The Nearly Neutral Theory of Molecular Evolution

Author: Tomoko Ohta
Source: Annual Review of Ecology and Systematics, Vol. 23 (1992)

Key Concepts

Introduction

The study of evolution has long been based on morphological observations like the giraffe's long neck. Darwin's theory of natural selection has been qualitative in explaining these traits, but population genetics aims to explain evolution quantitatively by focusing on gene frequency changes.
Molecular biology advances, especially comparing DNA sequences, now provide data for evolutionary studies.

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Kimura's Neutral Mutation-Random Drift Hypothesis (1968) proposed that most molecular evolutionary changes are due to random genetic drift of neutral or nearly neutral mutations rather than natural selection.

Population Genetics

Population genetics focuses on gene frequency changes within populations. It incorporates factors like:

Selection: Changes due to natural selection.
Mutation: Genetic changes within the population.
Migration: Movement of alleles between populations.
Random Drift: Random changes in gene frequencies.

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Genetic drift refers to the random fluctuations in the frequency of alleles (gene variants) within a population over time. Unlike natural selection, which is driven by environmental pressures and survival advantages, genetic drift is a stochastic (random) process. It occurs due to chance events that cause certain alleles to become more or less common in a population, especially in smaller populations. These events can lead to the loss or fixation of alleles regardless of their impact on an organism's fitness.

Key Characteristics of Genetic Drift:

Random Nature: It is not influenced by how advantageous or disadvantageous an allele is.
Stronger in Small Populations: Genetic drift has a more pronounced effect in smaller populations where random events can significantly alter allele frequencies.
Leads to Loss of Genetic Variation: Over time, genetic drift can cause alleles to disappear from the population entirely, reducing genetic diversity.
Allele Fixation: In some cases, one allele becomes the only variant at a particular gene locus within a population, a phenomenon called fixation.

Example:

Consider a population of rabbits where two coat color alleles exist: black (B) and white (b). By chance, more rabbits with the black allele reproduce in one generation, causing the black allele to increase in frequency. If this pattern continues by random chance over multiple generations, the white allele could disappear entirely, even if it doesn’t confer any disadvantage.

Types of Genetic Drift:

Bottleneck Effect: When a population is drastically reduced in size due to an event (e.g., natural disaster), the genetic diversity is reduced, and allele frequencies may change due to the limited number of individuals that survive.
Founder Effect: When a small group from a population migrates and forms a new population, the alleles in the new population may differ from the original due to the smaller gene pool.

In summary, genetic drift is a random process that can change allele frequencies in populations over time, and it plays a significant role in evolution, particularly in small populations.

A key development was the use of electrophoresis by Lewontin and Hubby to study protein variation, showing abundant variation in species like humans and Drosophila.

Rate of Molecular Evolution

The rate of molecular evolution is measured through amino acid or DNA sequence changes.

Example: Hemoglobin Sequence Comparisons

Human and gorilla hemoglobin differ by just one amino acid.
Human and horse hemoglobin differ by 18 amino acids.

This highlights a uniform rate of amino acid substitution that is consistent across different species.

Key Formula:

The evolutionary rate ( $k_g$ ) can be calculated with:

k_g = 2Nv_gu

where:

$N$ = population size,
$v_g$ = mutation rate per site,
$u$ = fixation probability.

If mutations are neutral, then $u = \frac{1}{2N}$ , and $k_g$ becomes simply $v_g$ .

Mutation Occurs:

Mutations appear in the population.

Fixation:

Over time, some mutations become fixed.

Rate Calculation:

The overall rate of molecular evolution is the mutation rate multiplied by the probability of fixation.

Selective Constraints and Evolutionary Rate

Proteins with strong functional constraints evolve more slowly because they tolerate fewer mutations. For example:

Histones evolve slowly due to their structural rigidity.
Fibrinopeptides evolve rapidly due to fewer constraints.

Polymorphisms at the Molecular Level

The neutral mutation theory predicts that molecular polymorphisms (genetic variations within a species) are transient and represent an intermediate stage of neutral gene substitution.

Example: Drosophila melanogaster shows about 12% heterozygosity at enzyme loci.

Formula for Virtual Heterozygosity:

H = \frac{4Nv}{1 + 4Nv}

Where $N$ is the effective population size and $v$ is the mutation rate.

Meaning of Near Neutrality

In many cases, mutations are nearly neutral, meaning their selective impact is minimal. The fixation probability depends on (Ns) (the product of population size and selection coefficient).

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For nearly neutral mutations, both drift and selection influence their fate. This is particularly important in species with varying population sizes.

In larger populations, weakly deleterious mutations may be eliminated more effectively, while in smaller populations, these mutations may persist due to drift.

Conclusion

The Nearly Neutral Theory provides a framework for understanding molecular evolution where most mutations have minor selective effects. The balance between genetic drift and weak selection shapes the evolutionary landscape.

This theory continues to explain patterns of genetic variation and molecular evolution across different species.

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