Genomic Evolvability and the Origin of Novelty - talk for ASMGM 2008 by @phylogenomics

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Genomic Evolvability and the Origin of Novelty

Jonathan A. Eisen

U. C. Davis Genome Center

ASM General Meeting

Boston, MA

June 4, 2008





Secret Message Coming …

Jonathan A. Eisen


ASM General Meeting

Boston, MA

June 4, 2008





Genomic Evolvability and the Origin of Novelty

Jonathan A. Eisen


ASM General Meeting

Boston, MA

June 4, 2008







Origin of New Functions and

Processes

Species Evolution

Genome Dynamics

Eisen Lab - Phylogenomics of Novelty

•New genes•Changes in old genes•Changes in pathways

•Phylogenetic history•Vertical vs. horizontal descent•Needed to track gain/loss of processes, infer convergence

•Evolvability•Repair and recombination processes•Intragenomic variation





“Nothing in biology makes senseexcept in the light of evolution.”

T. H. Dobzhansky (1973)





Origin of Novelty

• How does novelty originate?• What are the constraints on evolvability?• What leads to variation within the genome

and within and between species in evolvability

• This information helps interpret the past, understand the present and (maybe) predict the future





Phylogenomic Analysis

• Evolutionary reconstructions greatly improve genome analyses

• Genome analysis greatly improves evolutionary reconstructions

• There is a feedback loop such that these should be integrated





Phylogenomic Tales

• Predicting functions with evolutionary trees

• Recently evolved new functions

• Uncharacterized genes

• Stealing functions

• Knowing what we do not know





Phylogenomics I:

Predicting Functions with Evolutionary Trees





SNF2 Family of Proteins (1995)

• SNF2 family defined by presence of conserved DNA-dependent ATPase domain

• 100s of proteins• Diversity of functions:

– transcriptional activation (SNF2)– transcriptional repression (MOT1)– Recombination (RAD54)– transcription-coupled repair (CSB)– post-replication repair (RAD5)– chromosome segregation (lodestar)– Many with unknown functions

• Some species have 15+ representatives



Bork and Koonin 1993





ETL1_M.m YA19_S.c CHD1_M.m SYGP4_S.c MOT1_S.c ERCC6_H.s RAD26_S.c NUCP_H.s NUCP_M.m YB53_S.c RAD54_S.c DNRPPX_S.p RAD5_S.c RAD8_S.p HIP116A_H.s RAD16_S.c LODE._D.mNPHCG_42HEPA._E.c YB95_S.c F37A4_C.e ISWI_D.m SNF2L_H.s BRM_D.m BRM_H.s BRG1_H.s BRG1_M.m STH1_S.c SNF2_S.c SNF2SNF2LCHD1ETL1CSBRAD54RAD16LODEEvolution of the SNF2 Family of Proteins





SNF2 Tree and F(x) Prediction

• Function conserved within but not between subfamilies/orthology groups

• Therefore, assignment of genes to subfamilies can be used to predict functions of unknowns

• Grouping into subfamilies helps identify motifs conserved within groups

• Phylogeny recovers subfamilies better than similarity searches





From Eisen et al. 1997 Nature Medicine 3: 1076-1078.





Blast Search of H. pylori “MutS” Score E Sequences producing significant alignments: (bits) Value sp|P73625|MUTS_SYNY3 DNA MISMATCH REPAIR PROTEIN 117 3e-25 sp|P74926|MUTS_THEMA DNA MISMATCH REPAIR PROTEIN 69 1e-10 sp|P44834|MUTS_HAEIN DNA MISMATCH REPAIR PROTEIN 64 3e-09 sp|P10339|MUTS_SALTY DNA MISMATCH REPAIR PROTEIN 62 2e-08 sp|O66652|MUTS_AQUAE DNA MISMATCH REPAIR PROTEIN 57 4e-07 sp|P23909|MUTS_ECOLI DNA MISMATCH REPAIR PROTEIN 57 4e-07

• 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.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9334711&query_hl=2







Phylogenetic Tree of MutS Family

Aquae Trepa

FlyXenlaRatMouse

HumanYeast

NeucrArath

BorbuStrpy

BacsuSynsp

EcoliNeigo

ThemaTheaqDeira

Chltr

SpombeYeast

YeastSpombe

MouseHumanArath

YeastHumanMouseArath

StrpyBacsu

CelegHuman

YeastMetthBorbu

AquaeSynsp

Deira Helpy

mSaco

YeastCeleg

Human

Based on Eisen, 1998 Nucl Acids Res 26: 4291-4300.










