The Neutral Theory of Molecular Evolution: A Review of Recent Evidence

by Motoo Kimura

Ever since the emergence of Mendelian genetics, or rather, the revolutionary birth of the
concept of genes, the evolution that takes place at the molecular level has been unraveled. In 1991,
Motoo Kimura proposed in a paper titled "The Neutral Theory of Molecular Evolution: A Review
of Recent Evidence" that the vast majority of evolutionary changes at the molecular level, as shown
by comparisons of protein and DNA sequences, are not brought about by Darwinian selection but
rather by random drift of selectively neutral or nearly neutral mutations. The neutral theory
highlights the prominent roles that mutation pressure and genetic drift play in evolutionary changes
at the molecular level, as opposed to the Darwinian theory of natural selection.

In his paper, Kimura made several crucial observations to support his claim, including the
following: First, conservative changes—substitutions of amino acids with similar biochemical
properties and thus less likely to affect a protein's function. Second, synonymous base substitutions
generally occur far more frequently than nonsynonymous base substitutions. Third, synonymous
sites and non-coding sequences like introns both develop rapidly. Lastly, dead genes, or
pseudogenes, evolve quickly and roughly at the same rate in three-codon positions. These findings
are in line with the neutral theory but go against the selectionist theory. After all, if the majority of
substitutions were adaptive, as suggested by selectionist theory, one would anticipate fewer
substitutions in DNA areas (such as pseudogenes, noncoding sequences, and synonymous sites)
than in regions that are crucial for function. Certainly, it is commonly assumed that evolutionary
changes at the phenotypic level are almost exclusively adaptive and caused by Darwinian positive
selection. However, Kimura insists that random drift plays a significant role, especially with
respect to quantitative characteristics, he asserted that neutral evolutionary changes, as driven by
random drift under mutational pressure, must have played a crucial role in evolution ever since the
beginning of life on Earth. The neutralists were persuaded that mutation pressure and genetic drift
account for the majority of variations between populations or species. However, what Kimura
meant by "appreciable fraction" of genetic variation has been a point of dispute until now. It is
even more challenging to determine what it means for a mutation to evolve neutrally. Kimura
stated that neutral mutations disperse at a gradual, constant pace that is simple to describe
statistically, in contrast to adaptive mutations, which move through populations as quickly as their
fitness advantages can support them. Theoretically, it is conceivable to gather DNA sequences
from individuals all around the world, tally and compare the neutral mutations that can occur on
different continents, one continent, and one individual, and then use this data to reconstruct
specifics about human migration across the world. However, it might be challenging to determine
in practice whether a particular mutation is evolving neutrally or not. The results can be deceptive
when variation under selection is wrongly categorized as neutral and applied to research on
historical migrations and population size fluctuations. In a paper entitled "The Neutral Theory in
Light of Natural Selection" by Kern and Hahn (2017), they indicated that the majority of human
adaptations resulted from genetic diversity already present in the genome rather than novel
mutations that quickly spread throughout the population. They further underlined that approaches
for estimating demography will work if you computationally model a population growing in a
neutral way, but if linked selection is present, those methods will not work. In a sense, it is yet
another process that affects genome evolution and is certainly not neutral.

In conclusion, Motoo Kimura, with his "neutral theory" of molecular evolution in 1991,
did offer crucial insight that allowed evolution to make sense in the context of molecular biology.
However, as beneficial as the neutral theory has been in its different iterations over the past 50
years, the future of evolutionary theory may depend on discovering ever-better ways to carry out
the difficult work of determining precisely how and how much selection is inevitably modifying
our genomes.

Reference

Kern, A. D., & Hahn, M. W. (2018). The neutral theory in light of natural selection. Molecular biology and
evolution, 35(6), 1366-1371. https://academic.oup.com/mbe/article/35/6/1366/4990884?login=false