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Homology assessment and molecular sequence alignment.

Homology assessment and molecular sequence alignment. Chris Stewart and Ka Yi Ling Genetics 677. Classical Phylogenetics. Molecular Phylogenetics. Homology. Big picture. Evolution. Divergent. Convergent. Homology. Analogy. Orthologs. Paralogs. Systematics. Homology.

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Homology assessment and molecular sequence alignment.

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  1. Homology assessment and molecular sequence alignment. Chris Stewart and Ka Yi Ling Genetics 677

  2. Classical Phylogenetics Molecular Phylogenetics Homology

  3. Big picture Evolution Divergent Convergent Homology Analogy Orthologs Paralogs Systematics

  4. Homology • Equal in position and details in structure 2. Equal in developmental origin (i.e. cellular/tissue structure) 3. Logical and continual series of character state transformations Figure from http://images-eu.amazon.com/images/P/0895262002.01.LZZZZZZZ.jpg

  5. Homology Speciation Duplication A B C

  6. Character Trait from group of organisms, which has two or more independent states that can be evaluated http://www.choose-life.org/Map_states_color.jpg

  7. Parsimony Working principle that prefers the least complex explanation for an observation Figure from http://www.cartoonchurch.com/cartoons/large/simple-living-cartoon.gif

  8. Classical phylogenetics Method of parsimony analysis used to develop cladograms explaining evolutionary relationships. Fig 1. Hypothetical cladogram

  9. Constructing cladograms B A C E F D G

  10. Matrix 1 1 1 1 1 1 1 1 1 0 1 1 1 1 0 0 1 1 1 1 0 0 1 0 1 0 0 0 1 0 0 0 0 0 1 0 0 0 0 0 0 0

  11. Possible cladograms ….which one do you pick?

  12. Homoplasy & subjective characters A faulty assignment of primary homology Figure from: http://www.blackwellpublishing.com/ridley/images/analogies.jpg

  13. Things to consider • Auxillary Principle • Congruence Test

  14. More things to consider • Weighting • Needs to respond to homoplasy • Independent characters http://ksuoncampus.com/2008/01/29/evolution-of-mario/

  15. Molecular Phylogenetics • Goal: • to infer process from pattern • Why • Not just the observables • Alternative method to derive evolutionary relationships

  16. Protein or Gene of interest Sequence alignment programs Sequence alignment programs Figure modified from http://bioinfo.ochoa.fib.es/docus/courses/Ali2005Filogenias/seq_analysis/images/SeqAnalFloChart.gif

  17. Molecular characters • What can be used? • Nucleotide sequences • Protein sequences • DNA • RNA • Protein • NO single universally accepted recipe Figure from http://www.ittc.ku.edu/bioinfo_seminar/images/wheel.gif

  18. List of alignment software

  19. Sequence Alignment • Types • Pairwise alignment • Multiple sequence alignment Figure from http://en.wikipedia.org/wiki/Sequence_alignment

  20. Human Molecular Genetics, 2006, Vol. 15, Review Issue 1, R54

  21. The nuts and bolts • Gene/ protein of interest • Homolog search • Sequence alignment • Tree building Figure from http://www.usingneuralnetworks.com/images/Face_But_Not_The_Name_Cartoon.jpg

  22. Database Search: BLAST • Basic Local Alignment Search Tool • Input: Protein and Nucleotide • Default algorithm: Blosum62 • Other algorithms: PAM family, Blosum family • Sites that use BLAST: NCBI, EBI, GenomeNet, PIR, DDBJ Figure: NCBI alignment result site.

  23. How does BLAST score an alignment? Default matrix in BLAST 2.0 BLOSUM= BLOcks Substitution Matrix Based on local alignments

  24. How does BLAST score an alignment? BLOSUM62: contributions from proteins more than 62% identical are weighted to sum to one. Scores: Number values

  25. BLAST

  26. The nuts and bolts • Gene/protein of interest • Homolog search • Sequence alignment • Tree building Figure from http://www.usingneuralnetworks.com/images/Face_But_Not_The_Name_Cartoon.jpg

  27. Homologene

  28. Aligning Genes

  29. Homologene scoring

  30. The nuts and bolts • Gene/protein of interest • Homolog search • Sequence alignment • Tree building Figure from http://www.usingneuralnetworks.com/images/Face_But_Not_The_Name_Cartoon.jpg

  31. Pair-alignment • Algorithm: Needleman-wunsch dynamic programming • Global alignment • DNA, protein • Find positional primary homology • Sites that use N-W: EBI server Figure from http://ww2.cs.fsu.edu/~hui/research/scanalyze_tutorial/pics/registered_group.jpg

  32. Needleman-Wunsch algorithm Figure from Journal of Medical Physics 39 (2006) pg 29

  33. Needle-wunsch algorithm

  34. BLAST align

  35. Multiple sequence alignment • Example: ClustalW • Progressive alignment • Nucleotide and Protein sequences • Local or Global alignment • Sites that use MSA: EBI, DDBJ, PBIL, EMBNet, GenomeNet Figure from www.cs.umbc.edu

  36. ClustalW @ EBI

  37. The nuts and bolts • Gene/protein of interest • Homolog search • Sequence alignment • Tree building Figure from http://www.usingneuralnetworks.com/images/Face_But_Not_The_Name_Cartoon.jpg

  38. SRD5A2 @ TreeFAM

  39. Discussion • Does sequence orthology relate to functional equivalence? • Can paralogs be functionally related? • Do unsequenced genomic regions affect the understanding of orthology and paralogy? Figures from: http://www.ndpgenderequality.ie/images/cartoons/cartoon_large_intro.gif and http://www.faithmouse.com/cartoon567.jpg

  40. Pros Cons

  41. Pros and cons • Best guess • Parsimony • Algorithms • Speed vs accuracy • Evolution vs religion • Evolutionary history • Find animal models • Relation between structure and function • Biological processes Figure from: http://www.pbrainprojects.com/images/angel_devil.jpg

  42. Assumptions, assumptions, assumptions • If Xs is true then the tree is true… Figure from: http://www.gdargaud.net/Humor/Pics/string_theory.png

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