Phylogenomics and the Diversity           and Diversification of Microbes                           Jonathan A. Eisen      ...
My Obsessions                           Jonathan A. Eisen                              UC Davis                           ...
Friday, January 28, 2011
Social Networking in ScienceHOME PAGE         MY TIMES       TODAYS PAPER   VIDEO   MOST POPULAR   TIMES TOPICS           ...
Bacterial evolveFriday, January 28, 2011
Research AreasFriday, January 28, 2011
Research Areas                           Mechanisms of                           Origin of New                            ...
Research Areas                           Mechanisms of     Variation in                           Origin of New    Mechani...
Research Areas                           Mechanisms of         Variation in                           Origin of New       ...
Research Areas                                  • Study the evolution of function                                  • Make ...
Research Areas                                           • Study the evolution of function                                ...
Research Areas   • Patterns of variation      • Within species      • Between species      • Comparative genomics plays   ...
Research Areas   • Patterns of variation      • Within species                  Variation in      • Between species       ...
Research Areas                    • Information needed to distinguish convergence from                    homology        ...
Research Areas                    • Information needed to distinguish convergence from                    homology        ...
Phylogenomics of Novelty                                                    Variation in       Mechanisms of              ...
Why do this?         • Discover causes and effects of differences in           evolvability         • Improve predictions ...
My microbial evolution obsessions         • Introduction         • Phylogenomic Stories                – Within genome inv...
Introduction                           Genome SequencingFriday, January 28, 2011
Fleischmann et al.                           1995Friday, January 28, 2011
From http://genomesonline.orgFriday, January 28, 2011
Friday, January 28, 2011
Friday, January 28, 2011
Friday, January 28, 2011
Human commensalsFriday, January 28, 2011
From http://genomesonline.orgFriday, January 28, 2011
Phylogenomics of Novelty I                           Origin of Functions from WithinFriday, January 28, 2011
Origin of New Functions                                       • Many different processes                                  ...
Origin of New Functions                                           • Many different processes                              ...
Phylogenomics of Novelty                                                    Variation in       Mechanisms of              ...
Example I:                Mutation Rates and Functional                         PredictionsFriday, January 28, 2011
From Eisen et al.                           1997 Nature                           Medicine 3:                           10...
Blast Search of H. pylori “MutS”         • Blast search pulls up Syn. sp MutS#2 with much higher p           value than ot...
MutL??                           Based on Eisen et al. 1997 Nature Medicine 3: 1076-1078.Friday, January 28, 2011
Phylogenetic Tree of MutS Family                                               Aquae                                      ...
MutS Subfamilies                                              MSH5                        MutS2                           ...
MutS Subfamilies          • MutS1	       	   Bacterial MMR          • MSH1	        	   Euk - mitochondrial MMR          • ...
Overlaying Functions onto Tree                                                                             MutS2          ...
Functional Prediction Using Tree                MSH5 - Meiotic Crossing Over                 MutS2 - Unknown Functions    ...
Friday, January 28, 2011
Evolutionary Functional Prediction                                        EXAMPLE A                                METHOD ...
Example 2: Recent Changes         • Phylogenomic functional prediction      NJ                                            ...
Example II:                           DuplicationFriday, January 28, 2011
Friday, January 28, 2011
Expansion of MCP Family in V. cholerae                           NJ                                                       ...
Tetrahymena Genome Processing                               • Probably exists as a defense mechanism                      ...
Phylogenomics of Novelty II               Sometimes, it is easier to steal, borrow, or                coopt functions rath...
Stealing DNAFriday, January 28, 2011
rRNA Tree of Life                           Bacteria                                                                  Arch...
Perna et al. 2003Friday, January 28, 2011
Network of Life                           Bacteria                                                                  Archae...
Non homology functional prediction                     methods         • Many genes have homologs in other species        ...
Phylogenetic profiling basis         • Microbial genes are lost rapidly when not           maintained by selection        ...
Non-Homology Predictions:                Phylogenetic Profiling          • Step 1: Search all genes in            organism...
Carboxydothermus hydrogenoformans   • Isolated from a Russian hotspring   • Thermophile (grows at 80°C)   • Anaerobic   • ...
Homologs of Sporulation Genes                                           Wu et al. 2005                                    ...
Carboxydothermus sporulates                           Wu et al. 2005 PLoS Genetics 1: e65.Friday, January 28, 2011
Wu et al. 2005 PLoS Genetics 1: e65.Friday, January 28, 2011
Stealing Organisms (Symbioses)Friday, January 28, 2011
Friday, January 28, 2011
Friday, January 28, 2011
Glassy Winged Sharpshooter                                      • Feeds on xylem                                        sa...
Xylem and Phloem                                              From                                              Lodish et ...
