The Neutral Theory of Molecular Evolution by Kimura states that most of the variation seen at the molecular level is selectively neutral -- that is, there are no important fitness advantages or disadvantages associated with particular alleles -- and that genetic drift, rather than natural selection, dominates the dynamics. This does not mean that mutations, when they occur, are all neutral, or that the genes themselves are unimportant. On the contrary, it is thought that most mutations are deleterious to the organism, and thus are unlikely to remain in the population long enough to contribute measurably to the ``standing" variation. Only those mutations that do not have a harmful effect have an appreciable chance of sticking around long enough for us to see them.
The Neutral Theory hypothesizes that this class of ``allowable" mutations is composed entirely of selectively neutral variants. The alternative viewpoint (much simplified) is that advantageous mutations, while perhaps exceedingly rare, do play a major role in evolution, and that polymorphism at the molecular level can best (or, at least, possibly) be explained by natural selection. For now, we develop some of the quantitative aspects of neutrality, considering selection separately. We are particularly interested in describing the dynamics and fate of a new (neutral) mutation. The natural measure of the state of the allele is its population frequency, and it is this that we consider in light of a specified model for mating and reproduction.
PseudogenesOn the neutral mutation hypothesis, the rate of nucleotide substitution is expected to be higher for functionally less important genes or parts of genes than for functionally more important genes, as the latter would be subject to stronger purifying (negative) selectio. On the other hand, selectionists believe that most nucleotide substitutions are caused by positive darwinian selection, in which case the rate of nucleotide substitution in functionally unimportant genes or parts of genes is expected to be relatively lower because the mutations in these regions of DNA would not produce any significant selective advantages. Kimura and Jukes have argued that the higher substitution rate observed at the third positions of codons than at the first two positions supports the neutral mutation hypothesis, as most third-position substitutions are synonymous and do not change the amino acids encoded, although others have discussed the possibility that third-position substitutions are subject to positive darwinian selection. Recently, Kimura noted that the mouse globin pseudogene, psi alpha 3, evolved faster than the normal mouse alpha 1 gene, although he did not compute the substitution rate. Here, we present a method of computing the rate of nucleotide substitution for pseudogenes, and report that the three recently discovered pseudogenes show an extremely high rate of nucleotide substitution. As these pseudogenes apparently have no function, this finding strongly supports the neutral mutation hypothesis.
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