Models of Molecular Evolution III

1
Models of Molecular Evolution III

• Level 3 Molecular Evolution and Bioinformatics
• Jim Provan

Page and Holmes Sections 7.5 7.8
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The nearly neutral theory
Variable rates of nucleotide substitution
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Development of the nearly neutral theory

• By the early 1970s it was becoming clear that
• Some amino acid substitution rates were
  inconsistent with a Poisson clock
• Levels of heterozygosity were not as high as
  expected in natural populations
• Tomoko Ohta suggested that most non-synonymous
  changes were not perfectly neutral

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Development of the nearly neutral theory

• Nearly neutral mutations are those where the
  product of the population size and the selection
  coefficient is near zero i.e. Ns ? 0
• These changes are subject to weak natural
  selection as well as genetic drift
• Rate of substitution (per year) for nearly
  neutral mutations will depend on population size,
  selective coefficient and mutation rate, set to
  generation time
• Mutations at non-coding and synonymous sites are
  still neutral
• Relative importance of selection or genetic drift
  and hence probability of fixation depends on
  population size

5
The nearly neutral theory and real time molecular
clocks
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The nearly neutral theory and real time molecular
clocks

• A study of 20 mammalian genes showed that R(t)
  values were generally well over 1.0, rejecting
  the Poisson clock
• After correcting for generation time and lineage
  effects
• Average R(t) for synonymous sites dropped from
  14.4 to 4.6
• Average R(t) for non-synonymous sites only
  dropped from 8.26 to 6.95
• Most variation in synonymous sites is due to
  lineage effects
• Non-synonymous rates are less generation time
  dependent than synonymous sites

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Testing the neutral theory within species

• Neutral theory makes two very important
  predictions about levels of genetic variation
  within species
• Extent of polymorphism is a function only of the
  population size (N) and the mutation rate (m)
• Levels of polymorphism are correlated with amount
  of variation between species i.e. genes that
  evolve slowly between species also exhibit low
  variation within a species
• Original allozyme studies cast doubt on these
  predictions
• Levels of heterozygosity were found to be too low
• Difficult to draw firm conclusions, since N and m
  are hard to quantify, and allozymes underestimate
  diversity levels
• Best to test theories at the DNA level

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Testing the neutral theory within species

• Important assessment of the neutral theory is to
  test proposed correlation between levels of
  within species polymorphism and between species
  divergence
• If synonymous and non-synonymous substitutions
  are neutral then ratio of both types of change
  will be the same within and between species
  because they result from the same neutral
  mutation process
• Positive natural selection would alter this ratio
  because an advantageous non-synonymous mutation
  would be fixed quicker by natural selection i.e.
  be a polymorphism for less time, leading to less
  within-species non-synonymous variation than
  expected given levels detected between species

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Patterns of substitution at the Adh locus in
Drosophila
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Recombination and DNA polymorphism in Drosophila

• Most dramatic example of incompatibility between
  levels of variation between and within a species
  occurs in regions of the Drosophila genome where
  recombination rates are low
• Distal tip of the X chromosome
• Small chromosome IV
• Neutralist explanation is that these regions have
  either lower mutation rates or are under
  selective constraint
• If this is the case, these regions should also
  show reduced levels of variation between species

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Recombination and DNA polymorphism in Drosophila

• The yellow-achaete (y, ac) region on the X
  chromosome of D. melanogaster has a reduced level
  of polymorphism
• Extent of divergence in this region between D.
  melanogaster and D. simulans (5.4) is similar to
  that observed in other genes (average 4.7)
  this contradicts the neutral theory
• Natural selection can explain this discrepancy
  through the dual action of selective sweeps and
  genetic hitchhiking

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Hitchhiking and selective sweeps
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Can we resolve the neutralist-selectionist debate?

• Most support for neutral theory has come from
  comparisons of genes across distantly related
  species
• Natural selection is more apparent over shorter
  time scales
• As time proceeds, fixation due to selection may
  be obscured by neutral mutations
• Majority of original selection events in adaptive
  radiations e.g. mammals
• Overall, it seems reasonable to conclude that
  both selection and drift shape evolutionary fate
  of mutations
• Majority of substitutions do not affect fitness
  (neutralist)
• The footprints of natural selection are still
  evident in more recently evolved levels,
  particularly at non-synonymous sites