1. Genomic Evolvability
and the Origin of Novelty
Jonathan A. Eisen
U. C. Davis Genome Center
ASM General Meeting
Boston, MA
June 4, 2008
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2. Secret Message Coming …
Jonathan A. Eisen
U. C. Davis Genome Center
ASM General Meeting
Boston, MA
June 4, 2008
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3. Genomic Evolvability
and the Origin of Novelty
Jonathan A. Eisen
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U. C. Davis Genome Center
ASM General Meeting
Boston, MA
June 4, 2008
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4. Eisen Lab - 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
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5. “Nothing in biology makes sense
except in the light of evolution.”
T. H. Dobzhansky (1973)
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6. 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
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7. 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
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8. Phylogenomic Tales
• Predicting functions with evolutionary trees
• Recently evolved new functions
• Uncharacterized genes
• Stealing functions
• Knowing what we do not know
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9. Phylogenomics I:
Predicting Functions with
Evolutionary Trees
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10. SNF2 Family of Proteins (1995)
• SNF2 family defined by presence of conserved DNA-
dependent ATPase domain Bork and Koonin 1993
• 100s of proteins
• Diversity of functions:
– transcriptional activation (SNF2)
– transcriptional repression (MOT1)
– Recombination (RAD54) QuickTimeª and a
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– post-replication repair (RAD5)
– chromosome segregation (lodestar)
– Many with unknown functions
• Some species have 15+ representatives
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11. HEPA._E.c
NPHCG_42
LODE._D.m
MOT1_S.c
SNF2_S.c
STH1_S.c
BRG1_M.m
BRG1_H.s
BRM_H.s
BRM_D.m
SNF2L_H.s
F37A4_C.e
DNRPPX_S.p
NUCP_M.m
NUCP_H.s
RAD26_S.c
ERCC6_H.s
SYGP4_S.c
CHD1_M.m
ETL1_M.m
ISWI_D.m
YB95_S.c
RAD16_S.c
HIP116A_H.s
RAD8_S.p
RAD5_S.c
RAD54_S.c
YB53_S.c
YA19_S.c
LODE
RAD16
RAD54
CSB
ETL1
CHD1
SNF2L
SNF2
Evolution of the SNF2 Family of Proteins
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12. 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
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13. From Eisen et al.
1997 Nature
Medicine 3: 1076-10
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14. Blast Search of H. pylori “MutS”
Score E
Sequences producing significant alignments: (bits) Value
sp|P73625|MUTS_SYNY3 DNA MISMATCH REPAIR PROTEIN 117 3e25
-
sp|P74926|MUTS_THEMA DNA MISMATCH REPAIR PROTEIN 69 1e10
-
sp|P44834|MUTS_HAEIN DNA MISMATCH REPAIR PROTEIN 64 3e09
-
sp|P10339|MUTS_SALTY DNA MISMATCH REPAIR PROTEIN 62 2e08
-
sp|O66652|MUTS_AQUAE DNA MISMATCH REPAIR PROTEIN 57 4e07
-
sp|P23909|MUTS_ECOLI DNA MISMATCH REPAIR PROTEIN 57 4e07
-
• 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
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15. 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
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Neigo

