686 THE STRUCTURE OF EVOLUTIONARY THEORY
ten been hailed as the most interesting revision of evolutionary theory since
Darwin.
When we consider the two properties of organisms that depress the frequency
of fixation by drift at this level, we easily spot the difference that makes
randomness so important at the lower genie level. Population size, also
characteristically large for gene-individuals, cannot supply the reason. But the
workings of DNA establish a strong supposition for absence of selective pressure
from the organismal level at a high percentage of nucleotide sites, where
alternative states do not influence the phenotypes of organisms—hence the
designation of drift at this level as the neutral theory of molecular evolution.
Kimura's classical categories of evidence all depend upon the observation that
maximal rates of nucleotide change occur at sites that do not influence the
organismal phenotype—on the reasonable assumption that organismal selection
usually acts in the stabilizing mode to preserve favorable sequences, and that sites
under selective influence must therefore change at less than the maximal rate. The
threefold confirmation of this prediction provides powerful evidence for the neutral
theory—(1) for synonymous substitutions of the third nucleotide in a triplet; (2) for
much higher rates of change in untranslated introns than in surrounding exons; and
(3) for entirely untranslated pseudogenes, where rates at all three positions of
triplets match the rapid third-position rate for translated DNA.
The move from mere plausibility to the important claim for high, or even
dominant, relative frequency arises both by implication from the basic theory, and
from observation. The three phenomena described above, after all, include a large
percentage of all nucleotide changes—so neutralism must maintain a high relative
frequency at this level if we have interpreted the rates of change correctly. At the
broadest scale of geological time, the (admittedly approximate) ticking of the
molecular clock in so many phylogenetic studies achieves its most plausible
reading as a consequence of generally comparable rates for the high percentage of
neutral substitutions. (The alternate explanation of averaging out for fluctuating
selective control over sufficiently long periods of time cannot be dismissed a
priori, but smacks of special pleading— whereas neutralism expects this result as
the consequence of a central proposition.)
Kimura has always stressed the high frequency of neutral substitutions as his
main challenge to Darwinian traditions. He writes, for example (1991a, p. 367), "in
sharp contrast to the Darwinian theory of evolution by natural selection, the neutral
theory claims that the overwhelming majority of evolutionary changes at the
molecular level are caused by random fixation (due to random sampling drift in
finite populations) of selectively neutral (i.e., selectively equivalent) mutants under
continued inputs of mutations." At the same time, Kimura also consistently
insisted—and not, I think, merely for diplomacy's sake, or for any lack of resolve,
but rather with genuine conviction (I discussed the matter several times with
Kimura in person, so I will also stand as witness)—that the neutral theory did not
contradict or dethrone