Jonathan Eisen talk for #SCS2012 at #ISMB "Networks in genomics and bioinformatics: from phylogeny to Twitter"
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Talk as part of http://www.iscb.org/ismb2012-program/ismb2012-scs "Networks in genomics and bioinformatics: from phylogeny to Twitter"
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Jonathan Eisen talk for #SCS2012 at #ISMB "Networks in genomics and bioinformatics: from phylogeny to Twitter"
- 1. Networks in genomics and bioinformatics: from phylogeny to Twitter ISCB2012 July 12, 2012 Jonathan A. Eisen University of California, Davis @phylogenomics Friday, July 13, 12
- 2. Networks in genomics and bioinformatics: from phylogeny to Twitter ISCB2012 July 12, 2012 Jonathan A. Eisen University of California, Davis @phylogenomics Friday, July 13, 12
- 3. A meandering path and lessons “learned” ISCB2012 July 12, 2012 Jonathan A. Eisen University of California, Davis @phylogenomics Friday, July 13, 12
- 4. Friday, July 13, 12
- 5. Social Networking in Science Friday, July 13, 12
- 6. Bacterial evolve Friday, July 13, 12
- 7. Friday, July 13, 12
- 8. Phylogenomics of Novelty Friday, July 13, 12
- 9. Phylogenomics of Novelty Friday, July 13, 12
- 10. Phylogenomics of Novelty Origin of New Functions and Processes Friday, July 13, 12
- 11. Phylogenomics of Novelty Origin of New Functions and Processes •New genes •Changes in old genes •Changes in pathways Friday, July 13, 12
- 12. Phylogenomics of Novelty Origin of New Functions and Processes •New genes •Changes in old genes •Changes in pathways Friday, July 13, 12
- 13. Phylogenomics of Novelty Origin of New Genome Functions and Dynamics Processes •New genes •Changes in old genes •Changes in pathways Friday, July 13, 12
- 14. Phylogenomics of Novelty Origin of New Genome Functions and Dynamics Processes •Evolvability •New genes •Repair and •Changes in old genes recombination processes •Changes in pathways •Intragenomic variation Friday, July 13, 12
- 15. Phylogenomics of Novelty Origin of New Genome Functions and Dynamics Processes •Evolvability •New genes •Repair and •Changes in old genes recombination processes •Changes in pathways •Intragenomic variation Friday, July 13, 12
- 16. Phylogenomics of Novelty Origin of New Genome Functions and Dynamics Processes •Evolvability •New genes •Repair and •Changes in old genes recombination processes •Changes in pathways •Intragenomic variation Species Evolution Friday, July 13, 12
- 17. Phylogenomics of Novelty Origin of New Genome Functions and Dynamics Processes •Evolvability •New genes •Repair and •Changes in old genes recombination processes •Changes in pathways •Intragenomic variation Species Evolution •Phylogenetic history •Vertical vs. horizontal descent •Needed to track gain/loss of processes, infer convergence Friday, July 13, 12
- 18. Undergrad Lesson 1: Be prepared for random events • Gould’s class b/c planned on not majoring in Biology • RMBL via backpacking trip • Geology library job w/ Nabokov collection b/c went to wrong building • Discovering Colleen Cavanaugh’s lab via street encounter Friday, July 13, 12
- 19. Undergrad Lesson 2: Phylogeny Matters • “MacClade” • Phylogenetic ecology • Phylotyping Friday, July 13, 12
- 20. Phylogeny Matters Eisen et al. 1992 Friday, July 13, 12