16. MutS Subfamilies
M S H 5A q u a e M utS 2
S trB y c S uns p
p a s y
D e ir a H e lp y
Ye a s t
Huma n B orbu M e tth
C e le g
mS a c o
MS H6 Ye a s t
Huma n
Mous e
A ra th
Ye a s t MS H4
C e le g
Huma n
A ra th
Huma n
MS H3 Mous e
F ly
S pombe
Ye a s t X e n la
Rat
Mous e
Ye a s t Huma n
MS H1 S pombe Ye a s t
MS H2
Neuc r
A ra th
Aquae Tre p a
C h lt r
D e ir a e a q
Th
B a c s u rbu
Bo
Th e m a
S y n sSpt r p y
E c o li
N e ig o Based on Eisen,
1998 Nucl Acids
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17. Overlaying Functions onto Tree
M utS 2
Aquae
MS H5 S t rB y c S yn s p
pa su
D e ir a H e lp y
Ye a s t
Huma n B orbu M e tth
C e le g
MS H6 mS a c o
Ye a s t
Huma n
Mous e
A ra th
MS H4
Ye a s t
C e le g
Huma n
A ra th
Huma n
MS H3 Mous e
S pombe F ly
Ye a s t X e n la
Rat
Mous e
Ye a s t Huma n
M S H 1 pombe
S Ye a s t MS H2
Neuc r
A ra th
Aquae Tre p a
C h lt r
D e ir a e a q
Th
B a c s u rbu
Bo
Th e m a
S y n sSpt r p y Based on Eisen,
E c o li
N e ig o
1998 Nucl Acids
M utS 1
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18. Functional Prediction Using Tree
M S H 5 - M e io t ic C r o s s in g O v e u t S 2 - U n k n o w n F u n c t io n s
M r
Aquae
S t rB y c S yn s p
pa su
D e ir a H e lp y
Ye a s t
Huma n B orbu M e tth
C e le g
M S H 6 - N u c le a r mS a c o
R e p a ir
Ye a s t
O f M is m a t c h e s Huma n M S H 4 - M e io t ic C r o s s in g
Mous e Y e a sO v e r
t
A ra th C e le g
Huma n
A ra th
M S H 3 - N u c le a r Huma n
Mous e
R e p a ir O f L o o p s o m b e
S p F ly
Ye a s t X e n la
Rat
M oM s eH 2 - E u k a r y o t i c N u c l e a r
u S
Ye a s t H u m ai n m a t c h a n d L o o p R e p a i r
M s
MS H1 S pombe Ye a s t
M it o c h o n d r ia l Neuc r
A ra th
R e p a ir
Aquae Tre p a
C h lt r
D e ir a e a q
Th
B a c s u rbu
Bo
Th e m a
S y n sSpt r p y
E c o li Based on Eisen,
N e ig o
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M u t S 1 - B a c t e r ia l M is m a t c h a n d L o o p R e p a ir Res 26: 4291-4300.
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19. QuickTimeª and a
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20. Evolutionary Functional Prediction
SpeciesMETHOD EVOLUTION
Duplication?SEQUENCES
5 IDENTIFY HOMOLOGS
4B EXAMPLE A B
3A CALCULATE GENE KNOWN
2CHOOSE GENE(S) OF FUNCTION
1ALIGNINFER LIKELY INTEREST
1ACTUAL
3EXAMPLE
Ambiguous
Duplication
1A
3B
2B
1B
3A
2A
6 2 OVERLAY TREE
(ASSUMED TO BE OFONTO TREE
OF GENE(S) UNKNOWN)
FUNCTIONS INTEREST
Based on Eisen,
1998 Genome
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Res 8: 163-167.
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21. 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 …
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22. Phylogenomics II
Recent Evolution
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23. 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
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24. 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
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25. Expansion of MCP Family in V. cholerae
NJ
V. choleraeVC 12 05
V. chole raeV C 03 4
A1
V. choleraeVC 97 4A0
** V. choleraeVC 06 8A0
* V. chole rae C 25
V 08
V. choleraeV C 82 02
V. chole rae C 90 6
V A0
V. chole raeV C 979
A0
V. chole rae C 05 6
V A1
V. choleraeV C 43 16
V. chole rae C 61
V 21
** V. choleraeVC 92 3
A0
** V. choleraeV C 14 05
V. choleraeVC 68 18
V. chole raeV C 77 3
A0
V. choleraeV C 13 13
V. chole raeV C 5918
V. choleraeV C 13 14
V. chole rae C 26 8
V A0
** V. chole raeV C 65 8
A0
V. choleraeV C 05 14
* V. cholerae 12 98
VC
V. choleraeV C 4812
V. chole raeV C 86 4
A0
V. choleraeVC 17 6 A0
** V chole raeV C 22 0
. A0
V. choleraeVC 89 12
** V. choleraeVC 06 9A1
V. choleraeV C 39 24
V. choleraeVC 67 19
V. chole rae C 031
V A0
V. choleraeV C 98 18
V. chole rae C 663
V A0
V. choleraeVC 988 A0
V. chole raeV C 16 02
* V. chole raeV C 49 04
V. chole rae C 00 8
V A0
V. choleraeVC 06 14
V. chole raeV C 35
15
V. choleraeV C 40 08
B.subtilis gi2633766
Synechocystis sp. gi1001299
* Synechocystis sp. gi1001300
* Synechocystis sp. gi1652276
* Synechocystis sp. gi1652103
H.pylori gi2313716
** H.pylori9Cj1190c
C.jejuni
9 gi4155097
**
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. choleraeV C 092 A1
V. choleraeVC 98 00
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. choleraeV C 03
14
V. chole rae C 08 8
V A1
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
* P.abyssi PAB1026
** P.horikoshii gi3256884
**
D.radiodurans DRA00354
D.radiodurans DRA0353
D.radiodurans DRA0352
Based on Heidelberg et al.
**
2000 Nature 406:477-483.
** V. choleraeVC 94 13
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M.tuberculosis gi1666149
V. choleraeV C 22
06