Sharpshooter Shotgun Sequencing                                                      shotgun                           Col...
Friday, January 28, 2011
Friday, January 28, 2011
Friday, January 28, 2011
Higher Evolutionary Rates in                           Endosymbionts   Wu et al. 2006 PLoS Biology 4: e188. Collaboration ...
Variation in Evolution Rates                                                                   MutS         MutL          ...
Baumannia is a Vitamin and                     Cofactor Producing Machine                                                 ...
No Amino-Acid SynthesisFriday, January 28, 2011
Friday, January 28, 2011
The Uncultured MajorityFriday, January 28, 2011
Great Plate Count Anomaly                           Culturing   Microscope                            Count       CountFri...
Great Plate Count Anomaly                           Culturing       Microscope                            Count      <<<< ...
Great Plate Count Anomaly                                                        DNA                           Culturing  ...
PCR Saves the DayFriday, January 28, 2011
rRNA: A Phylogenetic Anchor to                     Determine Who’s Out There                                              ...
rRNA: A Phylogenetic Anchor to                     Determine Who’s Out There                                              ...
Uses of rRNA sequences     The Hidden Majority                     Richness estimates                           Hugenholtz...
Friday, January 28, 2011
rRNA data increasing exponentially tooFriday, January 28, 2011
rRNA phylotyping issues         • Massive amounts of data                – 1 x 10^6 new partial sequences with new 454    ...
rRNA: A Phylogenetic Anchor to                     Determine Who’s Out There                                              ...
rRNA: A Phylogenetic Anchor to                     Determine Who’s Out There                                              ...
rRNA: A Phylogenetic Anchor to                     Determine Who’s Out There                                              ...
rRNA: A Phylogenetic Anchor to                     Determine Who’s Out There                                       Biology...
Perna et al. 2003Friday, January 28, 2011
Metagenomics                                    shotgun                                              cloneFriday, January ...
Friday, January 28, 2011
How can we best use                           metagenomic data?         • Many possible uses including:                – I...
Example I: Phylotyping with                    rRNA and other genesFriday, January 28, 2011
Weighted % of Clones                                                                                                      ...
Functional Diversity of Proteorhodopsins?                                          Venter et al., 2004Friday, January 28, ...
Example II: BinningFriday, January 28, 2011
Metagenomics ChallengeFriday, January 28, 2011
Binning challenge      A                                        T      B                                        U      C  ...
Binning challenge      A                                                             T      B                             ...
Binning challenge      A                                                             T      B                             ...
Binning challenge      A                                                           T      B                               ...
Binning challenge      A                                                           T      B                               ...
Friday, January 28, 2011
No Amino-Acid SynthesisFriday, January 28, 2011
Friday, January 28, 2011
???????Friday, January 28, 2011
Commonly Used Binning Methods                 Did not Work Well         • Assembly                – Only Baumannia generat...
CFB PhylaFriday, January 28, 2011
Binning by Phylogeny         • Four main “phylotypes”                –   Gamma proteobacteria (Baumannia)                –...
Binning by Phylogeny         • Four main “phylotypes”                –   Gamma proteobacteria (Baumannia)                –...
Wu et al. 2006 PLoS Biology 4: e188.Friday, January 28, 2011
Essential Amino Acid Synthesis                                        Wu et al. 2006 PLoS                                 ...
Sulcia makes amino acids   Baumannia makes vitamins and cofactors                            Wu et al. 2006 PLoS Biology 4...
