mkkuhner at kingman.genetics.washington.edu
Thu Jul 19 17:25:10 EST 2001
In article <9j786i$2ea$1 at mercury.hgmp.mrc.ac.uk>,
Thorsten Burmester <burmeste at mail.Uni-Mainz.de> wrote:
>Does anybody know why the synonymous and non-synonymous substition rates
>are correlated in many genes? I.e., in highly conserved genes one may
>find that both Ka and Ks are strongly reduced when compared to a less
>conserved paralogous gene.
I don't think anyone knows for sure, but there are several theories. Broad
classes of theories include:
--the mutation rate is different in different parts of the genome due to some
physical difference (chromatin organization, etc.)
--selection is acting on the silent sites. In support of this is the observation
that codon bias correlates with expression level, apparently because there is
some selection, in highly expressed genes, for easy-to-translate codons.
--some genes have longer or shorter histories than others, and thus
have more or fewer mutations. This is mainly an explanation for effects
at the species level or below, but it may sometimes apply to related species
as well--it basically applies to timescales over which polymorphism can be
maintained within a lineage.
A striking example of this is the human MHC, which has very high silent and
coding polymorphism. The coding part is believed to be under strong balancing
selection. As a consequence of the balancing selection, the common ancestor
of the human alleles dates back before the common ancestor of human, chimp
and gorilla. Thus, the observed silent substitutions could simply reflect the fact
that these are very old alleles. Most human genes have a *much* more recent
ancestor, and thus less chance to accumulate mutations.
--another population-genetics explanation involves the difference in recombination
level across the genome, with low-recombination regions tending to be homogenized
by selective sweeps. Again, this is mainly expected for closely related organisms.
There are probably more theories. Except for blatant cases like MHC I think we
seldom know which theory to believe for any given gene. Some insight can be
gotten by comparing within-population polymorphism and between-population
divergence. High mutation rate will be apparent in both settings, whereas the
population-genetic forces affect the two comparisons differently.
Mary Kuhner mkkuhner at genetics.washington.edu
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