26. Phylogenomics III
Uncharacterized genes
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27. 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
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28. 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
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29. 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)
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30. 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. )
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31. Homologs of Sporulation Genes
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Wu et al. 2005
PLoS
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32. Carboxydothermus sporulates
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33. QuickTimeª and a
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34. QuickTimeª and a
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36. PG Profiling Works Better Using
Orthology
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37. Phylogenomics IV
Acquiring functions
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38. 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
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39. QuickTimeª and a
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40. 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
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41. Xylem and Phloem
From
Lodish et
al. 2000
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42. Sharpshooter Shotgun Sequencing
shotgun
Collaboration with Nancy
Wu et al. 2006 PLoS Biology 4: e188.
Moran’s lab
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43. QuickTimeª and a
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44. QuickTimeª and a
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45. 1
600,000
100,000
500,000
200,000
400,000
300,000
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46. Baumannia is a Vitamin and
Cofactor Producing Machine
Wu et al.
2006
PLoS
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47. No Amino-Acid Synthesis
Wu et al.
2006
PLoS
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48. QuickTimeª and a
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49. ???????
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50. 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 at
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51. Host Sequence?
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52. CFB Phyla
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TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

53. QuickTimeª and a
TIFF (LZW) decompressor
Wu et al. 2006 PLoS Biology 4: e188.
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

54. Binning by Phylogeny
• Four main “phylotypes”
– Gamma proteobacteria (Baumannia)
– Arthropoda (sharpshooter)
– Bacteroidetes (Sulcia)
– Alpha-proteobacteria (Wolbachia)
QuickTimeª and a
TIFF (LZW) decompressor
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

55. Binning by Phylogeny
• Four main “phylotypes”
– Gamma proteobacteria (Baumannia)
– Arthropoda (sharpshooter)
– Bacteroidetes (Sulcia) - only a.a. genes here
– Alpha-proteobacteria (Wolbachia)
QuickTimeª and a
TIFF (LZW) decompressor
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

56. Essential Amino Acid Synthesis
QuickTimeª and a
Wu et al. 2006 PLoS
TIFF (LZW) decompressor
Biology 4: e188.
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

57. Co-Symbiosis?
Wu et al.
2006
PLoS
QuickTimeª and a
Biology 4: e
TIFF (LZW) decompressor
.
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

58. Model for Metagenomics
A T
B U
C V
D W
E X
F Y
G Z
QuickTimeª and a
TIFF (LZW) decompressor
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

59. Functional Diversity of Proteorhodopsins?
QuickTimeª and a
TIFF (LZW) decompressor
are needed to see this picture.
Venter et al., 2004 QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.

60. Phylogenomics V
Knowing What We Do Not Know
QuickTimeª and a
TIFF (LZW) decompressor
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

61. rRNA Tree of Life
QuickTimeª and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTimeª and a
TIFF (LZW) decompressor
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

62. The Tree is not Happy
QuickTimeª and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTimeª and a
TIFF (LZW) decompressor
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

63. As of 2002 Proteobacteria
TM6
OS-K
• At least 40
Acidobacteria
Termite Group
OP8
phyla of
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
QuickTimeª and a
OP11
TIFF (LZW) decompressor
Hugenholtz, 2002
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

64. As of 2002 Proteobacteria
TM6
OS-K
• At least 40
Acidobacteria
Termite Group
OP8
phyla of
Nitrospira
Bacteroides
bacteria
Chlorobi
Fibrobacteres
Marine GroupA • Genome
WS3
Gemmimonas
Firmicutes
sequences are
Fusobacteria
Actinobacteria
mostly from
OP9
Cyanobacteria three phyla
Synergistes
Deferribacteres
Chrysiogenetes
NKB19
Verrucomicrobia
Chlamydia
OP3
Planctomycetes
Spriochaetes
Coprothmermobacter
OP10
Thermomicrobia
Chloroflexi
TM7
Deinococcus-Thermus
Dictyoglomus
Aquificae
Thermudesulfobacteria
Thermotogae
QuickTimeª and a
OP1 Based on
TIFF (LZW) decompressor
OP11 Hugenholtz, 2002
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