Phylogenomics of Novelty III                           Knowing What We Don’t KnowFriday, January 28, 2011
As of 2002Friday, January 28, 2011
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11
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Phylogenomics and the Diversification of Microbes, J. A. Eisen at Genentech 1/27/11

  1. 1. Phylogenomics and the Diversity and Diversification of Microbes Jonathan A. Eisen UC Davis Genentech Talk January 27, 2011Friday, January 28, 2011
  2. 2. My Obsessions Jonathan A. Eisen UC Davis UCSD Talk January 19, 2011Friday, January 28, 2011
  3. 3. Friday, January 28, 2011
  4. 4. Social Networking in ScienceHOME PAGE MY TIMES TODAYS PAPER VIDEO MOST POPULAR TIMES TOPICS Welcome, fcollins Member Center Log OutSunday, April 1, 2007 HealthWORLD U.S. N.Y. / REGION BUSINESS TECHNOLOGY SCIENCE HEALTH SPORTS OPINION ARTS STYLE TRAVEL JOBS REAL ESTATE AUTOS FITNESS & NUTRITION HEALTH CARE POLICY MENTAL HEALTH & BEHAVIORScientist Reveals Secret of the Ocean: Its HimBy NICHOLAS WADEPublished: April 1, 2007 PRINT nytimes.com/sportsMaverick scientist J. Craig Venter has done it again. It was just a few years SINGLE-PAGEago that Dr. Venter announced that the human genome sequenced by Celera SAVEGenomics was in fact, mostly his own. And now, Venter has revealed a second SHAREtwist in his genomic self-examination. Venter was discussing his Global SHAREOcean Voyage, in which he used his personal yacht to collect ocean watersamples from around the world. He then used large filtration units to collect How good is your bracket? Compare your tournament picks to choices from members of The New York Times sportsmicrobes from the water samples which were then brought back to his high desk and other players.tech lab in Rockville, MD where he used the same methods that were used to Also in Sports: The Bracket Blog - all the news leading up to the Finalsequence the human genome to study the genomes of the 1000s of ocean Fourdwelling microbes found in each sample. In discussing the sampling methods, Venter let slip his Bats Blog: Spring training updates Play Magazine: How to build a super athletelatest attack on the standards of science – some of the samples were in fact not from the ocean, butwere from microbial habitats in and on his body.“The human microbiome is the next frontier,” Dr. Venter said. “The ocean voyage was just a cover.My main goal has always been to work on the microbes that live in and on people. And now that mygenome is nearly complete, why not use myself as the model for human microbiome studies as well.”It is certainly true that in the last few years, the microbes that live in and on people have become ahot research topic. So hot that the same people who were involved in the race to sequence the humangenome have been involved in this race too. Francis Collins, Venter main competitor and still the Friday, January 28, 2011director of the National Human Genome Research Institute (NHGRI), recently testified before
  5. 5. Bacterial evolveFriday, January 28, 2011
  6. 6. Research AreasFriday, January 28, 2011
  7. 7. Research Areas Mechanisms of Origin of New FunctionsFriday, January 28, 2011
  8. 8. Research Areas Mechanisms of Variation in Origin of New Mechanisms: Functions Patterns, Causes and EffectsFriday, January 28, 2011
  9. 9. Research Areas Mechanisms of Variation in Origin of New Mechanisms: Functions Patterns, Causes and Effects Species EvolutionFriday, January 28, 2011
  10. 10. Research Areas • Study the evolution of function • Make extensive use of genome sequence data • Requires integration of experimental information and genome analysis • Categorize and classify ways that novelty originates (examples) • Duplication and divergence • Recombination • Simple substitutions • Gene transferFriday, January 28, 2011
  11. 11. Research Areas • Study the evolution of function • Make extensive use of genome Mechanisms of sequence data Origin of New • Requires integration of Functions experimental information and genome analysis • Categorize and classify ways that novelty originates (examples) • Duplication and divergence • Recombination • Simple substitutions • Gene transferFriday, January 28, 2011