- 21. Grad school lesson I: find right people to work with • Went to work on butterfly population biology and phylogeny • Advisor and I did not see eye to eye • Despite great subject for me (combined phylogeny, molecular evolution, RMBL, etc), chose not to join lab • Did many rotations … • Picked final lab in part b/c advisor was right match Friday, July 13, 12
- 22. Grad school lesson II: never too late to change • Wanted to combine DNA repair studies and molecular evolution • I: Thymineless death • II: Adaptive mutation • III: Repair in archaea Friday, July 13, 12
- 23. Friday, July 13, 12
- 24. Grad school lesson II: never too late to change • Wanted to combine DNA repair studies and molecular evolution • I: Thymineless death • II: Adaptive mutation • III: Repair in archaea • IV: Bioinformatics and genome analysis … Friday, July 13, 12
- 25. Grad school lesson III: Get others to do your work • Interested in RecA structure function relationships • Using phylogeny to look for correlated substitutions in RecA structure, like done with rRNA • But not enough sequences … Friday, July 13, 12
- 26. Friday, July 13, 12
- 27. Shotgun Sequencing Allows Use of Alternative Anchors (e.g., RecA) Venter et al., 2004 Friday, July 13, 12
- 28. Grad school lesson IV: Stealing is good • Phylogenetic perspective in bioinformatics missing Friday, July 13, 12
- 29. “Nothing in biology makes sense except in the light of evolution.” T. H. Dobzhansky (1973) Friday, July 13, 12
- 30. Evolutionary Perspective and Comparative Biology • Comparative biology is the analysis of differences and similarities between species. • An evolutionary perspective is useful in such studies because this allows one to focus not just on the levels and degrees of similarity or difference but on how and why similarities and differences came to be. Friday, July 13, 12
- 31. Phylogenomics • Lots of sequences being produced with no functions associated with them • Much debate in community about how to predict functions Friday, July 13, 12
- 32. Predicting Function • Identification of motifs • Homology/similarity based methods • Highest hit • Top hits • Clusters of orthologous groups • HMM models • Structural threading and modeling • Evolutionary reconstructions Friday, July 13, 12
- 33. Phylogeny Matters Eisen et al. 1992 Friday, July 13, 12
- 34. 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, Duplication 1998 Genome Res 8: 163-167. Friday, July 13, 12
- 35. Similarity ≠ Relatedness Friday, July 13, 12
- 36. Evolutionary Rate Variation Friday, July 13, 12
- 37. Phylogenetic Prediction of Function • Many powerful and automated similarity based methods for assigning genes to protein families • COGs • PFAM HMM searches • Some limitations of similarity based methods can be overcome by phylogenetic approaches • Automated methods now available • Sean Eddy • Steven Brenner • Kimmen Sjölander • But … Friday, July 13, 12
- 38. Grad school lesson V: Teaching helps you learn Friday, July 13, 12
- 39. Grad school lesson VI: There are no career rules Friday, July 13, 12
- 40. Career Lesson I: Build on what you know • Phylogenetic approaches to genomics • Genomics of endosymbionts • Genomic studies of communities • Analysis of DNA repair genes in genome sequences • Phylogenomics of halophilic archaea • GEBA • Phylogenetic metagenomics • ... Friday, July 13, 12
