Tests of Neutrality and Selection
In 1971, Motoo Kimura and Tomoko Ohta claimed that one of
the principle virtues of the neutral theory was that it generated
testable predictions and in so doing promised to "emancipate"
biologists from "naïve panselectionism" (Kimura
and Ohta 1971, 469). Using the diffusion equation method,
Kimura and Ohta generated a number of quantitative predictions
for neutral alleles. For instance, in 1969, Kimura and Tomoko
Ohta calculated the average number of generations until a
neutral mutant was either lost or fixed in a finite population
(Kimura and Ohta 1969 a and b). The average time to fixation
was 4Ne. These kinds of quantitative predictions coupled with
the promise of electrophoretic data in the late 1960s spurred
Crow and others to argue in favor of the neutral theory; not
as a correct theory, but as a highly testable theory (Crow
1969). Selectionist critics such as G. Ledyard Stebbins, Richard
Lewontin, and Francisco Ayala were less convinced that decisive
tests could be conducted and deployed Popperian ideas of falsifiability
to assail neutralist hypotheses (Stebbins and Lewontin 1972,
Ayala et al.1974). Both attitudes were justified. The neutral
theory did indeed make a large number of testable quantitative
predictions, but most of the tests to detect neutrality and
selection from 1970 until 1985 were not considered decisive.
Testing the neutral theory ran afoul of two main problems.
On the one hand, statistical tests, such as the one proposed
by Warren Ewens in 1972, were very promising, but turned out
to have little statistical power. It was not possible to reject
the neutral null hypothesis using the Ewens test, for instance.
On the other hand, non-statistical tests were disputed and
considered indecisive. For instance, Francisco Ayala's group
used data about electrophoretic varaibility in natural populations
of Drosophila to test a range of neutralist predictions. Using
a measure of heterozygosity predicted using an infinite alleles
model, Ayala's and his coworkers noted that the frequency
distribution of heterozygous loci was signficantly different.
Instead of the predicted distribution clustered around the
average heterozygosity of 0.177, the distribution was fairly
even except for an excess of loci with very little heterozygosity.
This excess of rare alleles was seen as an explanatory failure
of the neutral theory (Ayala et al. 1974, 378). In response,
Jack King noted that many of the assumptions made in the infinite
alleles could be the source for the rare alleles discrepancy.
Others noted that the infinite alleles model was not appropriate
for electrophoretic data, since electrophoretic classes probably
encompassed many allelic differences (King 1976). Ayala and
his coworkers were sensitive to these criticisms and discussed
mutation models for electromorphs as well as the models' assumptions.
In the course of the give and take over these models, Kimura
and Ohta began to advocate a larger role for slightly deleterious
mutants whose frequencies would still be subject to drift.
Others, such as Masatoshi Nei, began to emphasize, shifting
population dynamics such as those resulting from population
bottlenecks. These kinds of results were influential, in that
they drove revisions of both the neutralist and selectionist
models, but they were not decisive in terms of resolving the
dispute between neutralists and selectionists.
The availability of DNA sequence data after 1985 represents
a significant turning point for the neutral theory and its
tests. Using DNA sequence data, Martin Kreitman and others
devised statistical tests that could statistically distinguish
between neutrality and selection. These statistical tests
subject a neutral null hypothesis to rejection (Kretiman 2000).
The success of this method has been hailed by Jim Crow as
one of the most important events in the history of molecular
evolution. However, it is important to note that the frequent
rejection of neutral null hypotheses does not necessarily
imply the demise of the neutral theory. The relationship between
statistical null hypotheses and the neutral theory is complicated
by the introduction of new neutral models of sequence evolution,
new data about DNA sequences, and new methods, such as coalescents,
which make neutral assumptions.
Francisco Ayala, Martin Tracey, Lorraine Barr, John McDonald,
and Santiago Perez-Salas, 1974, “Genetic Variation in
Natural Populations of Five Drosophila Species and the Hypothesis
of the Selective Neutrality of Protein Polymorphisms,”
Genetics 77: 343-384.
James Crow, 1969 “Molecular Genetics and Population
Genetics,” Proceedings of the Twelfth International
Congress of Genetics Vol 3: 105-113.
Kimura, M., 1969, "The Rate of Molecular Evolution Considered
from the Standpoint of Population Genetics," Proceedings
of the National Academy of Sciences, 63, 1181-1188.
Kimura, M. and Ohta, T. 1971. Protein polymorphism as a phase
in molecular evolution. Nature 229: 467-469.
King, J. 1976 “Progress in the Neutral Mutation Random
Drift Controversy,” Federation Proceedings 35: 2087-91.
Kreitman, M. 2000. Methods to Detect Selection in Populations
with Application to the Human. Annu. Rev. Genomics. Hum. Genet.
Lewontin R. C. and Hubby, J. L. 1966. Molecular Approach to
the Study of Genic Heterozygosity in Natural Populations.
II. Amount of Variation and Degree of Heterozygosity in Natural
Populations of Drosophila pseudoobscura, Genetics 54: 595-609.
Lewontin, R. C. 1974. The Genetic Basis of Evolutionary Change.
Columbia Univ. Press, New York.
Stebbin, G. L. and Lewontin, R. C. 1972. Comparative Evolution
at the Level of Molecules, Organisms, and Populations. Pp.
23-42 in LeCam, L. et al eds. Proceedings of the Sixth Berkeley
Symposium on Mathematical Statistics. Volume V: Darwinian,
Neo-Darwinian, and Non-Darwinian Evolution. Univ, of California
||Distribution of allele frequencies; actual
and effective numbers of alleles
|R. C. Lewontin &
||Heterogeneity among loci as a test of selection
T. Yamazaki &
||Relationship between gene frequency and
heterozygosity; actual and effective numbers of alleles
|M. Nei, P. Fuerst, &
||Gene frequency and heterozygosity
||Distribution of allele frequencies
|R. Hudson, M. Kreitman, & M. Aguade
Within v. Between Species (two loci)
||Tajima's D -- Within Species
J. McDonald &
Within v. Between Species (synonymous