  12. 12. Research Areas • Patterns of variation • Within species • Between species • Comparative genomics plays important role • Causes • Variation in RRR • Regulatory complexity • Effects • Differences in evolvability • Ecological niche • Short and long term genome evolutionFriday, January 28, 2011
  13. 13. Research Areas • Patterns of variation • Within species Variation in • Between species Mechanisms: • Comparative genomics plays Patterns, Causes important role and Effects • Causes • Variation in RRR • Regulatory complexity • Effects • Differences in evolvability • Ecological niche • Short and long term genome evolutionFriday, January 28, 2011
  14. 14. Research Areas • Information needed to distinguish convergence from homology • Allows inference of rates and patterns of change • Allows one to determine if something is a “one time” event or a common theme in many lineagesFriday, January 28, 2011
  15. 15. Research Areas • Information needed to distinguish convergence from homology • Allows inference of rates and patterns of change • Allows one to determine if something is a “one time” event or a common theme in many lineages Species EvolutionFriday, January 28, 2011
  16. 16. Phylogenomics of Novelty Variation in Mechanisms of Mechanisms: Origin of New Patterns, Causes Functions and Effects Species EvolutionFriday, January 28, 2011
  17. 17. Why do this? • Discover causes and effects of differences in evolvability • Improve predictions from genome analysis • Guide interpretation of biological datFriday, January 28, 2011
  18. 18. My microbial evolution obsessions • Introduction • Phylogenomic Stories – Within genome invention of novelty – Stealing novelty – Community serviceFriday, January 28, 2011
  19. 19. Introduction Genome SequencingFriday, January 28, 2011
  20. 20. Fleischmann et al. 1995Friday, January 28, 2011
  21. 21. From http://genomesonline.orgFriday, January 28, 2011
  22. 22. Friday, January 28, 2011
  23. 23. Friday, January 28, 2011
  24. 24. Friday, January 28, 2011
  25. 25. Human commensalsFriday, January 28, 2011
  26. 26. From http://genomesonline.orgFriday, January 28, 2011
  27. 27. Phylogenomics of Novelty I Origin of Functions from WithinFriday, January 28, 2011
  28. 28. Origin of New Functions • Many different processes contribute to the origin of novelty • Denovo invention of new genes • Simple substitutions within existing genes • Duplication and divergence • Domain swapping • Genome rearrangements • Regulatory changesFriday, January 28, 2011
  29. 29. Origin of New Functions • Many different processes contribute to the origin of novelty Mechanisms of • Denovo invention of new Origin of New genes Functions • Simple substitutions within existing genes • Duplication and divergence • Domain swapping • Genome rearrangements • Regulatory changesFriday, January 28, 2011
  30. 30. Phylogenomics of Novelty Variation in Mechanisms of Mechanisms: Origin of New Patterns, Causes Functions and Effects Species EvolutionFriday, January 28, 2011
  31. 31. Example I: Mutation Rates and Functional PredictionsFriday, January 28, 2011
  32. 32. From Eisen et al. 1997 Nature Medicine 3: 1076-1078.Friday, January 28, 2011
  33. 33. Blast Search of H. pylori “MutS” • Blast search pulls up Syn. sp MutS#2 with much higher p value than other MutS homologs • Based on this TIGR predicted this species had mismatch repair • Assumes functional constancy Based on Eisen et al. 1997 Nature Medicine 3: 1076-1078.Friday, January 28, 2011
  34. 34. MutL?? Based on Eisen et al. 1997 Nature Medicine 3: 1076-1078.Friday, January 28, 2011
  35. 35. Phylogenetic Tree of MutS Family Aquae Strpy Bacsu Synsp Deira Helpy Yeast Human Borbu Metth Celeg mSaco Yeast Human Yeast Mouse Arath Celeg Human Arath Human Mouse Spombe Fly Yeast Xenla Rat Mouse Yeast Human Spombe Yeast Neucr Arath Aquae Trepa Chltr DeiraTheaq Thema BacsuBorbu Based on Eisen, SynspStrpy 1998 Nucl Acids Ecoli Neigo Res 26: 4291-4300.Friday, January 28, 2011