- 41. Career Lesson II: Don’t Only Use What You Know Friday, July 13, 12
- 42. What We Don’t Know Can Hurt Us Friday, July 13, 12
- 43. D. radiodurans genome Friday, July 13, 12
- 44. DNA Repair Genes in D. radiodurans Process Genes in D. radiodur a n s Nucleotide Excision Repair UvrABCD, UvrA2 Base Excision Repair AlkA, Ung, Ung2, GT, MutM, MutY-Nths, MPG AP Endonuclease Xth Mismatch Excision Repair MutS, MutL Recombination Initiation RecFJNRQ, SbcCD, RecD Recombinase RecA Migration and resolution RuvABC, RecG Replication PolA, PolC, PolX, phage Pol Ligation DnlJ dNTP pools, cleanup MutTs, RRase Other LexA, RadA, HepA, UVDE, MutS2 Friday, July 13, 12
- 45. Problem ... • List of DNA repair gene homologs in D. radiodurans genome is not significantly different from other bacterial genomes of the similar size Friday, July 13, 12
- 46. Repair Studies in Different Species (via Medline searches as of 1998) Humans 7028 E. coli 3926 S. cerevisiae 988 Drosophila 387 B. subtilits 284 S. pombe 116 Xenopus 56 C. elegans 25 A. thaliana 20 Methanogens 16 Haloferax 5 Giardia 0 Friday, July 13, 12
- 47. Proteobacteria TM6 OS-K ~40 Phyla of Acidobacteria Termite Group OP8 Bacteria Nitrospira Bacteroides Chlorobi Fibrobacteres Marine GroupA WS3 Gemmimonas Firmicutes Fusobacteria Actinobacteria OP9 Cyanobacteria Synergistes Deferribacteres Chrysiogenetes NKB19 Verrucomicrobia Chlamydia OP3 Planctomycetes Spriochaetes 0.1 Coprothmermobacter OP10 Thermomicrobia Chloroflexi TM7 Deinococcus-Thermus Dictyoglomus Aquificae Tree based on Thermudesulfobacteria Thermotogae Hugenholtz (2002) OP1 with some OP11 modifications. Friday, July 13, 12
- 48. Proteobacteria TM6 OS-K Acidobacteria Most DNA Termite Group OP8 Nitrospira metabolism Bacteroides Chlorobi Fibrobacteres studies in Marine GroupA WS3 Gemmimonas two Phyla Firmicutes Fusobacteria Actinobacteria OP9 Cyanobacteria Synergistes Deferribacteres Chrysiogenetes NKB19 Verrucomicrobia Chlamydia OP3 Planctomycetes Spriochaetes 0.1 Coprothmermobacter OP10 Thermomicrobia Chloroflexi TM7 Deinococcus-Thermus Dictyoglomus Aquificae Tree based on Thermudesulfobacteria Thermotogae Hugenholtz (2002) OP1 with some OP11 modifications. Friday, July 13, 12
- 49. Proteobacteria TM6 OS-K Acidobacteria Deinococcus Termite Group OP8 Nitrospira is very distant Bacteroides Chlorobi Fibrobacteres from well Marine GroupA WS3 Gemmimonas studied Firmicutes Fusobacteria groups Actinobacteria OP9 Cyanobacteria Synergistes Deferribacteres Chrysiogenetes NKB19 Verrucomicrobia Chlamydia OP3 Planctomycetes Spriochaetes 0.1 Coprothmermobacter OP10 Thermomicrobia Chloroflexi TM7 Deinococcus-Thermus Dictyoglomus Aquificae Tree based on Thermudesulfobacteria Thermotogae Hugenholtz (2002) OP1 with some OP11 modifications. Friday, July 13, 12
- 50. Gain and Loss of Repair Genes BACTERIA ARCHAEA EUKARYOTES Helpy Trepa Ecoli Human Mycge Mycpn Bacsu Synsp Borbu Metth Neigo Yeast Arcfu Strpy Metjn Haein -Ogt -PhrI -AlkA -Nfo -AlkA -Ogt -PhrI -AlkA -Ogt -Ung -Xth -Rad25 -AlkA -AlkA -Nfo -Nfo -RecFRQN -Rad25? R + us -TagI -RecQ -RuvC +P53 UmuD + -Vsr -Nfo -SbcD? dRecQ -SbcCD -Dut +Rad7 +Nei? -Rec -Lon dRad23 -LexA -SMS +CCE1 +RecE -SbcCD -LexA +MAG? tRecT? -UmuC -LexA +Spr tTagI ? tRad25 t3MG -PhrI -PhrII -PhrI -Ogt -PhrI -Ogg tUvrABCD Ada + -PhrII -AlkA -Ogt