Re: AGING: Accumulation of DNA damage

From: Robert J. Bradbury (
Date: Sat Jul 15 2000 - 07:53:53 MDT

On Fri, 14 Jul 2000, phil osborn wrote:

> >From: "Joao Pedro de Magalhaes" <>

> >One thing that has always troubled me is: if non-coding regions are so easy
> >to mutate and lose, how come they exist in such large amounts? I don't
> >recall in detail my classes on the subject but I don't remember studying
> >DNA repair mechanisms specific of coding regions. Perhaps they exist but,
> >until further evidence, I cannot accept them.

>From "DNA Repair & Mutagenesis", E. C. Freidberg et al, 1995, pg 216:
 "Studies first carried out with mammalian cells demonstrated that
  nucleotide excision repair of DNA occurs preferentially in actively
  transcribed genes (see Chapters 7 & 8). A similar phenomenon has
  been demonstrated in E. Coli, for which it has been shown that in
  actively transcribed DNA nucelotide excision repair has a pronounced
  bias for the transcribed strand."

It goes on to discuss the involvement of the UVR proteins and the
"Transcription-repair coupling factor" (mfd gene).

Non-coding regions are easy to mutate, but difficult to lose.
There is little selective pressure to minimize your DNA (I once
thought there might be in birds, because their genomes are smaller
and decreased weight could be a survival promoting factor, but
the mass of the DNA in a body is so small, I am now doubtful
that it could contribute very much). Though in writing this,
I could see an advantage to decreased DNA if you had to develop
faster (less copying of unrequired DNA means cell division can
proceed more quickly).

The reason I think, that there are so many non-coding regions,
is because of the selective advantage (to the genes) for taking
preexisting "working protein fragments" and inserting them
into other genes. This is the work of the retrotransposons
and is why we have so much junk DNA -- it speeds up the
acceleration of evolution significantly beyond what simple
mutations of individual bases will do. There are many
examples of junk DNA and non-working pseudo-genes that
show that species can tolerate a very sloppy job of editing.
On the other hand I only know of at most 4 examples where
cutting and splicing DNA may be very accurate:
(VDJ recombination in immune cells, the CRE/LOX genes
in yeast, perhaps the activation of individual smell
receptor proteins in individual neurons and maybe
the insertion of adeno-associated virus). This is
separate from the mechanism of homologous recombination
that always trys to put things back together in their
original form. In short, random jumping DNA is easy
while specific splicing of DNA seems pretty difficult.

> Just a thought.. Suppose the introns, etc. are used for identification
> purposes? Like a fingerprint. I wonder if they could figure into viral
> defense?

I doubt it. I think the introns are just the leftovers
of the evolutionary process. Nature doesn't care much
for how much it has to throw away, so long as it gets
better results in the end. As a result the work is
pretty sloppy.

Paraphrasing Venter, "In looking at the genome, you can tell
it wasn't designed by a human" (when asked whether he believed
in God).


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