wagner chapter 3

Book club

Andreas Wagner,The Origins of Evolutionary Innovations

Chapter 3

Book club presented by G. M. Dall'Olio, Pompeu Fabra, IBE-CEXS

Reminder:Genotype network

A genotype network is a set of genotypes that have the same phenotype, and are connected by single pairwise differences

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AAACA AAACC AAACG AAACT AAATC

AACCA AACCC AACCG AACCT …..

ACCCA ACCCC ACCCG ACCCT …..

CCCCA CCCCC CCCCG CCCCT …..

….. ….. ….. ….. …..

Yellow = same phenotype = a genotype network Note: genotype network == neutral network

Chapter 3:Regulatory Innovations

This chapter describes the evolution of regulation mediated by Transcription Factors binding sites

Regulation is much more difficult to study than metabolic networks

Regulatory innovations,definitions (1)

Genotype: a square matrix, called “Gene regulatory Circuit”

Describes the interactions between regulation factors

Ciliberti, S., Martin, O.C. & Wagner, a, 2007. Innovation and robustness in complex regulatory gene networks.PNAS, 104(34), pp.13591-6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1959426

Understanding Gene Circuits

Gene 1 (first column): activates Gene 2 and 

Gene 5 (orange) inhibits Gene 4 

(blue)

Ciliberti, S., Martin, O.C. & Wagner, a, 2007. Innovation and robustness in complex regulatory gene networks.PNAS, 104(34), pp.13591-6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1959426(image adapter for color blind people)

Genotype Space of Regulatory Circuits

Each cell corresponds to a regulatory circuit matrix 

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Neighbors of Regulatory Circuits

Each circuit differs for one reaction

Ciliberti, S., Martin, O.C. & Wagner, a, 2007. Innovation and robustness in complex regulatory gene networks.PNAS, 104(34), pp.13591-6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1959426(image adapter for color blind people)

Regulatory innovations,definitions (2)

Et is the list of expression status of each gene at a 

time t:

Et = (E

gene1(t), E

gene2(t), E

gene3(t), E

gene4(t), E

gene5(t))

Phenotype: the expression state E∞ at equilibrium

Genotype Networks in Regulatory networks

Yellow cells have the same phenotype:

E∞ = (E

gene1(t=∞), E

gene2(t=∞), E

gene3(t=∞), E

gene4(t=∞), E

gene5(t=∞))

We can make some observations without knowing the identity of the genes.0000000000000000000000000

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Dimensions of Genotype networks

Genotype networks of regulatory circuits can be very big

An organism can stand many changes to its regulatory network, without changing the phenotype

Galactose metabolism in Yeast and C.albicans

In Yeast, GAL4 initiates the transcription of  enzymes required for galactose metabolism

In C.albicans, GAL4 is associated to telomere and has unknown function

Traven A, Jelicic B, Sopta M. Yeast Gal4: a transcriptional paradigmrevisited. EMBO Rep. 2006 May;7(5):496-9. Review. PubMed PMID: 16670683; PubMedCentral PMCID: PMC1479557

Regulation of mating in Yeast and C.albicans

In yeast, the Cph1 homologue is involved in mating type determination (...)

In C.albicans, Cph1 is involved in galactose metabolism

Galactose metabolism in Yeast and C.albicans

The regulatory network for galactose metabolism has changed drammatically from S.cerevisiae to C.albicans

Figure from: Rokas A, & Hittinger CT (2007). Transcriptional rewiring: the proof is in the eating. Current biology : CB, 17 (16) PMID: 17714646

See also: Martchenko, M., Levitin, A., Hogues, H., Nantel, A., & Whiteway, M. (2007). Transcriptional Rewiring of Fungal Galactose-Metabolism Circuitry Current Biology, 17 (12), 1007-1013 DOI: 10.1016/j.cub.2007.05.017

Galactose metabolism in fungii

Figure from: Rokas A, & Hittinger CT (2007). Transcriptional rewiring: the proof is in the eating. Current biology : CB, 17 (16) PMID: 17714646

See also: Martchenko, M., Levitin, A., Hogues, H., Nantel, A., & Whiteway, M. (2007). Transcriptional Rewiring of Fungal Galactose-Metabolism Circuitry Current Biology, 17 (12), 1007-1013 DOI: 10.1016/j.cub.2007.05.017

Evolvability of Gene Networks

Authors introduced 600 new regulatory interactions in E.coli, and it tolerated 95% of them

Isalan M, Lemerle C, Michalodimitrakis K, Horn C, Beltrao P, Raineri E,Garriga-Canut M, Serrano L. Evolvability and hierarchy in rewired bacterial gene networks. Nature. 2008 Apr 17;452(7189):840-5. PubMed PMID: 18421347; PubMedCentral PMCID: PMC2666274.

Example: Stem Cells transformation

Changes of very few transcription factors can transform a cell into a stem cell, or another type

Graf T, Enver T. Forcing cells to change lineages. Nature. 2009 Dec3;462(7273):587-94. Review. PubMed PMID: 19956253.

Robustness to change is a requisite for innovations

Ciliberti, S., Martin, O.C. & Wagner, a, 2007. Innovation and robustness in complex regulatory gene networks.PNAS, 104(34), pp.13591-6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1959426

The number of phenotypes is much smaller than

the number of genotypes Number of genotypes: 3^(S^2), where S=number of 

genes Number of phenotypes: 2^(2*S) There are much more genotypes than phenotypes

Some phenotypes have more genotypes than others

[1]: A. Wagner, The Origins of Evolutionary Innovations. Figure 3.2

Ciliberti, S., Martin, O.C. & Wagner, a, 2007. Innovation and robustness in complex regulatory gene networks.PNAS, 104(34), pp.13591-6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1959426

Distance between circuits with the same phenotype

On average, two circuits from the same genotype network differ by about 80% of their reactions

Ciliberti, S., Martin, O.C. & Wagner, a, 2007. Innovation and robustness in complex regulatory gene networks.PNAS, 104(34), pp.13591-6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1959426

Phenotypes of neighbors

Neighbors of two genotypes in the same network are usually different

[1]: A. Wagner, The Origins of Evolutionary Innovations. Figure 3.6

[1]: A. Wagner, The Origins of Evolutionary Innovations. Figure 2.6

Distance between two genotype networks

On average, all the genotype networks are interwoven 

The distance to pass from a phenotype to another is usually shorter than the distance between two circuits in the same network

Ciliberti, S., Martin, O.C. & Wagner, a, 2007. Innovation and robustness in complex regulatory gene networks.PNAS, 104(34), pp.13591-6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1959426

Take Home messages

Genotype networks of regulatory circuits are large

Regulatory phenotypes are robust to changes (e.g. GAT4 in S.cerevisiae/C.albicans)

Many more genotypes than phenotypes

Ciliberti, S., Martin, O.C. & Wagner, a, 2007. Innovation and robustness in complex regulatory gene networks.PNAS, 104(34), pp.13591-6. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1959426