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Evolution of Proteins and Genomes select subset of slides

Evolution of Proteins and Genomes select subset of slides. Evolution of Proteins. Jason de Koning. Description. Focus on protein structure, sequence, and functional evolution Subjects structural comparison and prediction, biochemical adaptation, evolution of protein complexes,

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Evolution of Proteins and Genomes select subset of slides

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  1. Evolution of Proteins and Genomesselect subset of slides

  2. Evolution of Proteins Jason de Koning

  3. Description • Focus on protein structure, sequence, and functional evolution • Subjects • structural comparison and prediction, biochemical adaptation, evolution of protein complexes, • probabilistic methods for detecting patterns of sequence evolution, effects of population structure on protein evolution, • lattice and other computational models of protein evolution, protein folding and energetics, • mutagenesis experiments, directed evolution, coevolutionary interactions within and between proteins, and • detection of adaptation, diversifying selection and functional divergence.

  4. Reconstruction of Ancestral Function

  5. Mouse: …TLSPGLKIVSNPL… Rat: …TLTPGLKLVSDTL… Baboon: …TVSPGLRIVSDGV… Chimp: …TISPGLVIVSENL... Mouse: …TLSPGLKIVSNPL… Rat: …TLTPGLKLVSDTL… Baboon: …TVSPGLRIVSDGV… Chimp: …TISPGLVIVSENL... Conserved proline Conserved proline Variable “High entropy” Comparative Sequence AnalysisLooking at sets of sequences A common but wrong assumption: sequences are a random sample from the set of all possible sequences Mouse: …TLSPGLKIVSNPL… Rat: …TLTPGLKLVSDTL… Baboon: …TVSPGLRIVSDGV… Chimp: …TISPGLVIVSENL...

  6. Comparative Sequence AnalysisLooking at sets of sequences In reality, proteins are related by evolutionary process

  7. Stochastic Realizations Fitness Selection Selective Pressure Mouse: …TLSPGLKIVSNPL… Rat: …TLTPGLKLVSDTL… Baboon: …TVSPGLRIVSDGV… Chimp: …TISPGLVIVSENL... Stability Folding A B Function C

  8. Data Understanding Model Selective Pressure Mouse: …TLSPGLKIVSNPL… Rat: …TLTPGLKLVSDTL… Baboon: …TVSPGLRIVSDGV… Chimp: …TISPGLVIVSENL... Stability Folding A B Function C

  9. Mutations result in genetic variation

  10. Substitution Insertion Deletion …UGUAUAAAG… …UGUAAAAG… …UGUUACAAAG… Genetic changes …UGUACAAAG…

  11. Substitutions Can Be: Transitions Purines: A G Pyrimidines: C T Transversions

  12. Substitutions in coding regions can be: CysArgLys UGU/AGA/AAG Silent Nonsense Missense UGU/CGA/AAG UGU/GGA/AAG UGU/UGA/AAG CysArgLys CysGlyLys CysSTOPLys First position: 4% of all changes silent Second position: no changes silent Third position: 70% of all changes silent (wobble position)

  13. Homologous crossover Uneven crossover leading to gene deletion and duplication Gene conversion

  14. Keep on doing whatever it originally was doing Lose ability to do anything (become a pseudogene) Learn to do something new (neofunctionalization) Split old functions among new genes (subfunctionalization) Fate of a duplicated gene

  15. Gene duplication a Hemoglobin b Hemoglobin Speciation Mouse a Hb Rat a Hb Mouse b Hb Rat b Hb Paralogs Orthologs Homologies

  16. 1-e-2s Probability of fixation = 1-e-2Ns 1 N = 10 10-02 N = 100 = 2s (large, positive S, large N) 10-04 N = 1000 10-06 Fixation probability = 1/(2N) when |s| < 1/(2N) 10-08 10-10 N = 10,000 10-12 10-14 -0.01 0 0.01 0.02 Selective advantage (s)

  17. Human vs. Rodent Comparison Highest substitution rates pseudogenes introns 3’ flanking (not transcribed to mature mRNA) 4-fold degenerate sites Intermediate substitution rates 5’ flanking (contains promoter) 3’, 5’ untranslated (transcribed to mRNA) 2-fold degenerate sites Lowest substitution rates Nondegenerate sites The Rate of Evolution Depends on Constraints

  18. Human versus Chimpanzee Mouse Opossum Pufferfish Size (Gbp) 3.0 2.5 4.2 0.4 Time since divergence ~5 MYA ~ 65 MYA ~150 MYA ~450 MYA Sequence conservation (in coding regions) >99% ~80% ~70-75% ~65% Aids identification of… Recently changed sequences and genomic rearrangements Both coding and non-coding sequences Both coding and non-coding sequences Primarily coding sequences Selection of Species for DNA comparisons

  19. UCSC Genome Browser

  20. Comparative analysis of multi-species sequences from targeted genomic regions Nature, 2003

  21. Looking backward from the human genome How much is still there after 450my (Fugu)

  22. Transposable ElementsGone Wild!

  23. Identifying Functionally Important RegionsHow many comparative genomes do we need?Can’t we just use the mouse? Using 12 species, 561 Multi-Species Conserved Sequences (MCSs) were found How can be found using just the Mouse genome (rather than all 12) False Pos. True Pos. False Neg.

  24. In evolution: what is the rate R(TR) at which Ts become Rs? 20 x 20 Substitution Matrix Interpreting Evolutionary Changes Requires a Model …IGTLS… …IGRLS... e.g. 0.00005 / my

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