directed mutations

Rumyana Mironova rumym at obzor.bio21.acad.bg
Wed Feb 11 11:41:57 EST 1998


At 09:01 06/02/98 -0800, Peter Wang wrote:

> Ig germline genes have evolved to take advantage of this by placing
hotspot sequences within some CDRs, where mutations are more likely to be
useful.  This is the closest thing I can think of to the "Lamarckian" idea,
but I would argue that it is still the result of Darwinian processes.>

I agree. In so far as hypermutations are targeted just to the appropriate
region of the genome
(VH-regions of Ig-genes) they seem to be "Lamarckian". But since the
improved antibody phenotype is a result of selection after mutation they are
rather "Darwinian". Of course, the talk is not about the real process of
evolution but still about a perfectly working mechanism created during
evolution.


>I did not understand what Rumy meant by:
>> hypermutations in the CDRs are neutral (in Kimura's sense) with respect to a
>> posteriory established improved antigen binding properties of the antibodies?

According to Motoo Kimura (The Neutral Theory of Molecular Evolution,
Cabridge University Press, 1983) molecular evolution is based on mutations
occuring with a constant rate (about 10^(-9) amino acid substitutions per
site per year) randomly in the genome which are neutral or nearly neutral
with respect to molecular functions. Selective pressure acts at the level of
entire phenotypes (organisms) but not at molecular level where mutations
generate genetic diversity which eventually may serve as material for
building a new function. In this context hypermutations are obviously
"neutral" although restricted to only a small part of the genome.

One more question I'm afraid:

Environmental factors may:
a) directly act as mutagens causing lesions in DNA which escape repair and
result in mutations; and
b) they may signal yet unknown cellular pathways to elevate the levels of
imperfect DNA synthesis, error-prone postreplicational repair and
illegitimate movement of transposable elements.
 
The following question seems resonable to me:
Are we  capable to evaluate the relative contribution of these two types of
mutations to evolutionary changes in the genome?

Best regards!
Rumy (but not Violeta; Sorry, my mailbox was initially wrongly named)
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