The neutral theory of molecular evolution

1
The neutral theory of molecular evolution

• Motoo Kimura (1968)
• High levels of polymorphism (variation) in
  protein and DNA sequences among individuals and
  species are difficult to reconcile with
  mutation-selection equilibrium (Ch 5.4)
• Most mutations affecting fitness are deleterious,
  hence quickly eliminated by selection
• Ergo Essentially all new mutations eventually
  fixed are neutral, and evolve only by genetic
  drift
• Do evolutionary biologists ever tire of debating
  whether selection or drift dominates the
  evolutionary process?

2
Why use DNA and protein molecules to study
evolution?

• In principle, character homology and independence
  can be assured
• Very large number of characters can be studied
• Only 4 precisely-defined character states in DNA
  20 in protein
• DNA sequencing is easy, fast, and cheap genome
  projects
• Many (perhaps the majority) of living species
  lack distinctive morphological features
• Neutral mutations accumulate in a clocklike manner

3
Drawbacks to molecular methods

• In practice, orthology and paralogy can be
  difficult to distinguish in gene families
• Not generally applicable to fossil taxa
• Gene phylogenies vs. species phylogenies
• Not all mutations are neutral

4
What makes the molecular clock tick?

• Probability of fixation of a neutral allele p
  (the current allele frequency)
• What is the fixation probability for a new
  neutral mutation in a diploid population?
• 1/(2N)
• New mutations arise at a rate of m ( mutations
  per DNA base pair per generation typically
  10-8)
• What is the frequency of new mutations in a
  diploid population?
• (2N)m L (length of genome in base pairs
  typically 108-1010 in eukaryotes)
• Rate of fixation of new neutral mutations
• 1/(2N) (2N)m L mL
• Since genome length (L) is a constant within a
  species, neutral mutations go to fixation at a
  rate equal to the mutation rate m is the
  ticking speed of the clock.

5
Which type of mutation should tick faster?
6
Why do some clocks tick faster than others?
7
Empirical evidence for the molecular clock from
Hartl and Clark Principles of Population
Genetics, Fig. 12 p. 361
8
Evolutionary rates for different regions of
genes from Hartl and Clark Principles of
Population Genetics, Fig. 17 p. 373
9
Variation in substitution rates

• Nonsynonymous (replacement) substitution rates
  are variable and relatively low. Why?
• Promoter (5 upstream) flanking regions of genes
  have intermediate rates of substitution even
  though they are noncoding. Why?
• Synonymous (silent) substitution rates are
  high.
• Intron substitution rates are high.
• Pseudogene substitution rates are highest. Why?

10
dN/dS
When will dN/dS lt 1 ? When will dN/dS 1 ? When
will dN/dS gt 1 ?
11
Genes with dN/dS gtgt 1

• Major histocompatibility complex (MHC)
• Immunoglobulins
• Self-incompatibility loci in plants
• Sperm-egg recognition proteins in abalone