🚀 go-pugleaf

toms@kaylor.ncifcrf.gov (Tom Schneider) wrote:

>Ken Muldrew (kmuldrew@acs.ucalgary.ca) wrote:
>: toms@kaylor.ncifcrf.gov (Tom Schneider) wrote:
>: >Ken Muldrew (kmuldrew@acs.ucalgary.ca) wrote:

>: >I seem to recall that Schroedinger did some calculations about the target size
>: >of DNA for radiation.  The point is that you can't "hide" because if you
>: >increase the total genomic size, the important genes are still going to be hit
>: >at the same rate because they still present the same physical cross section to
>: >radiation.  Also, the polymerase won't make fewer mistakes in one place just
>: >because it (or an entirely different molecule) also has to function at another,
>: >as this may be mostly from thermal noise, which is [everywhere].  Further,
>: >increasing the size increases the likelyhood of generating binding sites that
>: >sop up proteins from where they are needed.  (The system can eventually evolve
>: >to get rid of many if not most, but the probability of them coming up randomly
>: >is increased.)  Finally, increased size increases the likelyhood of damage to
>: >the long fragile molecule.

>: OK, the coding region presents the same cross-section, no doubt about
>: that. I had an uneasy feeling when I was typing in that bit. I think
>: that what you typed here supports the idea that this DNA isn't simply
>: "junk"--a lot of energy goes into taking care of these long, fragile
>: molecules.

>So the mystery intensifies!  What is the function of the non-coding regions?

>: Just to give people an idea of how fragile DNA can be, a
>: [Caucasian] without sunscreen, standing in the noon-day sun of the
>: tropics, will suffer about 50 000 single strand breaks in every skin
>: cell that's exposed per hour (just about the maximal rate of repair,
>: coincidence?).

>Fascinating!

>Perhaps you have references you can share with us for both numbers?

Oh boy! I knew I was going to be pulled over sooner or later. Well,
the numbers come from a graduate course in Oncology that I took about
11 years ago, the lecturer being a chap named Paterson at the
University of Alberta. I'll take a look tonight to see if I still have
the course notes. A quick look in Kornberg (DNA Replication, 2nd ed.)
didn't reveal any numbers for SS breaks, but there is a number for
missing base mutations--about 10 000 purines and a few hundred
pyrimidines are lost in each cell per day (section 21-1). Anyone who
doesn't believe that DNA is fragile should take a flip through chapter
21, you'll soon be convinced.

>: Another purpose for introns may be to signal the DNA repair or
>: proof-reading enzymes to stop. I think that point mutations have
>: accrued in the hypervariable regions of immunoglobulin genes at a rate
>: that is higher than the replication error rate, implying that there is
>: a mechanism to promote mutation. If there was a sequence which told
>: the proof-reading enzymes to stop when they reached that particular
>: region, then that might be a way of generating the higher mutation
>: rate. 

>Introns are (presumably!) only on the transcribed RNA copy not the DNA.  One
>would generally imagine that repair enzymes do not distinguish the regions,
>although Andrez Konopka has shown that the intron and exon have distinct
>properties so maybe it is possible.  I'm pretty sure that mutations in
>immunoglobulins occur in specific places as part of their rearrangement
>mechanism.

Huh? Introns *are* in the DNA, that's what we're talking about. Was
that a typo? They're transcribed onto the primary RNA and then cut
out. Here I was just talking about DNA replication.

The somatic cell mutations that lead to antibody diversity are, of
course, strictly due to gene rearrangements. What I seem to remember
(and I'm not putting a lot of faith in my memory, here, but if I can
find my old immunogenetics text, then I'll look it up) is that
mutations in the hypervariable region have accumulated in an
evolutionary sense (ie. in the germ line), faster than would be
predicted by a 1 in 10^9 error rate for DNA replication (ie. if we
compare the sequences on a mouse and a human, then we can estimate the
rate of mutation since the species diverged).

The idea that there are sequences to alter the action of proof-reading
enzymes is, like everything else that I'm writing on this thread,
either speculation or recall from a rather poor memory. I'm not an
expert, or even a peripheral player, so if I don't give references,
then treat my opinions with a healthy skepticism.
Ken Muldrew
kmuldrew@acs.ucalgary.ca