MutS Subfamilies

Aquae Trepa

FlyXenlaRatMouse

HumanYeast

NeucrArath

Borbu

StrpyBacsu

SynspEcoli

Neigo

ThemaTheaqDeira

Chltr

SpombeYeast

YeastSpombe

MouseHumanArath


StrpyBacsu

CelegHumanYeast

MetthBorbu

AquaeSynsp

Deira Helpy

mSaco

YeastCeleg

Human

MSH4

MSH5 MutS2

MutS1

MSH1

MSH3

MSH6

MSH2











Overlaying Functions onto Tree

Aquae Trepa

Rat

FlyXenla

MouseHumanYeast

NeucrArath

Borbu

SynspNeigo

ThemaStrpy

Bacsu

Ecoli

TheaqDeiraChltr

SpombeYeast

YeastSpombe

MouseHuman

Arath


StrpyBacsu

HumanCeleg

YeastMetthBorbu

AquaeSynsp

Deira Helpy

mSaco

YeastCeleg

Human

MSH4

MSH5MutS2

MutS1

MSH1

MSH3

MSH6

MSH2











Functional Prediction Using Tree

Aquae Trepa

FlyXenlaRatMouse

HumanYeast

NeucrArath

Borbu

StrpyBacsu

SynspEcoli

Neigo

ThemaTheaqDeira

Chltr

SpombeYeast

YeastSpombe

MouseHumanArath


MSH1MitochondrialRepair

MSH3 - Nuclear RepairOf Loops

MSH6 - Nuclear RepairOf Mismatches

MutS1 - Bacterial Mismatch and Loop Repair

StrpyBacsu

CelegHumanYeast

MetthBorbu

AquaeSynsp

Deira Helpy

mSaco

YeastCeleg

Human

MSH4 - Meiotic CrossingOver

MSH5 - Meiotic Crossing Over MutS2 - Unknown Functions

MSH2 - Eukaryotic NuclearMismatch and Loop Repair

















Evolutionary Functional Prediction1234563531A2A3A1B2B3B2A1B11222311A3A1A2A3A1A2A3A464564562B3B1B2B3B1B2B3B1A3A1B2B3B12462A2A535 EXAMPLE BMETHODDuplication?Duplication?IDENTIFY HOMOLOGSOVERLAY KNOWN

FUNCTIONS ONTO TREE INFER LIKELY FUNCTIONOF GENE(S) OF INTEREST

ALIGN SEQUENCESCALCULATE GENE TREECHOOSE GENE(S) OF INTERESTSpecies 3Species 1Species 2ACTUAL EVOLUTION(ASSUMED TO BE UNKNOWN)

EXAMPLE ADuplication?DuplicationAmbiguous

Based on Eisen, 1998 Genome Res 8: 163-167.









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 …





Phylogenomics II

Recent Evolution





Recent Functional Changes• Phylogenomic functional prediction may not work

well for very newly evolved functions• Can we use understanding of origin of novelty to

better understand these cases?• Screen genomes for genes that have changed

recently– Pseudogenes and gene loss– Contingency Loci– Acquisition (e.g., LGT)– Unusual dS/dN ratios– Rapid evolutionary rates– Duplication and divergence





Lineage Specific Gene Family Expansions

• Lineage specific expansions frequently associated with adaptive evolution

• Can screen genomes for such expansions by looking for genes more closely related to other genes in the genome than to genes from other species





Expansion of MCP Family in V. cholerae

E.coli gi1787690

B.subtilis gi2633766Synechocystis sp. gi1001299

Synechocystis sp. gi1001300Synechocystis sp. gi1652276

Synechocystis sp. gi1652103H.pylori gi2313716H.pylori99 gi4155097C.jejuni Cj1190c

C.jejuni Cj1110cA.fulgidus gi2649560A.fulgidus gi2649548

B.subtilis gi2634254B.subtilis gi2632630B.subtilis gi2635607B.subtilis gi2635608B.subtilis gi2635609

