Peter Wang wrote:>>>>>>>>>>>>>>>>>>>>>>>>
I think that the evidence is that immunoglobulin (Ig) hypermutation is a
"Darwinian" evolution.
Certainly the (poorly understood) mutational process is directed or targeted, in
the sense that it only occurs in the variable region of active Ig genes. There
appears to be an elaborate machinery for the targeting of this mutational
process, and there are no examples to date of it being targeted to any other
parts of the genome.
However, the apparent targeting of mutations in CDRs is for the most part due to
selection after mutation for those cells that are more "fit", that is, that now
encode antibodies with higher affinity. The different mutated offspring of a
initially clonal cell arise in a special structure called a "germinal center",
and compete with each other within the germinal center for binding to a limiting
amount of antigen. Only mutations in CDRs are likely to make a difference to
binding of antigen, while mutations elsewhere in the gene are likely to harm the
antibody by affecting folding/stability; cells bearing the latter mutations will
tend to be eliminated from the population by selection.
In artificial cases where genes are subject to the mutational process without
subsequent selection, the mutations are widely distributed (though still only in
the targeted region).
Certain locations, termed "hotspots", are more prone to mutation than others.
This seems to be due to some sequence specificity of the mutational process:
certain four-base sequences are more frequently mutated than others. 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.<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<<
It seems to me that, once we accept targeting as a paradigm, we are
Lamarckians and no longer Darwinians. Let me try to illustrate this on
the classical example of some "pre-giraffe" stretching out its neck for
high tree leaves. If the process has its target area in the genome where
an increased occurence of random mutations has made the appearance of
individuals with longer necks more probable, the whole process is
Lamarckian despite the facts that the mechanism could be pre-formed
and that most of the mutations in the target area could be harmful.
Simply because in another flock, e.g. of "pre-goats", where this
particular targeting is absent, the probability of evolutionary neck
extension is zero.
Targeting (Lamarckism?) seems to be the driving force of evolution,
whereas randomness of mutations and subsequent selection (Darwinism?)
may prove to be just details of the process.
I realize that this view is too extreme but sometimes approaching the
problem in this way proves better for a discussion.
Best regards,
Pentcho
