near neutrality & compensatory evolution

Ohta T 1974 Mutational pressure as the main cause of molecular evolution and polymorphism. Nature 252:351-354.

it becomes increasingly necessary to re-examine evolutionary theories
in particular the orthodox neo-Darwinian view that the rate and direction of evolution are determined almost exclusively by positive natural selection

it is probable that molecular evolution proceeds essentially by mutational pressure rather than by positive Darwinian selection

this view is essentially an extension of the neutral mutation-random drift hypothesis of Kimura¹ and King and Jukes²
and takes into account the idea of "frozen accidents" proposed by Crick²¹ and Ohno²²
once the structure and function of a molecule are determined in the course of evolution, natural selection acts mainly to maintain them
because all later evolutionary changes proceed under selective constraints
natural selection then becomes mostly 'negative'
positive Darwinian selection is only a minor part of both total selection and the total number of mutant substitutions
if selection pressure is weak, a mutant allele, even if slightly deleterious, can occasionally replace the original allele by random drift
such chance events are likely to be important in molecular evolution

I have suggested before that the coupled base substitutions in the paired region of this molecule, in the course of evolution, represent a very slightly deleterious base substitution in the first stage
followed by a slightly advantageous complementary base substitution
this corresponds to Fitch's concomitantly variable codons (covarions)

the majority of "nearly neutral" mutations is likely to be very slightly deleterious
especially if the proteins and biochemical pathways are very highly organised
and if environmental factors cannot interact directly with the primary structure of proteins
the present hypothesis differs from the original neutral mutation-random drift hypothesis in emphasising a very small selection pressure
in fact, it is an extended form of neutral theory, conceived as the lower limit of the selective process

there should be no distinct borderline between deleterious and neutral, between deleterious and advantageous, or even between deleterious and overdominant mutations
random genetic drift and mutational pressure play a much bigger part than has been believed

we have already suggested from a comparison of actual observations with the results of our simulation experiments assuming stepwise production of neutral alleles, that there are more rare alleles than predicted form the strictly neutral hypothesis
if we bring very slight negative selection into the model, the discrepancy between the observation and the simulation should disappear completely
the recent analysis of Yamazaki and Maruyama⁴² needs re-examination in the light of this

if the borderline cases between slightly deleterious and completely neutral mutations are important, as I assume here, then the population size becomes most crucial and the rate of evolution is higher in small populations
the true pattern of molecular evolution and variation can only emerge from further investigation
bearing in mind particularly the importance of intra-molecular organisation which derives from the polypeptide folding mechanism
here ecological conditions are likely to be much less significant than has traditionally been supposed
in the light of such considerations, the original concept of the integrated gene pool⁵⁴ may have to be modified

the distinction between the strict neutral theory and my theory should be clarified
the neutral theory classifies new mutations into discrete classes
in my theory, there is no clear-cut distinction among these classes and the borderline cases are assumed to be more important
the rate of amino acid substitution is higher in small populations in my theory
it is independent of population size in the strict neutral theory
my theory predicts that substitutions will be concentrated at the time of speciation, when small population size creates a "bottle neck"