near neutrality & compensatory evolution

Nei M 2005 Selectionism and neutralism in molecular evolution. Mol Biol Evol 22:2318-2342.

Charles Darwin proposed that evolution occurs primarily by natural selection
this view has been controversial from the beginning
this controversy is partially caused by Kimura's definition of neutrality, which was too strict
if we define neutral mutations as the mutations that do not change the function of gene products appreciably, many controversies disappear because slightly deleterious and slightly advantageous mutations are engulfed by neutral mutations

it is important to study the mechanisms of gene family interaction for understanding phenotypic evolution
the randomness of phenotypic evolution is qualitatively different from allele frequency changes by random genetic drift
however, there is some similarity between phenotypic and molecular evolution with respect to functional or environmental constraints and evolutionary rate

many different theories such as overdominant selection, frequency-dependent selection, and varying selection intensity due to ecological factors have been proposed particularly with respect to the maintenance of genetic variation (Lewontin 1974; Nei 1975, 1987; Gillespie 1991)
most of them are no longer seriously considered as a general explanation
but the theory of slightly deleterious mutation of Ohta (1973, 1974) has recently received considerable attention

Ohta's original proposal of the slightly deleterious mutation theory was to explain this apparent constancy of average heterozygosity

another problem with Ohta's theory is that if deleterious mutations accumulate in a gene, the gene gradually deteriorates and eventually loses its function
if this event occurs in many important genes, the population or species would become extinct
in some genes such as ribosomal RNA (rRNA) genes the effects of initial mutations occurring in the stem regions may be detrimental
but the effects can be nullified by subsequent compensatory mutations
Ohta (1973) included these mutations in the category of slightly deleterious mutations
these mutations do not change the gene function when long-term evolution is considered
therefore they should be called neutral mutations
evolution cannot happen by deleterious mutations
it should be caused by either advantageous or neutral mutations
as recognized by Darwin (1859)

in recent years Ohta (1992, 2002) modified her theory calling it the nearly neutral theory
she now assumes that both positive and negative mutations occur
with the condition of |Ns| ≤ 4
this theory is essentially the same as the original neutral theory conceived by many early molecular biologists
actually, mutations with even larger |Ns| values can be called neutral if N is large