B.subtilis gi2635610B.subtilis gi2635882

E.coli gi1788195E.coli gi2367378E.coli gi1788194

E.coli gi1789453

C.jejuni Cj0144

C.jejuni Cj0262c

H.pylori gi2313186H.pylori99 gi4154603

C.jejuni Cj1564

C.jejuni Cj1506cH.pylori gi2313163H.pylori99 gi4154575

H.pylori gi2313179H.pylori99 gi4154599

C.jejuni Cj0019cC.jejuni Cj0951c

C.jejuni Cj0246cB.subtilis gi2633374

T.maritima TM0014

T.pallidum gi3322777T.pallidum gi3322939

T.pallidum gi3322938B.burgdorferi gi2688522

T.pallidum gi3322296B.burgdorferi gi2688521

T.maritima TM0429T.maritima TM0918T.maritima TM0023

T.maritima TM1428T.maritima TM1143

T.maritima TM1146P.abyssi PAB1308

P.horikoshii gi3256846P.abyssi PAB1336P.horikoshii gi3256896

P.abyssi PAB2066P.horikoshii gi3258290P.abyssi PAB1026

P.horikoshii gi3256884D.radiodurans DRA00354

D.radiodurans DRA0353D.radiodurans DRA0352

P.abyssi PAB1189P.horikoshii gi3258414

B.burgdorferi gi2688621M.tuberculosis gi1666149

V.cholerae VC0512V.cholerae VCA1034

V.cholerae VCA0974V.cholerae VCA0068

V.cholerae VC0825V.cholerae VC0282


V.cholerae VCA1056V.cholerae VC1643







V.cholerae VC1248V.cholerae VCA0864V.cholerae VCA0176





V.cholerae VCA0988V.cholerae VC0216V.cholerae VC0449





V.cholerae VC1394

V.cholerae VC0622

NJ

**

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*

****

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*

Based on Heidelberg et al. 2000 Nature 406:477-483.








Phylogenomics III

Uncharacterized genes





Non homology functional prediction

• Many genes have homologs in other species but no homologs have ever been studied experimentally

• Non-homology methods can make functional predictions for these





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





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)





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. )





Homologs of Sporulation Genes



Wu et al. 2005 PLoS Genetics 1: e65.





Carboxydothermus sporulates





















PG Profiling Works Better Using Orthology





Phylogenomics IV

Acquiring functions





Acquiring functions

• Sometimes, it is easier to steal, borrow, or coopt functions rather than evolve them anew

• Two main pathways for this– Lateral gene transfer– Symbioses









Glassy Winged Sharpshooter

• Obligate xylem feeder• Can transmit Pierce’s

Disease agent• Potential bioterror agent• Needs to get amino-

acids and other nutrients from symbionts like aphids





Xylem and Phloem

From Lodish et al. 2000





Sharpshooter Shotgun Sequencing

shotgunshotgun

Wu et al. 2006 PLoS Biology 4: e188.Collaboration with Nancy Moran’s lab













400,000

100,000

200,000

300,000

500,000

600,000

1





Baumannia is a Vitamin and Cofactor Producing Machine

Wu et al. 2006 PLoS Biology 4: e188.





No Amino-Acid Synthesis










???????





Commonly Used Binning MethodsDid 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 at





Host Sequence?





CFB Phyla




are needed to see this picture. Wu et al. 2006 PLoS Biology 4: e188.





Binning by Phylogeny

• Four main “phylotypes”– Gamma proteobacteria (Baumannia)– Arthropoda (sharpshooter)– Bacteroidetes (Sulcia)– Alpha-proteobacteria (Wolbachia)





Binning by Phylogeny

• Four main “phylotypes”– Gamma proteobacteria (Baumannia)– Arthropoda (sharpshooter)– Bacteroidetes (Sulcia) - only a.a. genes here– Alpha-proteobacteria (Wolbachia)





Essential Amino Acid Synthesis






Co-Symbiosis?






ABCDEFG

TUVWXYZ

Model for Metagenomics





Functional Diversity of Proteorhodopsins?

Venter et al., 2004





Phylogenomics V

Knowing What We Do Not Know





rRNA Tree of Life







The Tree is not Happy







Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi

FirmicutesFusobacteria Actinobacteria

Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira

SynergistesDeferribacteres

Thermudesulfobacteria

Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter

• At least 40 phyla of bacteria

As of 2002

Based on Hugenholtz, 2002





Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter


• Genome sequences are mostly from three phyla

As of 2002






Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter



• Some other phyla are only sparsely sampled

As of 2002






Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter




• Same trend in Archaea, Eukaryotes

As of 2002






Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter




• Solution I: sequence more phyla

• Eisen-Ward NSF Tree of Life Project

• A genome from each of eight phyla






Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter




• Solution II: Fill in Phyla

• JGI - Genomic Encyclopedia of Bacteria and Archaea














Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter




• Solution III: Sequence Uncultured





The Tree of Life is Still Angry







Circular Maps





DNA Repair Genes in D. radiodurans Complete Genome

Process Genes in D. radiodurans

Nucleotide Excision Repair UvrABCD, UvrA2Base Excision Repair AlkA, Ung, Ung2, GT, MutM, MutY-Nths,

MPGAP Endonuclease XthMismatch Excision Repair MutS, MutLRecombination Initiation Recombinase Migration and resolution

RecFJNRQ, SbcCD, RecDRecARuvABC, RecG

Replication PolA, PolC, PolX, phage PolLigation DnlJdNTP pools, cleanup MutTs, RRaseOther LexA, RadA, HepA, UVDE, MutS2





Problem:

List of DNA repair gene homologs in D. radiodurans genome is not significantly different from other bacterial genomes

of the similar size





0.1

Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter

Tree based on Hugenholtz (2002) with some modifications.

