Lecture 48: The Neutral Theory of Molecular Evolution

Is evolution at the molecular level different?

3 billion nucleotides in each of us. Is the nature of evolutionary forces on most of these nucleotides different from the forces acting on proteins or specific phenotypes?

Is selection weaker at the molecular level?

• Not all DNA variation translates into protein variation
  • Example: synonymous codons, pseudogenes, non-coding DNA

• Not all protein variation translates into phenotypic variation

• Not all phenotypic variation translated into differences in fitness

Estimates of levels of variation in natural populations

• On average, two randonly-choosen alleles differ by 1/1000 to 1/100 nucleotides

• Hence, any two humans (genome size = 3 x 10⁹) differ by an average of 21 million nucleotides!

The Neutralist-Selectionist Debate

• Motto Kimura (1969) suggested that much of the variation at the molecular level is due to the interaction between drift and mutation, rather than being actively maintained by selection.

• The view of others is that most of this variation is being actively maintained by selection (hence are overdominant).

An example of the interaction between drift removing variation and mutation introducing variation (new mutants indicate by *).

At any particular time, the population has roughly the same level genetic variation. However, the actual alleles in the population change over time.

Molecular clocks

• The substitution rate of amino acids in any particular protein appears to be clock-like
  • Recall that this is predicted from the netural theory, with the average substitution rate is the mutation rate, u..

• However, different proteins have different clock rates
  • How can we account for this with the neutral theory?

Neutral theory Assumptions

• Most new mutants that arise are either
  • deleterious (and hence are lost)
  • neutral
  • Advantagous mutants occur, but they are rare.

Under the neutral theory, molecules with fewer functional constraints evolve faster, because the number of effectively neutral mutants is higher

Summary of the neutral theory

• Neutral mutants have no effect on fitness

• Neutral theory assumes
  • favorable (selectively advantagous) mutants are sufficiently rare that we can ignore them
  • unfavorable (selectively disadvantagous) mutants are removed quickly by selection
  • Hence, most segregating alleles are selectively neutral
  • Likewise, most fixed differences between species are due to drift fixing netural alleles

• The rate at which two populations divergence (fix differences in DNA sequences) is 2tu_n, where
  • t = time of last common ancestor
  • u_n= neutral mutation rate
• Hence neutral theory predicts the clock-like rates of change seen for proteins.

• The more functional constraints on a sequence, the smaller the fraction of total new mutants which are neutral, decreasing u_n.

Adaptive versus neutral substitutions

• Evidence for the predominance of neutral substitutions
  • Substitution rates higher in 3rd base positions (synonmous codon changes)

  • Rates highest in nonfunctional genes

How do adaptive changes occur?

The erector set model

• Changes in regulation versus changes in structure
• The current notion is that most changes are due more to differences in gene regulation rather than the actual structure of gene products (A. C. Wilson).

Example: Frogs versus mammals

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Example: Human-chimp divergence

• While farily similiar, humans and chimpanzees still have some major differences.

• Yet, the DNA sequences of humans and chimps are 98.7% identical.

• Thus suggests that the differences between the two are due to differences in patterns of gene regulation, rather than major structural differences in the gene products themselves

• Initial response due to mutants in genes with an initial weak affinity for the new function. These mutants overproduce the gene product, generating some function simply by sheer numbers.

• Later mutants refine the structural function of these genes with weak affinities.

• epsilon-crystallin makes up 23% of the total eye protein in birds and crocodiles.

• However, amino-acid sequencing shows that epsilon-crystallin is the same as lactate dehydrogenase, an important glycolytic enzyme.

• It thus appears that in the bird-crocodile line, a mutant arose in which lactate dehydrogenase became overexpressed in eye tissue.