  36. 36. MutS Subfamilies MSH5 MutS2 Aquae Strpy Bacsu Synsp Deira Helpy Yeast Human Borbu Metth Celeg mSaco MSH6 Yeast Human Mouse Arath Yeast MSH4 Celeg Human Arath Human MSH3 Mouse Fly Spombe Yeast Xenla Rat Mouse Yeast MSH1 Spombe Human Yeast MSH2 Neucr Arath Aquae Trepa Chltr DeiraTheaq BacsuBorbu Thema SynspStrpy Ecoli Neigo Based on Eisen, 1998 Nucl Acids MutS1 Res 26: 4291-4300.Friday, January 28, 2011
  37. 37. MutS Subfamilies • MutS1 Bacterial MMR • MSH1 Euk - mitochondrial MMR • MSH2 Euk - all MMR in nucleus • MSH3 Euk - loop MMR in nucleus • MSH6 Euk - base:base MMR in nucleus • MutS2 Bacterial - function unknown • MSH4 Euk - meiotic crossing-over • MSH5 Euk - meiotic crossing-overFriday, January 28, 2011
  38. 38. Overlaying Functions onto Tree MutS2 Aquae MSH5 Strpy Bacsu Synsp Deira Helpy Yeast Human Borbu Metth Celeg MSH6 mSaco Yeast Human Mouse Arath Yeast MSH4 Celeg Human Arath Human MSH3 Mouse Fly Spombe Yeast Xenla Rat Mouse Yeast Human MSH1 Spombe Yeast MSH2 Neucr Arath Aquae Trepa Chltr DeiraTheaq BacsuBorbu Thema SynspStrpy Based on Eisen, Ecoli Neigo 1998 Nucl Acids MutS1 Res 26: 4291-4300.Friday, January 28, 2011
  39. 39. Functional Prediction Using Tree MSH5 - Meiotic Crossing Over MutS2 - Unknown Functions Aquae Strpy Bacsu Synsp Deira Helpy Yeast Human Borbu Metth Celeg MSH6 - Nuclear mSaco Repair Of Mismatches Yeast Human MSH4 - Meiotic Crossing Mouse Yeast Over Arath Celeg Human Arath MSH3 - Nuclear Human Mouse RepairOf Loops Spombe Fly Yeast Xenla Rat Mouse MSH2 - Eukaryotic Nuclear Yeast Human Mismatch and Loop Repair MSH1 Spombe Yeast Mitochondrial Neucr Arath Repair Aquae Trepa Chltr DeiraTheaq BacsuBorbu Thema SynspStrpy Ecoli Based on Eisen, Neigo 1998 Nucl Acids MutS1 - Bacterial Mismatch and Loop Repair Res 26: 4291-4300.Friday, January 28, 2011
  40. 40. Friday, January 28, 2011
  41. 41. Evolutionary Functional Prediction EXAMPLE A METHOD EXAMPLE B 2A CHOOSE GENE(S) OF INTEREST 5 3A 1 3 4 2B 2 IDENTIFY HOMOLOGS 5 1A 2A 1B 3B 6 ALIGN SEQUENCES 1A 2A 3A 1B 2B 3B 1 2 3 4 5 6 CALCULATE GENE TREE Duplication? 1A 2A 3A 1B 2B 3B 1 2 3 4 5 6 OVERLAY KNOWN FUNCTIONS ONTO TREE Duplication? 1 2 3 4 5 6 1A 2A 3A 1B 2B 3B INFER LIKELY FUNCTION OF GENE(S) OF INTEREST Ambiguous Duplication? Species 1 Species 2 Species 3 1A 1B 2A 2B 3A 3B 1 2 3 4 5 6 ACTUAL EVOLUTION (ASSUMED TO BE UNKNOWN) Based on Eisen, 1998 Genome Duplication Res 8: 163-167.Friday, January 28, 2011
  42. 42. Example 2: Recent Changes • Phylogenomic functional prediction NJ * ** V.cholerae0512 VC V.cholerae VCA1034 V.cholerae VC V.cholerae VC V.cholerae VC A0974 A0068 V.cholerae VC 0825 0282 may not work well for very newly V.cholerae VCA0906 V.cholerae VC A0979 V.cholerae VCA1056 V.cholerae VC1643 V.cholerae VC2161 ** V.cholerae VCA0923 ** V.cholerae VC0514 V.cholerae VC 1868 V.cholerae VC A0773 V.cholerae VC1313 evolved functions V.cholerae VC 1859 V.cholerae VC1413 V.cholerae VCA0268 ** V.cholerae VC A0658 V.cholerae VC 1405 * V.cholerae VC1298 V.cholerae VC1248 V.cholerae VCA0864 V.cholerae VCA0176 ** V.cholerae VCA0220 V.cholerae VC 1289 ** V.cholerae VC1069 A V.cholerae VC2439 • Can we use understanding of origin of V.cholerae VC967 1 V.cholerae VC A0031 V.cholerae VC1898 V.cholerae VC A0663 V.cholerae VC0988 A V.cholerae VC0216 * V.cholerae VC0449 V.cholerae VCA0008 V.cholerae VC1406 V.cholerae VC 1535 novelty to better understand these V.cholerae VC0840 B.subtilis gi2633766 Synechocystis sp. gi1001299 * Synechocystis sp.gi1001300 * Synechocystis sp. gi1652276 * Synechocystis sp. gi1652103 H.pylori gi2313716 ** **H.pylori 99 gi4155097 C.jejuni Cj1190c C.jejuni Cj1110c A.fulgidus gi2649560 cases? A.fulgidus gi2649548 ** B.subtilis gi2634254 B.subtilis gi2632630 B.subtilis gi2635607 B.subtilis gi2635608 ** B.subtilis gi2635609 ** ** B.subtilisgi2635882 gi2635610 B.subtilis E.coligi1788195 E.coli gi2367378 * ** E.coligi1788194 E.coli A1092 gi1787690 V.cholerae VC • Screen genomes for genes that have V.cholerae VC 0098 E.coli gi1789453 H.pylori gi2313186 H.pylori 99 