Neutral Theory of Molecular Evolution

The neutral theory holds that most molecular variation within species and substitution between species is selectively neutral and governed by random genetic drift rather than positive selection.

Definition

The neutral theory of molecular evolution proposes that the great majority of evolutionary changes at the molecular level are caused not by selection but by the random drift of mutant alleles that are selectively neutral. The nearly neutral theory extends this to slightly deleterious mutations whose fate depends on effective population size.

Scope

This topic covers Kimura's neutral theory and Ohta's nearly neutral extension, their predictions about substitution rates and standing variation, the historical neutralist-selectionist debate, and the central role of the neutral model as the null hypothesis in molecular population genetics.

Core questions

• What does the neutral theory predict about substitution rates and genetic variation?
• Why is the neutral substitution rate independent of population size?
• How does the nearly neutral theory incorporate slightly deleterious mutations?
• Why does the neutral model serve as the null hypothesis for detecting selection?

Key theories

Kimura's neutral theory

Most molecular polymorphism and substitution is selectively neutral, so the rate of neutral substitution equals the neutral mutation rate and is independent of population size, predicting a roughly clock-like accumulation of changes.

Ohta's nearly neutral theory

A large class of mutations is only slightly deleterious; whether such mutations behave as neutral and drift or are eliminated by selection depends on the product of the selection coefficient and effective population size, tying molecular rates to demography.

Mechanisms

For a strictly neutral mutation, the probability of eventual fixation equals its initial frequency, and the long-term substitution rate equals the neutral mutation rate per generation, independent of population size. Genetic variation within a population reflects a balance between mutation introducing neutral alleles and drift removing them, scaled by effective population size. In the nearly neutral theory, mutations with small selection coefficients are effectively neutral in small populations but visible to selection in large ones, so substitution rates and the efficiency of selection vary with demography. These predictions provide the quantitative null against which positive and balancing selection are detected.

Clinical relevance

The neutral framework underlies methods that identify functionally constrained, and therefore likely clinically important, regions of the genome by detecting departures from neutral expectation, and it calibrates molecular dating used in pathogen surveillance.

History

Kimura proposed the neutral theory in 1968, with King and Jukes independently arguing for non-Darwinian molecular evolution in 1969. Ohta added the nearly neutral theory in the early 1970s, and Kimura's 1983 book synthesized the framework, which remains the standard null model despite decades of debate over the prevalence of selection.

Debates

How neutral is molecular evolution?

The neutralist-selectionist debate concerns what fraction of molecular variation and divergence is neutral versus selected; genomic data show substantial adaptive evolution in some organisms, refining rather than overturning the neutral null.

Key figures

• Motoo Kimura
• Tomoko Ohta
• Jack King
• Thomas Jukes

Seminal works

• kimura1983
• ohta1973
• saetreRavinet2019

Frequently asked questions

Does the neutral theory mean evolution is random?

Only at the molecular level for neutral changes. The theory holds that most molecular substitutions are neutral and fixed by drift, while still accepting that adaptive evolution of organisms is driven by natural selection.

Why is the neutral substitution rate independent of population size?

Because in a larger population more neutral mutations arise each generation but each has a proportionally smaller chance of fixation; the two effects cancel, leaving the substitution rate equal to the mutation rate.