~40 Phyla of Bacteria





0.1

Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter


Most DNA metabolism studies in two Phyla





0.1

Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter


Deinococcus is very distant from well studied groups





-Ogt-RecFRQN-RuvC-Dut-SMS

-PhrI-AlkA-Nfo-Vsr-SbcCD-LexA-UmuC

-PhrI-PhrII-AlkA-Fpg-Nfo-MutLS-RecFORQ-SbcCD-LexA-UmuC-TagI

-PhrI-Ogt-AlkA-Xth-MutLS-RecFJORQN-Mfd-SbcCD-RecG-Dut-PriA-LexA-SMS-MutT

-PhrI-PhrII?-AlkA-Fpg-Nfo-RecO-LexA-UmuC

-PhrI-Ung?-MutLS-RecQ?-Dut-UmuC

-PhrII-Ogg

-Ogt-AlkA-TagI-Nfo-Rec-SbcCD-LexA

-Ogt-AlkA-Nfo-RecQ-SbcD?-Lon-LexA

-AlkA-Xth-Rad25?

-AlkA-Rad25

-Nfo

-Ogt-Ung-Nfo-Dut-Lon

-Ung

-PhrII

-PhrI

Ecoli

Haein

Neig

o

Help

y

Bacsu

Str

py

Mycg

e

Mycp

n

Borb

u

Tre

pa

Syn

sp

Metj

n

Arc

fu

Mett

h

Hu

man

Yeast

BACTERIA ARCHAEA EUKARYOTES

from mitochondria

+Ada+MutH+SbcB

dPhr

+TagI?+Fpg

+UvrABCD+Mfd

+RecFJNOR+RuvABC

+RecG+LigI

+LexA+SSB

+PriA+Dut?

+Rus+UmuD

+Nei?+RecE

tRecT?

+Vsr+RecBCD?

+RFAs+TFIIH

+Rad4,10,14,16,23,26+CSA

+Rad52,53,54+DNA-PK, Ku

dSNF2dMutSdMutLdRecA

+Rad1+Rad2

+Rad25?+Ogg+LigII

+Ung?+SSB,

+Dut?

+PhrI, PhrII+Ogt

+Ung, AlkA, MutY-Nth+AlkA

+Xth, Nfo?+MutLS?

+SbcCD+RecA

+UmuC+MutT

+LondMutSI/MutSII

dRecA/SMSdPhrI/PhrII

+Sprt3MG

+Rad7+CCE1

+P53dRecQ

dRad23+MAG?

-PhrII-RuvC

tRad25

+TagI?

+RecT

tUvrABCD

tTagI ?

Gain and Loss of Repair Genes

Eisen and Hanawalt, 1999 Mut Res 435: 171-213





Solution - Experiments







0.1

Acidobacteria

Bacteroides

Fibrobacteres

Gemmimonas

Verrucomicrobia

Planctomycetes

Chloroflexi

Proteobacteria

Chlorobi


Cyanobacteria

Chlamydia

Spriochaetes

Deinococcus-Thermus

Aquificae

Thermotogae

TM6OS-K

Termite GroupOP8

Marine GroupAWS3

OP9

NKB19

OP3

OP10

TM7

OP1OP11

Nitrospira



Chrysiogenetes

Thermomicrobia

Dictyoglomus

Coprothmermobacter


Need experimental studies from across the tree too













MICROBES





A Happy Tree of Life







TIGRTIGR

Other peopleOther people

Mom and DadMom and Dad

H. OchmanH. OchmanF. RobbF. Robb

J. BattistaJ. Battista

E. OriasE. Orias

D. BryantD. BryantS. O’NeillS. O’Neill

M. EisenM. Eisen

N. MoranN. Moran

R. MyersR. Myers

C. M. CavanaughC. M. Cavanaugh

P. HanawaltP. Hanawalt

J. HeidelbergJ. HeidelbergN. WardN. Ward

J. VenterJ. Venter

C. FraserC. Fraser

S. SalzbergS. Salzberg

I. PaulsenI. Paulsen

$$$$$$

NSFNSFDOEDOE

NIHNIH

M. WuM. Wu

D. WuD. Wu

S. ChatterjiS. Chatterji

H. HuseH. Huse

A. HartmanA. Hartman

MooreMoore

JCVIJCVI

D. RuschD. Rusch

A. HalpernA. Halpern

Eisen Eisen Group/Group/DavisDavis

J. MorganJ. Morgan

JGIJGI

E. EisenstadtE. Eisenstadt

M. FrazierM. Frazier

T. WoykeT. Woyke

E. RubinE. Rubin

Health & Medicine

Genomic Evolvability and the Origin of Novelty - talk for ASMGM 2008 by @phylogenomics