction (PPI).
The evolutionary model:
We start with transcription factor A → regulates a set of genes (TG-1, TG-2, and TG-3 → when
there is a mutation in protein B that is not involved in the transcription → if it yields higher
fitness, evolution will tend to fix B into the transcription of DNA so that B works as a transcription
factor → protein-protein interactions between A and B → evolve together.
This allows B to become a regulator of the target genes in a modular manner. This means that
tissues / developmental time windows are already regulated by A rather than in a haphazard
way. This could potentially allow the complete replacement of A by B for a set of genes another
reason why trans-regulatory change may be more meanable for evolution.
