wagner chapter 3
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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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ACCCA ACCCC ACCCG ACCCT …..
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….. ….. ….. ….. …..
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