MutH + -PhrII? -AlkA -Xth -AlkA -Ung SbcB + -Fpg -MutLS -Nfo -Fpg -Nfo -RecFJORQN -Nfo -Dut -MutLS -Mfd -RecO -Lon -PhrI -RecFORQ -SbcCD -LexA -Ung? -PhrII -SbcCD -RecG -UmuC -MutLS -LexA -Dut -RecQ? + sr V -UmuC -PriA -Dut RecBCD? + -TagI+RecT -LexA -UmuC -SMS -MutT RFAs + -PhrII +TFIIH -RuvC +Rad4,10,14,16,23,26 CSA + Rad52,53,54 + +TagI? dPhr DNA-PK, Ku + SNF2 d TagI? + dMutS +Fpg dMutL UvrABCD + dRecA Mfd + RecFJNOR + Ung? + RuvABC + SSB, + +RecG Rad1 + +Dut? LigI + +Rad2 from mitochondria LexA + +Rad25? SSB + Ogg + +PriA LigII + +Dut? PhrI, PhrII + +Ogt +Ung, AlkA, MutY-Nth +AlkA +Xth, Nfo? +MutLS? +SbcCD +RecA +UmuC +MutT +Lon Eisen and Hanawalt, 1999 Mut dMutSI/MutSII dRecA/SMS Res 435: 171-213 dPhrI/PhrII Friday, July 13, 12
- 51. Solution - Experiments Friday, July 13, 12
- 52. What We Don’t Know Can Hurt Us Friday, July 13, 12
- 53. As of 2002 Proteobacteria TM6 OS-K • At least 40 phyla of Acidobacteria Termite Group OP8 Nitrospira Bacteroides bacteria Chlorobi Fibrobacteres Marine GroupA WS3 Gemmimonas Firmicutes Fusobacteria Actinobacteria OP9 Cyanobacteria Synergistes Deferribacteres Chrysiogenetes NKB19 Verrucomicrobia Chlamydia OP3 Planctomycetes Spriochaetes Coprothmermobacter OP10 Thermomicrobia Chloroflexi TM7 Deinococcus-Thermus Dictyoglomus Aquificae Thermudesulfobacteria Thermotogae OP1 Based on Hugenholtz, OP11 2002 Friday, July 13, 12
- 54. As of 2002 Proteobacteria TM6 OS-K • At least 40 Acidobacteria Termite Group phyla of OP8 Nitrospira Bacteroides bacteria Chlorobi Fibrobacteres Marine GroupA • Most genomes WS3 Gemmimonas from three Firmicutes Fusobacteria phyla Actinobacteria OP9 Cyanobacteria Synergistes Deferribacteres Chrysiogenetes NKB19 Verrucomicrobia Chlamydia OP3 Planctomycetes Spriochaetes Coprothmermobacter OP10 Thermomicrobia Chloroflexi TM7 Deinococcus-Thermus Dictyoglomus Aquificae Thermudesulfobacteria Thermotogae OP1 Based on Hugenholtz, OP11 2002 Friday, July 13, 12
- 55. As of 2002 Proteobacteria TM6 OS-K • At least 40 Acidobacteria Termite Group phyla of OP8 Nitrospira Bacteroides bacteria Chlorobi Fibrobacteres Marine GroupA • Most genomes WS3 Gemmimonas from three Firmicutes Fusobacteria phyla Actinobacteria OP9 Cyanobacteria • Some studies Synergistes Deferribacteres Chrysiogenetes in other phyla NKB19 Verrucomicrobia Chlamydia OP3 Planctomycetes Spriochaetes Coprothmermobacter OP10 Thermomicrobia Chloroflexi TM7 Deinococcus-Thermus Dictyoglomus Aquificae Thermudesulfobacteria Thermotogae OP1 Based on Hugenholtz, OP11 2002 Friday, July 13, 12
- 56. As of 2002 Proteobacteria TM6 OS-K • At least 40 Acidobacteria Termite Group phyla of OP8 Nitrospira Bacteroides bacteria Chlorobi Fibrobacteres Marine GroupA • Most genomes WS3 Gemmimonas from three Firmicutes Fusobacteria phyla Actinobacteria OP9 Cyanobacteria • Some other Synergistes Deferribacteres Chrysiogenetes phyla are only NKB19 Verrucomicrobia sparsely Chlamydia OP3 Planctomycetes sampled Spriochaetes Coprothmermobacter • Same trend in OP10 Thermomicrobia Chloroflexi Eukaryotes TM7 Deinococcus-Thermus Dictyoglomus Aquificae Thermudesulfobacteria Thermotogae OP1 Based on Hugenholtz, OP11 2002 Friday, July 13, 12
