Origins
In the 1960s, protein sequencing and electrophoresis made it possible to measure molecular variation directly. Zuckerkandl and Pauling (1965) proposed a molecular clock, observing that amino-acid substitutions in proteins such as hemoglobin accumulate at a roughly constant rate over time, and Lewontin and Hubby (1966) showed that natural populations carry far more genetic polymorphism than expected. Motoo Kimura of Japan's National Institute of Genetics calculated in Nature in 1968 that if substitutions at such rates were all driven by natural selection, populations would bear an intolerable genetic load, and argued that most molecular change is selectively neutral. The following year King and Jukes (1969) independently made the same case in "Non-Darwinian Evolution."
Core ideas
Under the neutral theory most new mutations are either harmful or neutral; harmful ones are swiftly removed by purifying selection. The fate of the remaining neutral mutations is decided by genetic drift, the chance variation in which alleles are passed on each generation. A neutral mutation's probability of fixation equals its initial frequency, 1/(2N), and 2Nμ new mutations arise each generation, so the substitution rate is k = 2Nμ × 1/(2N) = μ: the rate of molecular evolution equals the neutral mutation rate, independent of population size. This is the theoretical basis of the molecular clock. The theory also predicts that functionally constrained regions, having fewer neutral mutations, evolve more slowly; indeed synonymous sites and pseudogenes evolve fast while core proteins such as histones evolve slowly. Polymorphism is interpreted as a transient phase of the fixation process (Kimura and Ohta, 1971). Together with Hardy–Weinberg equilibrium, the model serves as a null hypothesis in population genetics.
Debate and current assessment
Misread as a rejection of Darwinism, the neutral theory sparked fierce debate with selectionists. Yet Kimura accepted that natural selection drives the evolution of form and adaptation; he claimed only that most molecular variation is unrelated to adaptation. Tomoko Ohta (1973, 1992) proposed the nearly neutral theory, in which slightly deleterious mutations can be fixed by drift in small populations, explaining differences in evolutionary rates by population size. McDonald and Kreitman (1991) devised a test comparing within-species polymorphism with between-species divergence and found signs of adaptive evolution in a Drosophila gene, prompting Kreitman's (1996) verdict: "The neutral theory is dead. Long live the neutral theory." Kern and Hahn (2018) challenged its dominance, citing pervasive signatures of selection in genomic data, while Jensen et al. (2019) replied that it remains an indispensable null hypothesis for detecting selection.
FAQ
- What is the neutral theory in simple terms?
- Most changes at the DNA level happen not because they help survival but because variants with no advantage or disadvantage spread by chance.
- Does the neutral theory reject natural selection?
- No. It accepts that selection drives the evolution of form and adaptation, while holding that most molecular changes are neutral and fixed by chance.
Sources reviewed: 2026-10-26
References
- Kimura, M. (1968). Evolutionary rate at the molecular level. Nature, 217(5129), 624–626.
- Kimura, M. (1983). The Neutral Theory of Molecular Evolution. Cambridge: Cambridge University Press.
- King, J. L., & Jukes, T. H. (1969). Non-Darwinian evolution. Science, 164(3881), 788–798.
- Ohta, T. (1973). Slightly deleterious mutant substitutions in evolution. Nature, 246(5428), 96–98.
- Ohta, T. (1992). The nearly neutral theory of molecular evolution. Annual Review of Ecology and Systematics, 23, 263–286.
- Zuckerkandl, E., & Pauling, L. (1965). Evolutionary divergence and convergence in proteins. In V. Bryson & H. J. Vogel (Eds.), Evolving Genes and Proteins (pp. 97–166). New York: Academic Press.
- Kimura, M., & Ohta, T. (1971). Protein polymorphism as a phase of molecular evolution. Nature, 229(5285), 467–469.
- Lewontin, R. C., & Hubby, J. L. (1966). A molecular approach to the study of genic heterozygosity in natural populations. II. Genetics, 54(2), 595–609.
- Kreitman, M. (1996). The neutral theory is dead. Long live the neutral theory. BioEssays, 18(8), 678–683.
- McDonald, J. H., & Kreitman, M. (1991). Adaptive protein evolution at the Adh locus in Drosophila. Nature, 351(6328), 652–654.
- Kern, A. D., & Hahn, M. W. (2018). The neutral theory in light of natural selection. Molecular Biology and Evolution, 35(6), 1366–1371.
- Jensen, J. D., Payseur, B. A., Stephan, W., et al. (2019). The importance of the neutral theory in 1968 and 50 years on. Evolution, 73(1), 111–114.
- Nei, M. (2005). Selectionism and neutralism in molecular evolution. Molecular Biology and Evolution, 22(12), 2318–2342.