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Hickory Dickory Dock: Understanding the Molecular Clock

Hickory Dickory Dock: Understanding the Molecular Clock. Felisa Wolfe wolfe@imcs.rutgers.edu ERUPT: Biocomplexity Seminar 28 Feb 2003. Structure of Talk: Making (shakin’) a Tree Basis Assumptions Methods Applying a Clock Types Examples (general) Pros and Cons. Making a Tree: Basis.

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Hickory Dickory Dock: Understanding the Molecular Clock

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  1. Hickory Dickory Dock: Understanding the Molecular Clock Felisa Wolfe wolfe@imcs.rutgers.edu ERUPT: Biocomplexity Seminar 28 Feb 2003

  2. Structure of Talk: • Making (shakin’) a Tree • Basis • Assumptions • Methods • Applying a Clock • Types • Examples (general) • Pros and Cons

  3. Making a Tree: Basis Allele: alternative form of a gene N population size 2N  gene copies • What can change allele frequency? • Mutation • Natural Selection • Genetic drift • migration

  4. Making a Tree: Basis (con’d) Mutations: 3 types 1- silent 2- missense (change in AA) 3- nonsense (termination codon) 4- indels- change length of codon

  5. Making a Tree: Assumptions Natural Selection: 1- Hardy-Weinberg before selection 2- selection = survivorship (diploid) 3- Infinite population size

  6. Making a Tree: Assumptions (con’d) Neutral Mutation Theory (Kimura and Ohta, 1974) 1- AA substitution rate is ~ constant 2- functionally less important evolves faster 3- deleterious and neutral more common 4- gene duplication precedes new function 5- deleterious and neutral mutation loss more often than positive beneficial fixation

  7. Making a Tree: Methods Phylogenetic Trees as NETWORKS Ancestral species vs. ancestral sequence • Branch Lengths: • Distance • # changes • Time Two methods to build trees: 1- Distance 2- Character

  8. Making a Tree: Methods (con’d) n OTUs external nodes n-2  internal nodes

  9. Making a Tree: Methods (con’d) • Distance: • Build a matrix requires decision • Construct tree according to algorithm • Ex. UPGMA, Neighbor Joining • Character: • Consider data and tree together • Predict character states of internal nodes • Ex. Max. Parsimony, Max. Likelihood • Alignments- • Line up sequences (AA or DNA), • High similarity strongly suggests homology • Basis for determining tree topologies & branch lengths

  10. Making a Tree: Methods (con’d) Maximum Likelihood: Best tree is most likely under model of the probability of mutations. Ex. 1 A C T G 2 A C T G 3 A C A G 4 A C A C

  11. Applying a Clock “The molecular clock hypothesis postulates that for any given macromolecule (a protein or DNA sequence) the rate of evolution is approximately constant over time in all evolutionary lineages” Li 1997 Can be used similar to dating of geologic time using radioactive elements.

  12. Applying a Clock: Types • No Clock – each branch has an independent rate; n sequences then (2n-3) parameters (branch lengths) • Global Clock – all braches have same rate; (n-1) parameters  ( (n-1) internal nodes) • Local Clock - default rate for all branches; except for predefined branches • TipDate – depends on when isolated, i.e. pathogens (virus, etc.)

  13. Applying a Clock: Examples

  14. Applying a Clock: Examples (con’d) • 3 taxa • 1 fossil taxa around at time of common ancestor? • Fossils tend to come with data • Ex. X @ 106 Y

  15. Applying a Clock: Pros and Cons Causes of rate variation among lineages 1- efficiency of DNA repair 2- Generation-time effect hypothesis 3- Metabolic-rate hypothesis

  16. Conclusions: • Natural selection and genetic drift both active; dependent on N. • Neutral Mutation Theory widely accepted be cautious! • Analyses on “gene” evol.; remember not organism evolution (i.e. molecule vs. whole phenotype) • Trees dependent on model. Maybe misleading- ML most robust. • After the above 4 points: • clock can be applied in wide variety of situations to understand the relationships AND timing between organisms.

  17. Many thanks to: Ken Miller Mimi Katz Paul Falkowski Oscar Schofield Costantino Vetriani John Reinfelder Jody HeyEd Stiefel Lee Kerkhof Colomban de Vargas Yi Sun Daniel Grzbeyk Rob Sherrell Yibu Chen Antonietta Quigg Tuo Shi Augie Trey Nick DeVito Nashwa Choudhry

  18. General References: Hudson, R.R., (1990) “Gene genealogies and the coalescent process.” inOxford Surveys on Evolutionary Biology. D. Futuyma and J. Antonovics, Eds. Oxford Univ. Press, NY. Pp. 1-44 Kimura, M. and T. Ohta. (1974) “On some principles governing molecular evolution.” PNAS 71:2848- 2852 Li, W-H. Molecular Evolution 1997 Yang, Z. (1997). “PAML: A program package for phylogenetic analysis by maximum likelihood.” CABIOS.13:555-556 Zuckerkandl, E. and L. Pauling (1965) “Molecules as documents of evolutionary history.” Journal of Theoretical Biology.8(2):357-366 …and many, MANY others.

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