The Robustness and Evolvability of Transcription Factor Binding Sites

Presented by,

Sandeep SatapathyBS-MS, 4th Year (10079)

• Gene expression is commonly modulated by a set of regulating gene products, which bind to a gene’s cis-regulatory region.

• an input-output function, referred to as signal-integration logic, that maps a specific combination of regulatory signals (inputs) to a particular gene expression state (output).

• It is not known how this degeneracy contributes to the mutational robustness of TF binding sites, nor to their evolvability, which is defined as the ability to bind different TFs after mutation.

• "If a system is robust, it will persist in the face of mutations. But if you actually want to be able to evolve, you need to be able to vary in response to mutations.

• Living things need robust genes; otherwise, any mutation could spell death.

• At the same time, a species needs to exploit mutations to evolve, adapt, and survive in a changing world.

Pioneer TFs binding is sufficient to enable change in chromatin structure to create a nucleosome-free region.

Pioneer transcription factors: establishing competence for gene expression

TF Binding Sites

• Transcription factor binding sites are typically between 6 and 10 nucleotides long.

• TF binding sites can be degenerate, with some TFs binding hundreds of different sequences, whereas others bind merely dozens.

Why Transcription Factor Binding Sites Are Ten Nucleotides Long???

• Inherent trade-off between specificity, which is greater in long binding sites

• robustness to mutation, which is greater in short binding sites.

• Do they represent cases in which cooperative regulatory interactions play a less important role in regulating gene expression levels

• or where transcription factor binding sites are rarely saturated?

• Robustness, the maintenance of a character in the presence of genetic change, can help preserve adaptive traits but also may hinder evolvability, the ability to bring forth novel adaptations.

• Of particular importance are mutations in the specific sequences that determine transcription factor (TF) binding sites and coordinate gene expression in both space and time.

the identity of the the affinity with which a site cognate TF bound

• This may, in turn, change the structure or logic of the transcriptional regulatory circuits in which these sites are embedded and lead to adaptations in the form of novel gene expression patterns.

evolutionary innovations

genotype-to-phenotype map

• A genotype network is a set of genotypes that have the same phenotype, where two genotypes are connected by an edge if they differ by a single mutation.

• Large genotype networks confer robustness because genetic perturbations are unlikely to drive a genotype off the network, and these networks confer evolvability because they extend throughout genotype space, providing mutational access to a diversity of genotypes that have different phenotypes.

Fig. 1. Genotype networks of TF binding sites

The mutational robustness and evolvability of TF binding sites.

Large genotype networks confer repertoire robustness and evolvability. Repertoire

The architecture of the gene regulatory networks of different tissues

Jie Li1,2, Xu Hua1. The architecture of the gene regulatory networks of different tissues . BIOINFORMATICS

Contributions to advanced genetics

“QUASI EVOLUTION”

Conclusion

• The mutational robustness of TF binding sites can be fine-tuned via mutation.

• number of point mutations with a regulatory effect can vary greatly among sites, and with comparative studies of binding site turnover in closely related species.

• Analysis of TF binding repertoires indicate that decreased TF specificity yields large connected genotype networks that confer robustness and evolvability to the binding sites they harbor.