History of Molecular Evolution - The Neutral Theory of Molecular Evolution

The Neutral Theory of Molecular Evolution

The intellectual threat of molecular evolution became more explicit in 1968, when Motoo Kimura introduced the neutral theory of molecular evolution. Based on the available molecular clock studies (of hemoglobin from a wide variety of mammals, cytochrome c from mammals and birds, and triosephosphate dehydrogenase from rabbits and cows), Kimura (assisted by Tomoko Ohta) calculated an average rate of DNA substitution of one base pair change per 300 base pairs (encoding 100 amino acids) per 28 million years. For mammal genomes, this indicated a substitution rate of one every 1.8 years, which would produce an unsustainably high substitution load unless the preponderance of substitutions was selectively neutral. Kimura argued that neutral mutations occur very frequently, a conclusion compatible with the results of the electrophoretic studies of protein heterozygosity. Kimura also applied his earlier mathematical work on genetic drift to explain how neutral mutations could come to fixation, even in the absence of natural selection; he soon convinced James F. Crow of the potential power of neutral alleles and genetic drift as well.

Kimura's theory—described only briefly in a letter to Nature—was followed shortly after with a more substantial analysis by Jack L. King and Thomas H. Jukes—who titled their first paper on the subject "non-Darwinian evolution". Though King and Jukes produced much lower estimates of substitution rates and the resulting genetic load in the case of non-neutral changes, they agreed that neutral mutations driven by genetic drift were both real and significant. The fairly constant rates of evolution observed for individual proteins was not easily explained without invoking neutral substitutions (though G. G. Simpson and Emil Smith had tried). Jukes and King also found a strong correlation between the frequency of amino acids and the number of different codons encoding each amino acid. This pointed to substitutions in protein sequences as being largely the product of random genetic drift.

King and Jukes' paper, especially with the provocative title, was seen as a direct challenge to mainstream neo-Darwinism, and it brought molecular evolution and the neutral theory to the center of evolutionary biology. It provided a mechanism for the molecular clock and a theoretical basis for exploring deeper issues of molecular evolution, such as the relationship between rate of evolution and functional importance. The rise of the neutral theory marked synthesis of evolutionary biology and molecular biology—though an incomplete one.

With their work on firmer theoretical footing, in 1971 Emile Zuckerkandl and other molecular evolutionists founded the Journal of Molecular Evolution.