65. As of 2002 Proteobacteria
TM6
OS-K
• At least 40
Acidobacteria
Termite Group
OP8
phyla of
Nitrospira
Bacteroides
bacteria
Chlorobi
Fibrobacteres
Marine GroupA • Genome
WS3
Gemmimonas
Firmicutes
sequences are
Fusobacteria
Actinobacteria
mostly from
OP9
Cyanobacteria three phyla
Synergistes
Deferribacteres
Chrysiogenetes • Some other
NKB19
Verrucomicrobia
Chlamydia phyla are
OP3
Planctomycetes
Spriochaetes
only sparsely
Coprothmermobacter
OP10 sampled
Thermomicrobia
Chloroflexi
TM7
Deinococcus-Thermus
Dictyoglomus
Aquificae
Thermudesulfobacteria
Thermotogae
QuickTimeª and a
OP1 Based on
TIFF (LZW) decompressor
OP11 Hugenholtz, 2002
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

66. As of 2002 Proteobacteria
TM6
OS-K
• At least 40
Acidobacteria
Termite Group
OP8
phyla of
Nitrospira
Bacteroides
bacteria
Chlorobi
Fibrobacteres
Marine GroupA • Genome
WS3
Gemmimonas
Firmicutes
sequences are
Fusobacteria
Actinobacteria
mostly from
OP9
Cyanobacteria three phyla
Synergistes
Deferribacteres
Chrysiogenetes • Some other
NKB19
Verrucomicrobia
Chlamydia phyla are
OP3
Planctomycetes
Spriochaetes
only sparsely
Coprothmermobacter
OP10 sampled
Thermomicrobia
Chloroflexi
TM7 • Same trend in
Deinococcus-Thermus
Dictyoglomus
Aquificae Archaea,
Thermudesulfobacteria
QuickTimeª and a
Thermotogae
OP1
Eukaryotes
Based on
TIFF (LZW) decompressor
OP11 Hugenholtz, 2002
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.

67. Proteobacteria
• Eisen-Ward TM6 • At least 40
OS-K
NSF Tree of Acidobacteria
Termite Group phyla of
OP8
Life Project Nitrospira
Bacteroides
bacteria
Chlorobi
• A genome Fibrobacteres
Marine GroupA • Genome
WS3
from each of Gemmimonas sequences are
Firmicutes
eight phyla Fusobacteria mostly from
Actinobacteria
OP9
Cyanobacteria three phyla
Synergistes
Deferribacteres
Chrysiogenetes • Some other
NKB19
Verrucomicrobia
Chlamydia phyla are only
OP3
Planctomycetes
Spriochaetes
sparsely
Coprothmermobacter
OP10 sampled
Thermomicrobia
Based on Chloroflexi
TM7 • Solution I:
Hugenholtz, Deinococcus-Thermus
2002
Dictyoglomus
Aquificae sequence more
Thermudesulfobacteria
QuickTimeª and a
Thermotogae
OP1
phyla
TIFF (LZW) decompressor
are needed to see this picture. OP11 QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.

68. Proteobacteria
• JGI - TM6 • At least 40
OS-K
Genomic Acidobacteria
Termite Group phyla of
OP8
Encyclopedia Nitrospira
Bacteroides
bacteria
of Bacteria Chlorobi
Fibrobacteres
• Genome
Marine GroupA
and Archaea WS3
Gemmimonas sequences are
Firmicutes
Fusobacteria
Actinobacteria
mostly from
OP9
Cyanobacteria three phyla
Synergistes
QuickTimeª and a
TIFF (LZW) decompressor
are needed to see this picture.
Deferribacteres
Chrysiogenetes • Some other
NKB19
Verrucomicrobia
Chlamydia phyla are only
OP3
Planctomycetes
Spriochaetes
sparsely
Coprothmermobacter
OP10 sampled
Thermomicrobia
Based on Chloroflexi
TM7 • Solution II: Fill
Hugenholtz, Deinococcus-Thermus
2002
Dictyoglomus
Aquificae in Phyla
Thermudesulfobacteria
Thermotogae
OP1
QuickTimeª and a
TIFF (LZW) decompressor
are needed to see this picture. OP11 QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.

69. QuickTimeª and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTimeª and a
TIFF (LZW) decompressor
QuickTimeª and a
TIFF (Uncompressed) decompressor
are needed to see this picture.
are needed to see this picture.