- 57. As of 2002 Proteobacteria TM6 OS-K • At least 40 Acidobacteria Termite Group phyla of OP8 Nitrospira Bacteroides bacteria Chlorobi Fibrobacteres Marine GroupA • Most genomes WS3 Gemmimonas from three Firmicutes Fusobacteria phyla Actinobacteria OP9 Cyanobacteria • Some other Synergistes Deferribacteres Chrysiogenetes phyla are only NKB19 Verrucomicrobia sparsely Chlamydia OP3 Planctomycetes sampled Spriochaetes Coprothmermobacter • Same trend in OP10 Thermomicrobia Chloroflexi Viruses TM7 Deinococcus-Thermus Dictyoglomus Aquificae Thermudesulfobacteria Thermotogae OP1 Based on Hugenholtz, OP11 2002 Friday, July 13, 12
- 58. Friday, July 13, 12
- 59. GEBA http://www.jgi.doe.gov/programs/GEBA/pilot.html Friday, July 13, 12
- 60. rRNA Tree of Life Bacteria Archaea Eukaryotes Figure from Barton, Eisen et al. “Evolution”, CSHL Press. 2007. Based on tree from Pace 1997 Science 276:734-740 Friday, July 13, 12
- 61. PD: Genomes From Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 62. PD: Genomes + GEBA From Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 63. PD: Isolates From Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 64. rRNA Tree of Life Bacteria Archaea ?????? Eukaryotes Figure from Barton, Eisen et al. “Evolution”, CSHL Press. 2007. Wu et al. (2011) PLoS ONE 6(3): e18011. doi:10.1371/ Based on tree from Pace 1997 Science journal.pone.0018011 276:734-740 Friday, July 13, 12
- 65. ???? Phage Phage ???? Thaumarchaeot Friday, July 13, 12
- 66. GEBA uncultured Number of SAGs from Candidate Phyla 406 1 OD1 OP1 OP3 SAR Site A: Hydrothermal vent 4 1 - - Site B: Gold Mine 6 13 2 - Site C: Tropical gyres (Mesopelagic) - - - 2 Site D: Tropical gyres (Photic zone) 1 - - - Sample collections at 4 additional sites are underway. Phil Hugenholtz 56 Friday, July 13, 12
- 67. Uncharacterized genes Friday, July 13, 12
- 68. Non homology functional • Many genes have homologs in other species but no homologs have ever been studied experimentally • Non-homology methods can make functional predictions for these Friday, July 13, 12
- 69. 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 functions Friday, July 13, 12
- 70. 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, July 13, 12
- 71. 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, July 13, 12
- 72. Homologs of Sporulation Genes Wu et al. 2005 PLoS Genetics 1: e65. Friday, July 13, 12
- 73. Carboxydothermus sporulates Wu et al. 2005 PLoS Genetics 1: e65. Friday, July 13, 12
- 74. Wu et al. 2005 PLoS Genetics 1: e65. Friday, July 13, 12
- 75. PG Profiling Works Better Using Orthology Friday, July 13, 12
- 76. PG Profiling Works Better Using Independent Contrasts Friday, July 13, 12
- 77. Career Lesson III: Networks Matter Friday, July 13, 12
- 78. Protein Family Rarefaction Curves • Take data set of multiple complete genomes • Identify all protein families using MCL • Plot # of genomes vs. # of protein families Friday, July 13, 12
- 79. Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 80. Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 81. Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 82. Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 83. Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 84. Synapomorphies exist Wu et al. 2009 Nature 462, 1056-1060 Friday, July 13, 12
- 86. Binning challenge Friday, July 13, 12
- 87. B A C Sharpton et al. submitted Friday, July 13, 12
- 88. Career Lesson IV: Openness Helps Friday, July 13, 12