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Exploiting new Genome Data and Web Resources for the Phylogenetic Analyisis of  Proteases, Substrates and Inhibitors Chris...
Introduction  <ul><li>Multiple alignments and phylogenetic trees are established techniques for examining the evolutionary...
Evolutionary Context of Mapping Proteases to Functions From: Searls DB.  Pharmacophylogenomics: genes, evolution and drug ...
Once upon a time:  all we had was …
So what we used to do was …..
But now we have …… http://www.ensembl.org/index.html
Much more data …. Human Mouse Rat Fugu Tetraodon  Zebrafish C. savignyi * Fruitfly Malaria mosquito, C. elegans  Medaka Rh...
So what can we do with all these sequences … <ul><li>Filter conserved features by comparisons at all levels from 5 million...
You can use Ensembl for orthologue prediction - but its getting complicated …
So you can use http://www.treefam.org/ <ul><li>TreeFam is a database of phylogenetic trees of animal genes </li></ul><ul><...
To get  pre-cooked protease trees
And sub-trees with schematic P-fam matches
You can then look at substrate evolution
… .and compare the two
Trees can give clear ancestry  And structural inferences from Pfam
They can also show divergence between protease and substrate
You can also track  protease complex members
…  here’s a new one (see poster 13)
And tight conservation of some substrates
You can resolve complex non-orthology López-Otín  et al.   TreeView
You may find cases of pre-cooked mapping of conservation onto structure http://www.ebi.ac.uk/thornton-srv/databases/pdbsum/
Advantages of Pre-cooked Alignments and Trees <ul><li>Instant results </li></ul><ul><li>Automaticaly synchromised with gen...
Advantages of DIY  <ul><li>Inspecting alignments and building your own trees helps you understand their interpretation </l...
Conclusions <ul><li>Don’t drown in the genome deluge – mine it ! </li></ul><ul><li>Pre-cooked Web bioinformatic sources of...
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Protease Phylogeny

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Review of sources for protease phylogeny. Presented at Biochemical Society Protease meeting, Cirencester , UK Jan07

