A brief description on Molecular Evolution, Kimura's theory of Molecular evolution, Neutral theory vs. Natural Selection, Neutral theory: The Null Hypothesis of Molecular Evolution

1. Neutral Theory
of Molecular
Evolution
Name: Rishika Maji
Course: BSc.(H) Zoology 3rd year
Semester: 6th sem
Subject: Evolutionary Biology
Roll no.: 18/154
University roll no.: 18043569010

2. INTRODUCTION
What is Molecular Evolution?
Molecular evolution is the study of the changes in the sequence of
macromolecules (DNA and proteins) leading to variations among
individuals and species and their evolutionary relationship.
What leads to molecular evolution?
The cause of variation in the DNA sequences is mutations which
causes mutation either in the form of genetic variability or change
in allele frequency.
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Synonymous substitution Non-Synonymous substitution
Source: Daniel L. Hartl, Elizabeth W. Jones. Molecular Evolution and Population Genetics. Essential Genetics A Genomic Perspective

3. FATE OF THESE MUTATIONS
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Natural Selection
Positive/ Directional
Selection
Negative/ Purifying
Selection
Balancing Selection
Source: https://www.nature.com/scitable/topicpage/neutral-theory-the-null-hypothesis-of-molecular-839/
Genetic Variability
• fraction of the gametes that are produced will succeed in developing into adults.
• allelic frequencies may change simply as a consequence of this random process of gamete
sampling.
Directional Process Survival of the fittest

4. NEUTRAL THEORY OF MOLECULAR EVOLUTION
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Source: Kimura, M. Evolutionary rate at the molecular level. Nature 217, 624–626 (1968) doi:10.1038/217624a0
"This neutral theory claims that the overwhelming majority of evolutionary changes at the molecular level are not
caused by selection acting on advantageous mutants, but by random fixation of selectively neutral or very nearly
neutral mutants through the cumulative effect of sampling drift (due to finite population number) under continued input
of new mutations" (Kimura, 1991)
Mutations in the introns Synonymous substitution
What about the mutations does not affect the fitness of the individuals?
No Phenotypic changes
Formation of Polymorphs
Neutral
mutations
Driven by genetic drift

5. KIMURA’S EXPLANATION OF NEUTRAL THEORY
NEUTRAL THEORY
The neutral theory states:
• Change at the molecular level
• Driven by random drift.
• Evolution at the level of the DNA
and proteins.
• Most evolution at the molecular
level would then be non-adaptive.
NATURAL SELECTION
Natural Selection states:
• Change at the morphological level
• Driven by adaptive fitness
• Evolution due to mutations that had
been fixed by positive selection—
mutations that contributed to
the adaptation of a species to
its environment.
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Neutral Theory is not
Anti Darwinian
Neutral theory accepts that Natural Selection
is responsible for the adaptation of organisms
to their environment.
Both also recognize that most new mutations
in functionally important regions are
deleterious and that purifying selection
quickly removes these deleterious mutations
from populations.
Source: https://www.nature.com/scitable/topicpage/neutral-theory-the-null-hypothesis-of-molecular-839/

6. KIMURA’S EXPLANATION OF NEUTRAL THEORY
Kimura proposed the neutral theory in 1968.
Kimura in his paper pointed out the sequences in
which most of the neutral mutations occurred
leading to evolutionary divergence from a common
ancestor. He suggested that:
• In protein sequences, conservative changes
occur much more frequently than radical
changes.
• Synonymous base substitutions occur at a rate
much higher than nonsynonymous substitutions.
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• Noncoding sequences, such as introns, evolve at a
higher rate than genes coding for proteins with
essential function.
• Pseudogenes, or dead genes, evolve at a high rate.
Source: https://www.nature.com/scitable/topicpage/neutral-theory-the-null-hypothesis-of-molecular-839/
Neutral Theory: More substitutions in DNA regions where changes have little or no effect on phenotype than
in functionally important regions.
Image Source: Makalowski, W. et al. (1998) and Zheng, D. et. al. (2007).

7. ARGUMENTS OF NEUTRAL THEORY
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Source: Ridley M., Molecular Evolution and Neutral theory, https://www.blackwellpublishing.com/ridley/tutorials/Molecular_evolution_and_neutral_theory15.asp
Neutral Theory explains the rate of molecular evolution.
• Haldane's estimated that the rate of evolution was one substitution per 300 generations
whereas Kimura estimated that there was one change in the genome every two or three years.
• Thus, The absolute rate of molecular evolution and degree of polymorphism, both of which
have been argued to be too high to be explained by natural selection.
Neutral Theory explains Degree of Polymorphism
• Neutral theory explains the high rate of polymorphism and heterozygosity.
• Natural selection fails to explain high degree of polymorphism because it would lead to
building up of segregational load.

8. ARGUMENTS OF NEUTRAL THEORY
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Source: Kimura, M. Evolutionary rate at the molecular level. Nature 217, 624–626 (1968) doi:10.1038/217624a0
Neutral Theory explains Functional constraints
• The neutral theory holds that as functional constraint diminishes, the probability that a mutation is neutral rises, and so
should the rate of sequence divergence.
Kimura and Ohta estimated that the alpha and beta chains on the surface of hemoglobin protein evolve at a rate
almost ten times faster than the inside heme group proteins implying that iron-containing heme groups is more
functionally significant.
There is evidence that rates of nucleotide substitution are
particularly high in the third position of a codon, where there
is little functional constraint.
GCA GCC
ALANINE

9. Neutral Theory: The Null Hypothesis of Molecular
Evolution
It provides a theoretical framework for developing methods that detect the action of selection within genomes. Serves as
a null hypothesis which can only be rejected if the population evolves by natural selection.
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At Selectively neutral sites:
K = u
Rate of
substitution
Rate of mutation
When K>u
Sequences subject to positive selection evolve faster
than neutral sites.
When K<u
Sequences subject to negative selection evolve more
slowly
Source: Kimura, M. Evolutionary rate at the molecular level. Nature 217, 624–626 (1968) doi:10.1038/217624a0

10. CONCLUSION
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Source: Ridley M., Molecular Evolution and Neutral theory, https://www.blackwellpublishing.com/ridley/tutorials/Molecular_evolution_and_neutral_theory15.asp
Neutral Theory has proved to be an effective theory for studying molecular evolution yet it has
some limitations as well:
Kimura while stating his argument for neutral theory says that natural selection is ineffective for
explaining the high degree of polymorphism and evolution rate. But Kimura’s thoughts against
natural selection was too rigid leading to certain limitations:
1. There is a distinction between hard and soft selection. Proponents of the neutral theory have
assumed that selection is too hard.
2. Natural selection can act jointly on many genetic loci. Kimura assumed that selection operates
independently at each locus.
3. Frequency-dependent selection can maintain polymorphism.