gi4154603 ** C.jejuni Cj0144 C.jejuni Cj1564 **C.jejuni C.jejuni Cj0262c Cj1506c ** H.pylori gi2313163 * H.pylori 99 gi4154575 changed recently **H.pylori gi2313179 ** H.pylori 99 gi4154599 ** C.jejuni Cj0019c C.jejuni Cj0951c C.jejuni Cj0246c B.subtilis gi2633374 T.maritima TM0014 V.cholerae VC1403 V.cholerae VCA1088 T.pallidum gi3322777 ** T.pallidum gi3322939 ** T.pallidum gi3322938 – Pseudogenes and gene loss B.burgdorferi gi2688522 T.pallidum gi3322296 B.burgdorferi gi2688521 * T.maritima TM0429 **T.maritima TM0918 * **T.maritima T.maritima TM0023 TM1428 T.maritima TM1143 T.maritima TM1146 P.abyssi PAB1308 P.horikoshii gi3256846 – Contingency Loci ** P.abyssiPAB1336 ** P.horikoshii gi3256896 ** **P.abyssi PAB2066 ** P.horikoshii ** P.abyssi gi3258290 * PAB1026 ** P.horikoshii DRA00354 gi3256884 D.radiodurans D.radiodurans ** D.radioduransDRA0353 ** DRA0352 ** V.cholerae VC 1394 P.abyssi PAB1189 P.horikoshii gi3258414 – Acquisition (e.g., LGT) ** B.burgdorferi gi2688621 M.tuberculosis gi1666149 V.cholerae VC 0622 – Unusual dS/dN ratios – Rapid evolutionary ratesFriday, January 28, 2011
  43. 43. Example II: DuplicationFriday, January 28, 2011
  44. 44. Friday, January 28, 2011
  45. 45. Expansion of MCP Family in V. cholerae NJ V.cholerae VC0512 V.cholerae VCA1034 V.cholerae VCA0974 V.cholerae VCA0068 ** V.cholerae VC0825 * V.cholerae VC0282 V.cholerae VCA0906 V.cholerae VCA0979 V.cholerae VCA1056 V.cholerae VC1643 V.cholerae VC2161 V.cholerae VCA0923 ** V.cholerae VC0514 ** V.cholerae VC1868 V.cholerae VCA0773 V.cholerae VC1313 V.cholerae VC1859 V.cholerae VC1413 V.cholerae VCA0268 ** V.cholerae VCA0658 V.cholerae VC1405 V.cholerae VC1298 * V.cholerae VC1248 V.cholerae VCA0864 V.cholerae VCA0176 ** V.cholerae VCA0220 V.cholerae VC1289 ** V.cholerae VCA1069 V.cholerae VC2439 V.cholerae VC1967 V.cholerae VCA0031 V.cholerae VC1898 V.cholerae VCA0663 V.cholerae VCA0988 V.cholerae VC0216 * V.cholerae VC0449 V.cholerae VCA0008 V.cholerae VC1406 V.cholerae VC1535 V.cholerae VC0840 B.subtilis gi2633766 Synechocystis sp. gi1001299 * Synechocystis sp. gi1001300 * Synechocystis sp. gi1652276 * Synechocystis sp. gi1652103 H.pylori gi2313716 H.pylori99 gi4155097 ** C.jejuni Cj1190c ** C.jejuni Cj1110c A.fulgidus gi2649560 A.fulgidus gi2649548 ** B.subtilis gi2634254 B.subtilis gi2632630 B.subtilis gi2635607 B.subtilis gi2635608 ** B.subtilis gi2635609 ** ** B.subtilis gi2635610 B.subtilis gi2635882 E.coli gi1788195 E.coli gi2367378 ** E.coli gi1788194 * E.coli gi1787690 V.cholerae VCA1092 V.cholerae VC0098 E.coli gi1789453 H.pylori gi2313186 H.pylori99 gi4154603 ** C.jejuni Cj0144 C.jejuni Cj1564 ** C.jejuni Cj0262c ** C.jejuni Cj1506c H.pylori gi2313163 * H.pylori99 gi4154575 ** H.pylori gi2313179 ** H.pylori99 gi4154599 ** C.jejuni Cj0019c C.jejuni Cj0951c C.jejuni Cj0246c B.subtilis gi2633374 T.maritima TM0014 V.cholerae VC1403 V.cholerae VCA1088 T.pallidum gi3322777 ** T.pallidum gi3322939 ** T.pallidum gi3322938 B.burgdorferi gi2688522 T.pallidum gi3322296 B.burgdorferi gi2688521 * T.maritima TM0429 ** T.maritima TM0918 ** T.maritima TM0023 * T.maritima TM1428 T.maritima TM1143 T.maritima TM1146 P.abyssi PAB1308 P.horikoshii gi3256846 ** P.abyssi PAB1336 ** P.horikoshii gi3256896 ** ** P.abyssi PAB2066 ** ** P.horikoshii gi3258290 * Based on Heidelberg et al. P.abyssi PAB1026 ** P.horikoshii gi3256884 D.radiodurans DRA00354 ** D.radiodurans DRA0353 D.radiodurans DRA0352 2000 Nature 406:477-483. ** ** V.cholerae VC1394 P.abyssi PAB1189 P.horikoshii gi3258414 ** B.burgdorferi gi2688621 M.tuberculosis gi1666149 V.cholerae VC0622Friday, January 28, 2011
  46. 46. Tetrahymena Genome Processing • Probably exists as a defense mechanism • Analogous to RIPPING and heterochromatin silencing • Presence of repetitive DNA in MAC but not TEs suggests the mechanism involves targeting foreign DNA • Thus unlike RIPPING ciliate processing does not limit diversification by duplication Eisen et al. 2006. PLoS Biology.Friday, January 28, 2011
  47. 47. Phylogenomics of Novelty II Sometimes, it is easier to steal, borrow, or coopt functions rather than evolve them anewFriday, January 28, 2011
