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	==Objective==		==Objective==
	* Developed a model that detects loss of constraint on individual transcription factor binding sites (TFBs)		* Developed a model that detects loss of constraint on individual transcription factor binding sites (TFBs)

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Raj at 19:20, 3 January 2010

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==Objective==
* Developed a model that detects loss of constraint on individual transcription factor binding sites (TFBs)
* Found that loss of functional constraint in TFBs in 3 Yeast species according to the lineages
* There is also a case of high Gain in binding sites.
* Conclude that cis-regulatory functional binding sites are NOT CONSERVED
* And that contributes to species specific gene expression
==Introduction==
* Change in cis-regulatory sequences is most common
* Mostly characterized by insertion/deletion of repeats, transposable elements
* Even if the gene expression is conserved phenotypically, the TFBs are not conserved, meaning that there is a complex relationship between divergence in sequence and divergence in its function
* Investigating individual TFBs are necessary to understand the evolution.
* To compute the loss or gain of TFBs,
** the model should assume the sequence specific variation that have no effect on function or fitness
** Combining Models for natural evolution and models for conserved binding sites can estimate the gain or loss of TFBs (eg: in Drosophila)
** A phylogenetic approach can also be used to identify the loss of functional TFBs.
* Here, phylogenetic approach is used in 4 species of Yeast (Saccharomyces species)
** All the 4 species provide sufficient signal to identify individual binding sites
** Found that 44/91 different transcription factors are NOT conserved across species and in some cases they affect the genome regulation
==Results==
# Model to identify semi-conserved TFBs
## Usually the semi-conserved model is identified by their patterns of substitution rate
## By combining neutral + conserved + semi conserved = semi-conserved sites can be identified.
## Statistics are:
### substitution rate
### substitution rate -> strength of selection
### synonymous substitution rate -> neutral substitution rate
# Frequency of semi-conserved binding sites in 4 genome
## Aligned the sequence -> used 91 TFBs models -> for 2000 positions
### 55% -> best explained by Conserved model
### 31% -> best explained by Semi-conserved model
### 14% -> best explained by Neutral model
### Plots showing the frequency of conserved/semi-conserved binding sites
#Characterization of semi-conserved sites
## In principle, conserved, semi-conserved sites => is basically sites with high and low binding energy
## Graph illustrating conserved binding sites have higher binding energy
<pre>How do you measure the binding energy for each binding site computationaly?</pre>
# Evolution of semi-conserved sites
## Lineage specific loss is due to:
### species experience new environment
### Gain in more than one redundant binding sites within a promoter enables loss of previously constrained binding site
## Table1 shows the substitution rates in conserved/semi-conserved sites
### In comparison, species-specific sites are present within 50% of the promoters with conserved sites
### species-specific sites are present within 47% of the promoters with semi-conserved sites
## Rate of turnover is different for species
### 50% of sites show turnover in S. cervisiae
### 55% of sites show turnover in S. paradoxus
### 60% of sites show turnover in S. mikatae
## similarly the loss of sites are also different for each species
# Substitutions due to site loss cause change in expression
# Limited conservation of Experimentally identified TFBs
## Substantial fraction of experimentally identified binding sites appear to be specific or weakly conserved across species, suggesting that binding site gain may be common
#Conclusion:
## Provide an efficient method to identify loss of constraint on a putative binding site sequence
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[[Category:Readings]]

Gain and Loss of Functional TFBs - Revision history

Raj at 08:41, 23 June 2016

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Raj at 19:20, 3 January 2010