From: colby@bu-bio.bu.edu (Chris Colby)
Newsgroups: talk.origins
Subject: proposed mechanisms of directed mutagenesis
Date: 28 Jan 93 01:39:33 GMT
Organization: animal -- coelomate -- deuterostome

In article <1993Jan27.110100@IASTATE.EDU> danwell@IASTATE.EDU (Daniel A Ashlock) writes:

Dan asks some questions about directed mutagenesis (adaptive mutations):

>#1
>   Is there room for redundancy that does not use the same coding?

I'm not sure what you mean here.

>#1a (muy stupido variant)
>   Are all the copies of the wild genes modified?  If not that would be a 
>great place to ge the information from.

Bacteria only have one copy of each gene. Their genome isn't large 
enough to carry "spare copies" of genes around. Eukaryotes (like
yeast) have enough room but this mechanism is doubtful.

>#2
>   As I recall derected mutagenisis is triggered (in at least one example)
>by starving the organism.  Does a hungry bacteria start splicing the part
>of it's genome that code from food utilization enzymes as a response to the
>stress until the stress goes away? 

I'm not sure what this means, either. 

>#3
>   Chris, what ARE the leading proposed mechanisms anyway?  I mean the ones
>that won't cost you your fingernails to explain via keyboard.

Here's an overview of the proposed mechanisms and my assessment of them.

1.) *Selective conditions instruct the cell to repair the gene.*
If a mutant mRNA strand produces a protein that would
result in a fitness benefit to the organism, the mRNA could
be reverse transcribed into DNA. Strictly for the birds.

2.) *"Bad" genes that are needed are turned on by the cell and
transcribed over and over - transcription itself is mutagenic
so eventually the right mutation appears*
Transcription is slightly mutagenic, but the effect is orders
of magnitudes too small to explain the results of the experiments.
Nice idea... but it's wrong.

3.) *Errors in DNA occur continually but, in the absence of selection,
they are repaired* 
This way, mutation seems to be directed because "undirected" mutations
get fixed. DNA is double stranded so it could keep mutations on one 
strand for awhile, see if they are any good and, if not, correct the
error using the information from the other strand. Very nice idea, but
there is evidence against it from experiments with mutant strains of
bacteria that have their repair pathways knocked out.

4.) *The hypermutable state*
Cells under starvation will sit things out until the picture really
looks bleak for them, then mutate (randomly) the hell out of their
DNA on the off chance off hitting the jackpot (getting the right
mutation). Cells that don't get the right mutation die, cells that
do live. Directed mutation is just an artifact because scientists
never see all the mutations that didn't make it, only those that did.

This predicts however that, among cells that did make it, there should
be numerous other mutations. At first it seemed this was the case
but later investigations did not bear this out. Hall (who proposed
this model) torpedoed it himself in one of his papers. He took a
gene that needed two mutations to revert to wild type and sequenced the
revertants -- the only mutations he found were the "needed" ones!
An absolutely beautiful and elegant idea... but wrong.

5.) *Cells routinely duplicate small portions of their genome.
These duplications have many mutations. If they produce a protein that
leads to higher fitness they are retained and the old region they
are duplicated from is scrapped. If not, they eventually get scrapped*
Foster and Cairns favor this, but I think Hall's data rules it
out. Nice idea (very similar to the slow repair model), but I
don't think so.

All these assume that directed mutagenesis really occurs. Some
doubt this (they're out of their minds 8-). See the Science
article I cited in my previous post for their (mind numbingly
improbable and lame) interpretations.

See Foster and Cairns, 1992, Mechanisms of directed mutation,
Genetics 131: 783-789 for more detailed info on some of the
material above. 

>Eagerly awaiting Chris' report on that talk he mentioned...

I am _so_ psyched to hear this seminar. 

>Dan
>Danwell@IASTATE.EDU

Chris Colby 	---	 email: colby@bu-bio.bu.edu	---
"'My boy,' he said, 'you are descended from a long line of determined,
resourceful, microscopic tadpoles--champions every one.'"
 	--Kurt Vonnegut from "Galapagos"