Field of Science

Wait, there's a much simpler explanation! (For CRISPR-Cas, not for GTA)

I'm in Halifax for a couple of weeks, visiting Ford Doolittle and his philosophical colleagues,  We've spent much of the time considering the extent to which CRISPR-Cas systems can or should be considered 'Lamarckian'.  I started with the simplistic perspective that of course it is, because an acquired character (immunity to future phage or plasmid infection) becomes inherited because the Cas proteins insert short phage- or plasmid-derived DNA sequences as a CRISPR 'spacer' into the chromosome.

Here's a very detailed diagram I made of the evolutionary events (mutation and selection) affecting CRISPR-Cas systems (click to embiggen):

We ended up concluding that 'directed mutation' was a better perspective.

But, once our ideas started settling down, this detailed diagram got me thinking about how uncertain and far in the future the 'immunity to future infection' benefit is.  That's a problem for CRISPR-Cas evolution, since this uncertainty greatly weakens the selection maintaining and refining the system.  Iv selection is too weak, the system shouldn't be maintained at all.

A more urgent problem is that the cell needs to survive the immediate infection/invasion before it has any chance of benefiting from the long-term immunity.  This becomes especially important if the bias against potentially-lethal self-spacers arises because the cell contains many copies of the invader genome.

But the cell does have a very nice mechanism to clear the invader, because it has just created an invader-specific spacer in its CRISPR array.  Transcribing this new spacer would give it many copies of an invader-specific crRNA with which Cas9 can destroy all the copies of the invader genome.

So here's my new hypothesis:
The primary function of CRISPR-Cas systems is the detection and immediate destruction of phage and /or plasmid DNA.  Benefits from immunity to future infection are relatively unimportant. 
Things I need to find out:

 Is this a new idea?  I don't remember seeing it anywhere, but if any reader knows of a prior proposal please let me know in the comments or via Twitter (@rosieredfield).

Is relevant data available?  The basic experiment is, in principle at least, quite simple.  Do cells with an intact CRISPR-Cas system survive phage infection better than cells with a defective system?  Do they become transformed less efficiently by plasmids?  These tests would be most sensitively done under sub-optimal infection conditions.

How is transcription of the Cas genes and CRISPR array regulated?  In particular, how efficiently is the CRISPR array transcribed and processed immediately after a new spacer has been added?  In the context of my GTA-as-CRISPR-vaccine ideas (see this post from a few months ago) I'd been looking for reports that new CRISPR spacers can be immediately transcribed, creating crRNAs that can immediately attack the original invader.  I didn't find any solid data, but neither did I find anything that ruled this out. 

No comments:

Post a Comment

Markup Key:
- <b>bold</b> = bold
- <i>italic</i> = italic
- <a href="">FoS</a> = FoS