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The Punctuated Clock

Richard M Kliman rkliman at runet.edu
Fri Jun 13 11:14:58 EST 1997

In article <andrew.rambaut-ya023380001306971245430001 at news.ox.ac.uk>,
Andrew Rambaut <andrew.rambaut at zoology.ox.ac.uk> wrote:
>In article <5nmp30$ooh at ruacad.runet.edu>, rkliman at runet.edu (Richard M
>Kliman) wrote:
>> >Many mutations in protein coding DNA do not result in a change in amino
>> >acid due to the redundancy of code. Thus these occur despite natural
>> >selection as there is no phenotype to be selected. 
>> This is not always true.  There is considerable evidence for selection 
>> acting on silent substitutions, probably favoring those that increase the 
>> efficiency and/or fidelity of translation.
>The fact that many substitutions do not result in AA changes IS true. Some
>of these may be select for or against due to tendancies related to G/C bias
>etc. However it seems reasonably to say that most will simply be neutral -
>i.e. they had no affect on phenotype and were fixed by drift. Indeed is
>seems likely that many AA replacement substitutions will also be between
>AAs that have a minimal effect on the protein structure (i.e. changes tend
>to be withing AA groupings with respect to size and hydrophobicity).

Agreed, sort of.  There is a difference between neutral in an 
evolutionary sense and neutral in a phenotypic sense.  Silent 
substitutions *do* seem to be subject to selection in many 
microorganisms, C. elegans and Drosophila.  However, being subject to 
selection (i.e., having a phenotypic effect) and being predictably 
influenced by selection are two different things.

Take the case of Drosophila.  Let's assume 20,000 protein-coding genes, 
each with 500 codons on average - i.e., 10,000,000 codons in all.  A 
silent substitution at any site may have a very small phenotypic effect; 
thus, for any given site, a betting person would expect an optimal codon 
to be used.  However, mutational biases, selection on linked sites, etc. 
will also influence the history of a given silent mutation.  We would 
never expect optimal codon usage for all sites.  Nonselective influences, 
genetic drift and, possibly, other forms of selection on codon 
usage/base composition are important.

Take-home message: for a variety of reasons, silent substitutions may 
often be effectively neutral, in the sense that one can not reject a 
neutral model.  However, that does not make them truly neutral - i.e., 
they do not have a selection coefficient of zero.  I think there is 
considerable evidence for effective selection on silent mutations, and 
one should be careful about assuming neutrality.

And, of course, a molecular clock does not assume selective neutrality.  
I was simply trying to clear up a potentially misleading statement 
regarding the selective neutrality of silent mutations.

Rich Kliman

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