From: Aubrey de Grey (ag24@gen.cam.ac.uk)
Date: Thu Jun 12 2003 - 09:53:22 MDT
Rafal Smigrodzki wrote:
> > Ah, but it's not just as seen in real life: this is the whole problem.
> > We see two clear deviations from real life in his model: (1) his model
> > predicts lots of proliferation at modest heteroplasmy (say, under
> > 50%),
>
> ### Can you quote Chinnery on that?
Sure -- though not verbatim, of course, because he doesn't understand
it. Page 572 left in the JTB paper: "The feedback mechanism associated
with alpha acts to maintain the population of wild-type mtDNA near the
target level of Nopt." In other words, with 50/50 heteroplasmy the
steady-state total mtDNA copy number will be twice what it is when no
mutant mtDNA is present, so that the same number of wild-type molecules
are present. Similarly on p577 right, "Proliferation of mtDNA does
succeed in mainitaining the number of wild-type mtDNA at nearly optimal
levels, but at the expense of generating a large number of mutated
mtDNA."
- ----------------------------
> > Thresholds don't help re
> > the former, because in Chinnery's model the only reason there's a
> > threshold is that there's a maximum number of mt genomes in total (wt
> > plus mutant).
>
> ### I didn't get this one. Chinnery specifically predicts biochemical
> threshold effects for mutations with high E (the efficiency parameter).
> This would not be dependent on any maximum number of mt genomes, and
> does not predict lots of proliferation at modest heteroplasmy (see Fig
> 7 and page 578 in the J.Theor Biol article).
Don't you mean low E? High E means mild mutations, low E means severe
mutations. p578 says there is a threshold effect for severe mutations.
The threshold is biochemical in a way, but it's still a cap on the total
number of mt genomes -- namely, Nopt times alpha for E=0. (E=0 is the
only physiologically reevant case in aging, because all COX-negative
fibres contain clonal deletions - see Aiken's work.)
- ---------
> > and (2) it predicts (for parameters chosen to give the observed
> > number of COX-negative cells) a lot more heteroplasmic cells than
> > homoplasmic (or very nearly) mutant cells.
>
> ### Can you quote him?
>
> See fig 5 and p 580, where he says that within his model the levels of
> mutations and COX negativity can vary independently of each other.
Yeah -- at least I managed to get a big caveat included there to do
with the fact that the single cited study of COX-negativity with low
mutation load was in cell culture (where clonal expansion doesn't even
happen). But I was not talking above about the JTB paper, but rather
about Elson et al, AJHG 68:802, in which essentially the same model is
used to simulate the accumulation of mutations that have occurred
spontaneously (i.e. at an initial copy number of 1). This is the one
in which he asserts that a paper from his own group (Brierley 1998)
contradicts my 1997 model when in fact it robustly supports it....
But back to the point: see its Fig 1A and legend, which says that
three cells showed "a significant expansion" against only one going
to fixation.
Aubrey de Grey
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