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1 How do regulatory networks evolve? Module = group of genes co-regulated by the same regulatory system * Evolution of individual gene targets Gain or.

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Presentation on theme: "1 How do regulatory networks evolve? Module = group of genes co-regulated by the same regulatory system * Evolution of individual gene targets Gain or."— Presentation transcript:

1 1 How do regulatory networks evolve? Module = group of genes co-regulated by the same regulatory system * Evolution of individual gene targets Gain or loss of genes from a module * Evolution of activating signals Change in responsiveness but not regulators * Wholesale evolution of the entire module Transcription factor sites occur upstream of totally different genes, responding to totally different signals

2 2 How do regulatory networks evolve? Short time-scales: gene target turnover (gain and loss) Time

3 3 ChIP-chip of two cooperatively-acting TFs in 3 species (S. cerevisiae, S. mikatae, S. bayanus ~20 my diverged) Tec1Ste12 Pseudohyphal growth Genes Mating genes (haploid cells only) Science 2007

4 4 Scer Smik Sbay Ste12 Tec1 380167250 348185126 21% bound in all 3 species 20% bound in all 3 species Only ~20% of orthologous regions bound in all 3 species

5 5 * non-S. cer but otherwise conserved binding: enriched for Mating Genes

6 6 Only 20% of bound fragments conserved over 20 my (75% of these have underlying binding sites conserved) Tec1Ste12 Borneman et al. Science 2007 Substantial ‘rewiring’ of transcriptional circuits: * Gain and loss of individual gene targets * S.cer evolution of the module of mating genes How common will these trends be? Different trends for different functional processes?

7 7 Science April 2010 PLoS Biol. April 2010 ChIP-seq (NF  B and RNA-Pol II) and RNA-seq in 10 humans from 3 different populations Lots of variation (up to 25% variation in binding levels) ChIP-chip’d Ste12 in 43 S. cerevisiae segregants Nature. March 2010 ChIP-chip of 6 developmental TFs in D. mel vs. D. yakuba (5 my) * only 1-5% of genes are variable targets (gene target turnover) * lots of evidence of TF binding site turnover within CONSERVED target regions Cell. March 2013 40% mouse TF binding sites conserved over < 6my 10-22% of TF binding is conserved in mammals (diverged ~80 my) Science. 2010

8 8 How do regulatory networks evolve? Short time-scales: gene target turnover (gain and loss) Time Evolved Responsiveness Cooption of existing network

9 9 Ancestral GAL control likely by Cph1 … S. cerevisiae lineage picked up Gal4 and Mig1 sites upstream of GAL genes

10 10 In addition to changes in upstream cis-elements … Major changes in the Gal4 transcription factor & upstream along S. cerevisiae lineage: * Gained a domain that interacts with the Galactose-responsive Gal80 protein * Other changes in the upstream response (Gal1-Gal3 duplication) contributed to sensitized pathway

11 11 How do regulatory networks evolve? Short time-scales: gene target turnover (gain and loss) Time Evolved Responsiveness

12 12 How do regulatory networks evolve? Sub/neo-functionalization through TF duplication & divergence Time TF duplication Evolved TF sensitivity, binding specificity, and ultimately targets Gene targets can also duplicate (especially in WGD)

13 13 Example: Arg80 and Mcm1 duplication Tuch et al. 2008. PLoS Biol. Mcm1 is a co-factor that works with many different site-specific TFs Tuch. et al. performed ChIP-chip on Mcm1 orthologs in multiple fungi. * Found dramatic differences in inferred Mcm1-TF interactions and modules One case in particular: Arginine biosynthesis genes Mcm1 + Arg81 at arg genes is ancestral Duplication of Mcm1 (Arg80) at WGD Loss of Mcm1 binding at arg genes Presumably taken over by Arg80 Time (>150 my)

14 14 How do regulatory networks evolve? If co-regulation is so important, then how can tolerate many independent changes in upstream cis-elements? Conundrum: Clearest cases of regulatory switches are often for highly co-regulated genes, whose co-regulation is high conserved.

15 15 Here they ChIP’d 6 TFs implicated in RP regulation in S. cerevisiae and/or C. albicans Ifh1-Fhl1 co-activators are conserved in Sc-Ca (>200 my) Required co-factors have evolved: Hmo1 and Rap1 required for Ifh1-Fhl1 binding in S. cerevisiae * Hmo1 is a ‘generalist’ in C. albicans In C. albicans, Cbf1 (generalist) and Tbf1 (specialist) are required for Ifh1-Fhl1 binding

16 16 * They propose that ‘generalist’ factors can readily ‘specialize’ to regulate a specific module

17 * Species-specific connection of regulons: selection for alternate co-regulation Figure 6

18 18 * They propose that ‘generalist’ factors can readily ‘specialize’ to regulate a specific module * Species-specific connection of regulons: selection for alternate co-regulation * Co-evolution of binding sites AND interactions of regulators * They propose cycles of neutral accumulation of mutations (and binding sites) followed by deleterious mutation that is rapidly ‘corrected’ to rebalance co- regulation

19 19 They raise the question: Is wholesale rewiring common to all modules Or facilitated by very strong pressures to keep genes co-regulated?


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