1. Microbial response to changing environments

2. Changes in physiology Inherited reversible changes

3. Changes in physiology Signaling systems Two-component systems: paradigm model Often transcription Variations on this theme methyl-accepting chemotaxis proteins, di-guanylate and adenylate cyclases, and serine/threonine/tyrosine protein kinases

4. Rapid diversification Large expansions of a relatively small number of signaling families Each bacterial genome contains two-component signaling systems, some have up to 200 systems

5. The total number of encoded signal transducers proteins grows with genome size. Genome size often correlates with lifestyle: Large genomes and lots of signaling proteins associated with free-living lifestyle, Small genomes and few signaling proteins associated with obligate parasitic lifestyle Bacterial “IQ” = fraction of proteins involved in signaling = highest is environmental gram negative bacteria

6. Extroverts vs Introverts

7. How do new signaling pathways arise? Horizontal gene tranfser correlates with conserved function Lineage specific expansion involves new functions

8. Eukaryotes don’t often use two-component systems Similar ligand binding domains eg PAS, GAF and cyclic nucleotide binding domains More phosphorylation sites Similar architecture in network design

9. How to get specificity in the pathways? Spatial - Scaffolds and subcellular localization Temporal - Differential timing of expressing Molecular discrimination – Skerker et al Caulobacter crescentus

10. Inherited reversible changes Phase variation Repeats (polynucleotide or large duplications) Plasmid copy number DNA methylation Histone acetylation Regulatory circuits High rates of change Short term inheritance Discrete number of states Increased phenotypic variation In population Epigenetics – road to genetic changes? Epigenetic

11. Memory in regulatory circuits Off On [Lac] LacZ Induces not only activates LacZ but also substrate permease

12. Neiserria gonorrhea – phase variation in All of its surface antigens, especially the Pili proteins Hyper variable Analogous to the immune system Recombination between all different loci When does this occur? Selection to be different (evade the immune system)

13. Sporulation/ Competence – noisy circuits Changing environments – cost of being stochastic so ideally would match the the pace of the environment - taking a roll of the dice Excitable circuits - contain both fast positive and slow negative feedback loops

14. Exit from sporulation (germination) Signals Food (GTP, branched chain amino acids) What your neighbors are doing (Fragments of the cell wall released From other bacteria during division) Stochastic At what frequency? Gap between molecular biology and evolutionary biology

15. Persisters