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Understanding Genetic Distance: Definitions and Models of Nucleotide Substitution

Genetic distance measures the differences between two DNA or RNA sequences, representing the evolutionary events since their divergence. The simplest method of calculation is p-distance, the proportion of differing sites, though it has limitations. More refined models, such as Jukes-Cantor and Kimura 2-parameter, correct for biases in mutation rates and distinguish between transition and transversion substitutions. Additional models like HKY incorporate various biases, while gamma distributions help in analyzing evolutionary rates at different positions. Accurate assessment requires knowledge of the gamma shape and often multiple sequences.

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Understanding Genetic Distance: Definitions and Models of Nucleotide Substitution

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  1. Genetic Distance

  2. Definition Definition: A measure of how different two sequences are The number of evolutionary events that have occurred since two sequences diverged Simplest: p-distance = proportion of sites that are different (but p-distance is not a good metric – doesn’t add )

  3. A T T G C G C T C C A Correction for Multiple Substitution A T T G C G C C A A T A T Differences Substitutions

  4. Correcting for multiple substitutions Jukes and Cantor – all substitutions were created equal

  5. Jukes and Cantor d = -3/4 ln (1 – 4/3p)

  6. Jukes and Cantor - Graph Genetic Distance Proportion of sites that are different

  7. Correcting for multiple substitutions Jukes and Cantor – all substitutions were created equal Kimura 2-parameter – distinguish between transitions and transversions Models of nucleotide substitution correct for 2 things: - biases in the rate at which different mutations occur - biases in the equilibrium frequencies of different nucleotides

  8. Kimura 2P model: Allows for transition-transversion bias HKY model: Allows for nucleotide bias and transition - transversion bias General Reversible: Allows for nucleotide bias as well as different mutation rates for all nucleotide pairs

  9. Jukes-Cantor

  10. Kimura 2P

  11. HKY

  12. Note: Be careful not to confuse the transition/transversion rate ratio (k) with the transition/transversion ratio (R) In the case of the Kimura 2-P model

  13. Additional corrections for different rates of evolution at different sequence positions can also be applied - gamma distribution (incorporated analytically) - by codon position

  14. In order to perform a gamma correction for site specific rates you need to know the shape of the gamma distribution

  15. You need several sequences to work out the shape of the gamma distribution You normally don’t apply a gamma correction on just a pair of sequences unless you know the shape (alpha) of the gamma distribution in advance

  16. Codon substitution model

  17. Some general points: - genetic distances can be far greater than 1 - smaller genetic distances are more reliable - model choice has a bigger impact for distantly related sequences - normally positions with gaps are ignored (complete deletion) - IF you know the rate of evolution for a pair of sequences (and if the rate has remained more or less constant) you can estimate the date at which they diverged

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