Part III of the molecular biology review

This is the first draft of the final section of the review, after the survey of how competence is regulated in different bacteria.

How should the following ideas/issues be organized?First summarize the results of the survey (great diversity in regulatory mechanism, diversity in signals, core set of induced genes plus wide diversity of other induced genes, nutritional component.

Regulatory information is available for only a few species.  Where we do have information for close relatives we usually see differences, and at greater evolutionary distances the regulatory mechanisms appear unrelated. Are these generalizations justified (generalization that we usually can't generalize!)?

Make the distinction between the signal-transduction mechanism and the signals themselves, and between these and the output (the changed phenotype and its consequences for survival and growth).

Does the current knowledge of how competence is regulated suggest better ways of inducing competence in lab cultures?  The standard 'competence rituals' for the model organisms were developed by trial and error, long before we understood their regulation.  Are they unnecessarily troublesome?  Can new methods increase transformation efficiencies/frequencies?

Does this knowledge suggest ways of inducing competence in bacteria where it is apparently unregulated (Neisseria sp.), or where little is known about regulation (Helicobacter?)?  Look at this in phylogenetic context?  Or is regulation so evolutionarily variable that even comparisons within families are not very predictive?

Does it suggest better ways of testing for competence in bacteria not known to be transformable? For example, does the regulation by cAMP and CRP in the Past, Ent (?) and Vib families suggest that induction/stimulation by cAMP should be checked in other members of the gammaproteobacteria?

What do we learn from the breadth of 'competence' regulons?  Are there any consistencies in the genes that don't directly contribute to DNA uptake or transformation?  Do competence regulons overlap with other global regulons?  How many species do we have microarray (or other) surveys of what genes are regulated?  (Not only H. influenzae, B. subtilis, S. pneumoniae, right?)

Do genes that enhance transformation but don't contribute to uptake have specific other functions?

What can we conclude about how the regulation has evolved?  Which features of regulation have been conserved in related species?  Which have been particularly labile?

How is competence likely to be regulated in the natural environment(s) of the species?

What would be the biological/evolutionary significance of competence under these natural conditions?  (How would it enhance survival or reproduction?)

Given this diversity, are there any unifying features of the regulation of competence?  Is there always a nutrient component?  A 'stress' component?

Difficulty of drawing a line between nutrient signals and 'stress' signals?. Some signals are clear - PTS sugars, but even cAMP has subtle complications.  Same for phosphate and nitrogen limitation?  Signals of nucleotide depletion?  Purine syn regulated by guanine and hypoxanthine, pyrimidine by post-transcrptional effects (?), other effects on transcription likely.  Secreted autoinducers ('quorum sensing') integrate both local cell density and the physical properties of the microenvironment, such that may be activated by dense populations in well mixed cultures or by single cells in confined spaces. And we use 'stress' very loosely, rarely well enough defined that ideas about it can be rigorously tested. 

Here's a paragraph about the relationship between regulation and evolutionary function:  If uptake is selected because incoming DNA provides templates for DNA repair, competence should be regulated by the same damage signals that induce recA, or that induce the RecA-regulated SOS response.  If uptake is selected because incoming DNA provides nucleotides and other nutrients, competence should be regulated by nucleotide pools and/or by processes that sense availability of sources of C, N and P.  If uptake is selected because incoming DNA sometimes carries beneficial new alleles that replace 'inferior' alleles in the chromosome by recombination, then competence should be regulated by ... what? ... I've suggested that under this selection competence might be expected to be a 'when all else fails' response, induced when the cell's other stress responses have been mobilized but have failed to solve the problem.  How strictly this test (what test? the test of the other stress responses?) is applied would probably depend on how costly DNA uptake and recombination were, considering both the physiological costs/risks of DNA uptake and the genetic costs of recombining in alleles that reduce fitness.