  48. 48. Stealing DNAFriday, January 28, 2011
  49. 49. rRNA Tree of Life Bacteria Archaea Eukaryotes FIgure from Barton, Eisen et al. “Evolution”, CSHL Press. Based on tree from Pace NR, 2003.Friday, January 28, 2011
  50. 50. Perna et al. 2003Friday, January 28, 2011
  51. 51. Network of Life Bacteria Archaea Eukaryotes Figure from Barton, Eisen et al. “Evolution”, CSHL Press. Based on tree from Pace NR, 2003.Friday, January 28, 2011
  52. 52. Non homology functional prediction methods • Many genes have homologs in other species but no homologs have ever been studied experimentally • Non-homology methods can make functional predictions for these • Example: phylogenetic profilingFriday, January 28, 2011
  53. 53. Phylogenetic profiling basis • Microbial genes are lost rapidly when not maintained by selection • Genes can be acquired by lateral transfer • Frequently gain and loss occurs for entire pathways/processes • Thus might be able to use correlated presence/absence information to identify genes with similar functionsFriday, January 28, 2011
  54. 54. Non-Homology Predictions: Phylogenetic Profiling • Step 1: Search all genes in organisms of interest against all other genomes • Ask: Yes or No, is each gene found in each other species • Cluster genes by distribution patterns (profiles)Friday, January 28, 2011
  55. 55. Carboxydothermus hydrogenoformans • Isolated from a Russian hotspring • Thermophile (grows at 80°C) • Anaerobic • Grows very efficiently on CO (Carbon Monoxide) • Produces hydrogen gas • Low GC Gram positive (Firmicute) • Genome Determined (Wu et al. 2005 PLoS Genetics 1: e65. )Friday, January 28, 2011
  56. 56. Homologs of Sporulation Genes Wu et al. 2005 PLoS Genetics 1: e65.Friday, January 28, 2011
  57. 57. Carboxydothermus sporulates Wu et al. 2005 PLoS Genetics 1: e65.Friday, January 28, 2011
  58. 58. Wu et al. 2005 PLoS Genetics 1: e65.Friday, January 28, 2011
  59. 59. Stealing Organisms (Symbioses)Friday, January 28, 2011
  60. 60. Friday, January 28, 2011
  61. 61. Friday, January 28, 2011
  62. 62. Glassy Winged Sharpshooter • Feeds on xylem sap • Vector for Pierce’s Disease • Potential bioterror agentFriday, January 28, 2011
  63. 63. Xylem and Phloem From Lodish et al. 2000Friday, January 28, 2011
  64. 64. Sharpshooter Shotgun Sequencing shotgun Collaboration with Nancy Wu et al. 2006 PLoS Biology 4: e188. Moran’s labFriday, January 28, 2011
  65. 65. Friday, January 28, 2011
  66. 66. Friday, January 28, 2011
  67. 67. Friday, January 28, 2011
  68. 68. Higher Evolutionary Rates in Endosymbionts Wu et al. 2006 PLoS Biology 4: e188. Collaboration with Nancy Moran’ s LabFriday, January 28, 2011
  69. 69. Variation in Evolution Rates MutS MutL + + + + + + + + _ _ _ _ Wu et al. 2006 PLoS Biology 4: e188. Collaboration with Nancy Moran’ s LabFriday, January 28, 2011
  70. 70. Baumannia is a Vitamin and Cofactor Producing Machine Wu et al. 2006 PLoS Biology 4: e188.Friday, January 28, 2011
  71. 71. No Amino-Acid SynthesisFriday, January 28, 2011
  72. 72. Friday, January 28, 2011
  73. 73. The Uncultured MajorityFriday, January 28, 2011
  74. 74. Great Plate Count Anomaly Culturing Microscope Count CountFriday, January 28, 2011
  75. 75. Great Plate Count Anomaly Culturing Microscope Count <<<< CountFriday, January 28, 2011
  76. 76. Great Plate Count Anomaly DNA Culturing Microscope Count <<<< CountFriday, January 28, 2011
  77. 77. PCR Saves the DayFriday, January 28, 2011
  78. 78. rRNA: A Phylogenetic Anchor to Determine Who’s Out There Eisen et al. 1992Friday, January 28, 2011
  79. 79. rRNA: A Phylogenetic Anchor to Determine Who’s Out There Eisen et al. 1992Friday, January 28, 2011
  80. 80. Uses of rRNA sequences The Hidden Majority Richness estimates Hugenholtz 2002 Bohannan and Hughes 2003Friday, January 28, 2011
  81. 81. Friday, January 28, 2011
  82. 82. rRNA data increasing exponentially tooFriday, January 28, 2011