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Protease Phylogeny

  1. 1. Exploiting new Genome Data and Web Resources for the Phylogenetic Analyisis of Proteases, Substrates and Inhibitors Christopher Southan Global Compound Sciences, AstraZeneca R&D, Mölndal, Sweden
  2. 2. Introduction <ul><li>Multiple alignments and phylogenetic trees are established techniques for examining the evolutionary history of proteases </li></ul><ul><li>New complete genome data gives a broader and deeper phylogentic range </li></ul><ul><li>We have improved and expanded annotation of not only proteases but also their substrates, interaction partners in complexes and inhibitor proteins </li></ul><ul><li>This facilitates the mapping of conserved postions to structure and catalytic and/or binding functions </li></ul><ul><li>Structural coverage across protease classes is increasing </li></ul>
  3. 3. Evolutionary Context of Mapping Proteases to Functions From: Searls DB. Pharmacophylogenomics: genes, evolution and drug targets. Nat Rev Drug Discov . 2003
  4. 4. Once upon a time: all we had was …
  5. 5. So what we used to do was …..
  6. 6. But now we have …… http://www.ensembl.org/index.html
  7. 7. Much more data …. Human Mouse Rat Fugu Tetraodon Zebrafish C. savignyi * Fruitfly Malaria mosquito, C. elegans Medaka Rhesus macaque Chimpanzee Dog Cow Chicken Xenopus C. intestinalis Fever mosquito* 5 23 41 91 83 310 92 360 450 990 25 70 140 ? 550 250 70? 100 200 300 400 500 1000 Million years Honey bee 340 Yeast Opposum 170 1500? ? Stickleback Armadillo * Elephant * Tenrec * 105 ? Rabbit * 95 ? Chordata Vertebrata Amniota Tetrapoda Mammalia Eutheria Teleostei Urochordata Arthropoda Nematoda Fungi Aves Amphibia Metatheria
  8. 8. So what can we do with all these sequences … <ul><li>Filter conserved features by comparisons at all levels from 5 million to 1 billion years </li></ul><ul><li>Percieve more gradual changes </li></ul><ul><li>Root and/or outgroup trees at deeper levels </li></ul><ul><li>Follow lineage-specific duplications and losses more clearly </li></ul><ul><li>Resolve complex orthology questions </li></ul><ul><li>Asses the consequences of SNPs or alternative splicing </li></ul><ul><li>Spot horizonal gene transfer events </li></ul><ul><li>Look at the evolution of substrates and inhibitors </li></ul><ul><li>Spot discordant evolution where protease and substrate diverge </li></ul><ul><li>Design new experiments </li></ul>
  9. 9. You can use Ensembl for orthologue prediction - but its getting complicated …
  10. 10. So you can use http://www.treefam.org/ <ul><li>TreeFam is a database of phylogenetic trees of animal genes </li></ul><ul><li>Provides curated resources for ortholog and paralog assignments, and evolutionary history of various gene families </li></ul><ul><li>Includes yeast and plant outgroup genes to reveal these distant members </li></ul><ul><li>Infers orthologs by fiting a gene tree into the universal species tree and finds historical duplications, speciations and losses events </li></ul>
  11. 11. To get pre-cooked protease trees
  12. 12. And sub-trees with schematic P-fam matches
  13. 13. You can then look at substrate evolution
  14. 14. … .and compare the two
  15. 15. Trees can give clear ancestry And structural inferences from Pfam
  16. 16. They can also show divergence between protease and substrate
  17. 17. You can also track protease complex members
  18. 18. … here’s a new one (see poster 13)
  19. 19. And tight conservation of some substrates
  20. 20. You can resolve complex non-orthology López-Otín et al. TreeView
  21. 21. You may find cases of pre-cooked mapping of conservation onto structure http://www.ebi.ac.uk/thornton-srv/databases/pdbsum/
  22. 22. Advantages of Pre-cooked Alignments and Trees <ul><li>Instant results </li></ul><ul><li>Automaticaly synchromised with genome pipeline updates </li></ul><ul><li>Exploits massive global CPU horsepower resources </li></ul><ul><li>Standardised </li></ul><ul><li>Includes some curation </li></ul><ul><li>Good reliability for 1:1 orthologues </li></ul><ul><li>Operative bioinformatic skills not necessary </li></ul><ul><li>Conectivity with other Web resources including structure </li></ul><ul><li>Rapid exploration of large protein families </li></ul><ul><li>Can identify where to focus the DIY </li></ul>
  23. 23. Advantages of DIY <ul><li>Inspecting alignments and building your own trees helps you understand their interpretation </li></ul><ul><li>Good Web toolbox available </li></ul><ul><li>Automated default gapping parameters not always best </li></ul><ul><li>Global alignments not always suitable for paralogues </li></ul><ul><li>Can be informative to de-signal, de-gap, make domain-specific or non-contiguous comparisons </li></ul><ul><li>Can select sub-famly branches out of big trees </li></ul><ul><li>Need to look out for “dead” proteases </li></ul><ul><li>Can explore twighlight-zone relationships </li></ul><ul><li>cDNA/genome assembly/gene prediction errors can be identified and fixed </li></ul><ul><li>Can include new pre-assembly genomic or EST data </li></ul><ul><li>Can extend to DNA alignments and ka/ks comparison </li></ul><ul><li>Direct projection onto protein structures or models </li></ul><ul><li>Different pre-cooked resources don’t always agree </li></ul><ul><li>Can explore comparative expression data </li></ul>
  24. 24. Conclusions <ul><li>Don’t drown in the genome deluge – mine it ! </li></ul><ul><li>Pre-cooked Web bioinformatic sources offer increasing coverage for your favourite proteases </li></ul><ul><li>Don’t forget substrates and inhibitors </li></ul><ul><li>There are many tools to make DIY phylogenies easier </li></ul><ul><li>Not only can you plausibly interpret evolutionary histories but you can also perform experiments to test your hypotheses </li></ul><ul><li>We owe a big debt of gratitute to those who work to provide genome annotation pipelines and bioinformatic Web resources </li></ul>

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