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1. Book club
Andreas Wagner,
The Origins of Evolutionary Innovations
Chapter 3
Book club presented by G. M. Dall'Olio,
Pompeu Fabra, IBE-CEXS

2. Reminder:
Genotype network
 A genotype network is a set of genotypes that have the same
phenotype, and are connected by single pairwise differences
AAAAA AAAAC AAAAG AAAAT AAATT
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

3. 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

4. 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

5. 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)

6. Genotype Space of
Regulatory Circuits
 Each cell corresponds to a regulatory circuit matrix
00000 01000 01000 01000 01000
00000 00000 00100 00100 00100
00000 00000 00000 00010 00010
00000 00000 00000 00000 00001
00000 00000 00000 00000 00000
10000 11000 11000 11000 11000
00000 00000 00100 00100 00100
00000 00000 00000 00010 00010
00000 00000 00000 00000 00001
00000 00000 00000 00000 00000
10000 11000 11000 11000 11000
01000 01000 01100 01100 01100
00000 00000 00000 00010 00010
00000 00000 00000 00000 00001
00000 00000 00000 00000 00000

7. 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)

8. Regulatory innovations,
definitions (2)
 Et is the list of expression status of each gene at a
time t:
 Et = (Egene1(t), Egene2(t), Egene3(t), Egene4(t), Egene5(t))
 Phenotype: the expression state E∞ at equilibrium

9. Genotype Networks in
Regulatory networks
 Yellow cells have the same phenotype:
 E∞ = (Egene1(t=∞), Egene2(t=∞), Egene3(t=∞), Egene4(t=∞), Egene5(t=∞))
 We can make some observations without knowing the identity of the genes.
00000 01000 01000 01000 01000
00000 00000 00100 00100 00100
00000 00000 00000 00010 00010
00000 00000 00000 00000 00001
00000 00000 00000 00000 00000
10000 11000 11000 11000 11000
00000 00000 00100 00100 00100
00000 00000 00000 00010 00010
00000 00000 00000 00000 00001
00000 00000 00000 00000 00000
10000 11000 11000 11000 11000
01000 01000 01100 01100 01100
00000 00000 00000 00010 00010
00000 00000 00000 00000 00001
00000 00000 00000 00000 00000

10. 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

11. 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 paradigm
revisited. EMBO Rep. 2006 May;7(5):496-9. Review. PubMed PMID: 16670683;
PubMed
Central PMCID: PMC1479557

12. 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

13. 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

14. 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

15. 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; PubMed
Central PMCID: PMC2666274.

16. 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 Dec
3;462(7273):587-94. Review. PubMed PMID: 19956253.

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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