  83. 83. rRNA phylotyping issues • Massive amounts of data – 1 x 10^6 new partial sequences with new 454 – 2 x 10^6 full length sequences in DB • Alignments of new sequences not always straightforward • Solutions: – Reliance on similarity scores (bad) – High throughput automated phylogenetic tools • STAP • WATERsFriday, January 28, 2011
  84. 84. rRNA: A Phylogenetic Anchor to Determine Who’s Out There Eisen et al. 1992Friday, January 28, 2011
  85. 85. rRNA: A Phylogenetic Anchor to Determine Who’s Out There Eisen et al. 1992Friday, January 28, 2011
  86. 86. rRNA: A Phylogenetic Anchor to Determine Who’s Out There Eisen et al. 1992Friday, January 28, 2011
  87. 87. rRNA: A Phylogenetic Anchor to Determine Who’s Out There Biology not Eisen et similar enough al. 1992Friday, January 28, 2011
  88. 88. Perna et al. 2003Friday, January 28, 2011
  89. 89. Metagenomics shotgun cloneFriday, January 28, 2011
  90. 90. Friday, January 28, 2011
  91. 91. How can we best use metagenomic data? • Many possible uses including: – Improvements on rRNA based phylotyping and species diversity measurements – Adding functional information on top of phylogenetic/species diversity information • Most/all possible uses either require or are improved with phylogenetic analysisFriday, January 28, 2011
  92. 92. Example I: Phylotyping with rRNA and other genesFriday, January 28, 2011
  93. 93. Weighted % of Clones 0 0.1250 0.2500 0.3750 0.5000 Al ph ap ro t eo Be b ac ta pr t er ot e ia G ob am acFriday, January 28, 2011 m t er ap ia ro Ep te si ob lo ac np t er ro ia De t eo lta b ac pr te ot ria eo b C ac ya ter n ob ia ac t er Fi ia rm ic u te Ac s tin ob ac t er C ia hl or ob i C FB Major Phylogenetic Group Sargasso Phylotypes C hl or ofl xi e Sp iro ch ae te Fu so s De ba in ct er oc ia oc cu s- Eu The ry r ar mu ch s ae C ot re a na rc ha eo ta Shotgun Sequencing Allows Use of Other Markers EFG Venter et al., Science 304: 66-74. 2004 EFTu rRNA RecA RpoB HSP70
  94. 94. Functional Diversity of Proteorhodopsins? Venter et al., 2004Friday, January 28, 2011
  95. 95. Example II: BinningFriday, January 28, 2011
  96. 96. Metagenomics ChallengeFriday, January 28, 2011
  97. 97. Binning challenge A T B U C V D W E X F Y G ZFriday, January 28, 2011
  98. 98. Binning challenge A T B U C V D W E X F Y G Best binning method: reference genomes ZFriday, January 28, 2011
  99. 99. Binning challenge A T B U C V D W E X F Y G Best binning method: reference genomes ZFriday, January 28, 2011
  100. 100. Binning challenge A T B U C V D W E X F Y G No reference genome? What do you do? ZFriday, January 28, 2011
  101. 101. Binning challenge A T B U C V D W E X F Y G No reference genome? What do you do? Z Phylogeny ....Friday, January 28, 2011
  102. 102. Friday, January 28, 2011
  103. 103. No Amino-Acid SynthesisFriday, January 28, 2011
  104. 104. Friday, January 28, 2011
  105. 105. ???????Friday, January 28, 2011
  106. 106. Commonly Used Binning Methods Did not Work Well • Assembly – Only Baumannia generated good contigs • Depth of coverage – Everything else 0-1X coverage • Nucleotide composition – No detectible peaks in any vector we looked atFriday, January 28, 2011
  107. 107. CFB PhylaFriday, January 28, 2011
  108. 108. Binning by Phylogeny • Four main “phylotypes” – Gamma proteobacteria (Baumannia) – Arthropoda (sharpshooter) – Bacteroidetes (Sulcia) – Alpha-proteobacteria (Wolbachia)Friday, January 28, 2011
  109. 109. Binning by Phylogeny • Four main “phylotypes” – Gamma proteobacteria (Baumannia) – Arthropoda (sharpshooter) – Bacteroidetes (Sulcia) - only a.a. genes here – Alpha-proteobacteria (Wolbachia)Friday, January 28, 2011
  110. 110. Wu et al. 2006 PLoS Biology 4: e188.Friday, January 28, 2011
  111. 111. Essential Amino Acid Synthesis Wu et al. 2006 PLoS Biology 4: e188.Friday, January 28, 2011
  112. 112. Sulcia makes amino acids Baumannia makes vitamins and cofactors Wu et al. 2006 PLoS Biology 4: e188.Friday, January 28, 2011
  113. 113. Phylogenomics of Novelty III Knowing What We Don’t KnowFriday, January 28, 2011
  114. 114. As of 2002Friday, January 28, 2011
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