Measuring genetic change

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Measuring genetic change

• Level 3 Molecular Evolution and Bioinformatics
• Jim Provan

Page and Holmes Section 5.2
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Types of substitution
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Types of substitution (continued)

• Multiple substitutions can greatly obscure actual
  evolutionary history, particularly in cases where
  there have been many mutations i.e. over long
  evolutionary time scales
• Final three examples have serious implications
  for inference of evolutionary history
• Similarity inherited from an ancestor is called
  homology
• Independently acquired similarity is called
  homoplasy
• All tree-building methods rely on sufficient
  levels of homology

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Types of substitution (continued)

• Substitutions that exchange a purine for another
  purine or a pyrimidine for another pyrimidine are
  called transitions

• Substitutions that exchange a purine for a
  pyrimidine or vice-versa are called transversions

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Measuring evolutionary change

• Simplest measure is to count number of different
  sites
• Poor measure
• Some sites may undergo repeated substitutions
• As sequences diverge, measure becomes less
  accurate

• Saturation occurs - most sites changing have
  changed before

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Correction of observed sequence differences
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A general framework of sequence evolution models
f fA fC fG fT
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The Jukes-Cantor (JC) model

• Assumes that all four bases have equal
  frequencies and that all substitutions are
  equally likely

f ¼ ¼ ¼ ¼
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Kimuras 2 parameter model (K2P)

• Takes into account different frequencies of
  transitions vs. transversions

f ¼ ¼ ¼ ¼
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Felsenstein (1981) (F81)

• Takes into account differences in base
  composition
• Percentage (G C) can range from 25 - 75
• F81 model allows the frequencies of the four
  nucleotides to be different
• Does not allow for variation between genes/species

f ?A ?C ?G ?T
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Hasegawa, Kishino and Yano (1985) (HKY85)

• Essentially merges the K2P and F81 models to
  allow transitions and transversions to occur at
  different rates as well as allowing base
  frequencies to vary

f ?A ?C ?G ?T
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General reversible model (REV)

• Most general model - each substitution has its
  own probability

f ?A ?C ?G ?T

• By constraining a-f it is possible to generate
  all the other models

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Comparing the models
JC ?A?C?G?T ??
HKY85 ?A??C??G??T ???
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Comparing the models (continued)
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Assumptions independence

• Assumes that change at one site has no effect on
  other sites
• Good example is in RNA stem-loop structures

• Substitution may result in mismatched bases and
  decreased stem stability

• Compensatory change may occur to restore
  Watson-Crick base pairing

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Assumptions base composition

• Assumption that base composition is at
  equilibrium and that it is similar across all
  taxa studied

• In example opposite, trees inferred using models
  which do not allow for this will not group
  Thermus and Deinococcus

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Assumptions variation in substitution rate
across sites

• All sites are not equally likely to undergo a
  substitution

• Functional constraints
• Pseudogenes have lost all function and can evolve
  freely
• Fourfold degenerate sites do not change amino
  acid composition of proteins
• Non-degenerate sites are highly constrained

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Assumptions variation in substitution rate
across sites (continued)

• More rapidly evolving sequence shows most
  divergence initially but soon saturates
• Sequence A actually appears to be more rapidly
  evolving