1. Cédric Notredame (08/12/2015) Molecular Evolution Cédric Notredame

2. Cédric Notredame (08/12/2015) Molecular Evolution is a rapidly developing field………..

3. Cédric Notredame (08/12/2015) Phenotypic diversity in populations suggests underlying genetic diversity

4. Cédric Notredame (08/12/2015) Other molecular level studies reveal even more variation Nucleotide sequence variation

5. Cédric Notredame (08/12/2015) Is Modern Genetic Data Compatible with Darwinism

6. Cédric Notredame (08/12/2015) If each variable locus is influenced by selection, then how can populations be so genetically variable? Can each variable “locus” influence population fitness? Genotype:A 1 A 1 A 1 A 2 A 2 A 2 Fitness:1 11-s What about the total “cost of selection”when ALL these variable loci are taken into account? J.B.S. Haldane

7. Cédric Notredame (08/12/2015) Neutral Theory of Molecular Evolution M. Kimura Genotype:A 1 A 1 A 1 A 2 A 2 A 2 Fitness:1 1 1

8. Cédric Notredame (08/12/2015) How Do Sequences Evolve Each Portion of a Genome has its own Agenda.

9. Cédric Notredame (08/12/2015) The Genetic Code is Redundant: Third-position codon changes are often “silent”

10. Cédric Notredame (08/12/2015) Neutral Theory postulates that much of the genetic variation present in populations is not influenced by selection--rather it is a reflection of two interacting processes: (1)Mutation (2)Drift

11. Cédric Notredame (08/12/2015) H = 4Nu/[4Nu + 1], where N = population size and u = mutation rate (N) ^ (H)(H) ^ Neutral theory predicts a regular relationship between heterozygosity and population size

12. Cédric Notredame (08/12/2015) The Molecular Clock

13. Cédric Notredame (08/12/2015) Another prediction of Neutral Theory--Because mutation is regular (or “clocklike”) and because selection does not influence the rate of divergence, divergence of DNA and protein molecules in two separate lineages should occur in a REGULAR, clocklike manner i.e., the longer the time separating two species from their common ancestor, the more divergent will be a given protein or DNA molecule (and this relationship should be LINEAR) THE MOLECULAR CLOCK HYPOTHESIS

14. Cédric Notredame (08/12/2015) If most mutations are selectively neutral, we might expect to find that molecular divergence is “clocklike”. Do we, in fact, see this? 1 1.2 1.5 1.8 2 2.2 2.5 2.8 3 3.2 Amino Acid Substituions/Site x 10 150250350450550650 Independent evolution (MYA) Amino acid substitutions /site

15. Cédric Notredame (08/12/2015) Different molecular clocks for different proteins--another prediction

16. Cédric Notredame (08/12/2015) How Do Sequences Evolve ? CONSTRAINED Genome Positions Evolve SLOWLY EVERY Protein Family Has its Own Level Of Constraint FamilyK S K A Histone36.40 Insulin4.00.1 Interleukin I4.61.4  Globin5.10.6 Apolipoprot. AI4.51.6 Interferon G8.62.8 Rates in Substitutions/site/Billion Years as measured on Mouse Vs Human (80 Million years) Ks Synonymous Mutations, Ka Non-Neutral.

17. Cédric Notredame (08/12/2015)

18. How Can We Compare Sequences ? G C L I V A F Aliphatic Aromatic Hydrophobic C S T W Y Q H K R E DN Polar P G Small C Using Knowledge Could Work But we do not know enough about Evolution and Structure. Using Data works better.

19. Cédric Notredame (08/12/2015) How Do Sequences Evolve ? In a structure, each Amino Acid plays a Special Role OmpR, Cter Domain In the core, SIZE MATTERS On the surface, CHARGE MATTERS - - +

20. Cédric Notredame (08/12/2015) How Do Sequences Evolve ? Accepted Mutations Depend on the Structure Big -> Big Small->Small NO DELETION - - + Charged -> Charged Small Big or Small DELETIONS

21. Cédric Notredame (08/12/2015) Alignments and Evolution

22. Cédric Notredame (08/12/2015) An Alignment is a STORY ADKPKRPLSAYMLWLN ADKPKRPKPRLSAYMLWLN ADKPRRPLS-YMLWLN ADKPKRPLSAYMLWLN Mutations + Selection

23. Cédric Notredame (08/12/2015) An Alignment is a STORY ADKPRRP---LS-YMLWLN ADKPKRPKPRLSAYMLWLN Mutation InsertionDeletion ADKPKRPLSAYMLWLN ADKPKRPKPRLSAYMLWLN ADKPRRPLS-YMLWLN ADKPKRPLSAYMLWLN Mutations + Selection

24. Cédric Notredame (08/12/2015) Comparing Is Reconstructing Evolution

25. Cédric Notredame (08/12/2015) Divergeant or Convergeant Evolution ?

26. Cédric Notredame (08/12/2015) Evolution is NOT Always Divergent… AFGP with (ThrAlaAla)n Similar To Trypsynogen N AFGP with (ThrAlaAla)n S Chen et al, 97, PNAS, 94, 3811-16 NOT Similar to Trypsinogen

27. Cédric Notredame (08/12/2015) Evolution is NOT Always Divergent AFGP with (ThrAlaAla)n Similar To Trypsynogen AFGP with (ThrAlaAla)n NOT Similar to Trypsinogen N S SIMILAR Sequences BUT DIFFERENT origin

28. Cédric Notredame (08/12/2015) Orthologous And Paralogous Genes

29. Cédric Notredame (08/12/2015)

30. Speciation Duplication CC CC AA BB BB AA Orthology and Paralogy C  Paralogous C  C  Orthologous B  Duplication AA AA AA C  Orthologous A  and  A 

31. Cédric Notredame (08/12/2015) Koonin and the COGs: Best reciprocal BLAST matches

32. Cédric Notredame (08/12/2015) Koonin and the COGs: Best reciprocal BLAST matches

33. Cédric Notredame (08/12/2015)

36. Mixing Orthologs and Paralogs leads to inexact Phylogenetic trees

37. Cédric Notredame (08/12/2015) 0 My 1 My 3 My 2 My 1My 3 My 2 My

38. Cédric Notredame (08/12/2015) Positions are not enough to infer Orthology

39. Cédric Notredame (08/12/2015) Comparative Map of the Human and Mouse Genomes Human chromosomesMouse chromosomes Similar colored blocks = blocks of conserved synteny (blocks of similar genes)