Nothing in (computational) biology makes

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Comparative genomics, genome context and genome
annotation
Nothing in (computational) biology makes sense
except in the light of evolution
after Theodosius Dobzhansky (1970)
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Genome context analysis and genome annotation
Using information other than homologous
relationships between individual gene/proteins
for functional prediction (guilt by association)
Types of context analysis

• phyletic patterns
• domain fusion (Rosetta Stone proteins)
• gene order conservation
• co-expression
• .

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Goals

• Using gene sets from complete genomes,
  delineate families of orthologs and paralogs -
  Clusters of Orthologous Groups (of genes) (COGs)
• Using COGs, develop an engine
• for functional annotation of new
• genomes
• Apply COGs for analysis of phylogenetic
  patterns

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COG - group of homologous proteins such that
all proteins from different species are orthologs
(all proteins from the same species in a COG are
paralogs)
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CONSTRUCTION OF COGs FOR 8 COMPLETE GENOMES
Complete set of proteins from the analyzed
genomes
Merge triangles with common edges
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FULL SELF-COMPARISON (BLASTPGP, no cut-off)
Detect groups with multidomain proteins and
isolate domains
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Collapse obvious paralogs
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REPEAT STEPS 3-5
Detect all interspecies Best Hits (BeTs) between
individual proteins or groups of paralogs
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COGs
Detect all triangles of consistent BeTs
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A TRIANGLE OF BeTs IS A MINIMAL, ELEMENTARY COG
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A RELATIVELY SIMPLE COG PRODUCED BY MERGING
ADJACENT TRIANGLES
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A COMPLEX COG WITH MULTIPLE PARALOGS
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Current status of the COGs
Prokaryotes
11 Archaea 1 unicellular eukaryote 46
bacteria 58 complete genomes
149,321 proteins
105,861 proteins in 4075 COGs (71)
Eukaryotes
4 animals 1 plant 2 fungi 1 microsporidium
8 complete genomes 142,498 proteins
74,093 proteins in 4822 COGs
(52)
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COGnitor...
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IN ACTION
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The Universal COGs
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Search for genomic determinants of
hyperthermophily
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Search for unique archaeo-eukaryotic genes
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A complementary pattern search for unique
bacterial genes
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Essential function but holes in the
phyletic pattern
Strict complementary pattern
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Relaxed complementary pattern
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Relaxed complementary pattern with extra
restrictions
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Conservation of gene order in bacterial species
of the same genus
M. genitalium vs M. pneumoniae
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Conservation of gene order in closely related
bacterial genera
C. trachomatis vs C. pneumoniae
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Lack of gene order conservation - even in
closely related bacteria of the same
Proteobacterial subdivision
P. aeruginosa vs E. coli
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Genome Alignments - Method
Protein sets from completely genomes
BLAST cross-comparison
Table of Hits
Pairwise Genome Alignment Local alignment
algorithm Lamarck (gap opening penalty, gap
extension penalty) statistics with Monte Carlo
simulations
Template-Anchored Genome Alignment
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Genome Alignments - Statistics
Distribution of conserved gene string lengths
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Genome Alignments - Statistics
Pairwise No. No. in in alignments
strings genes Gen1 Gen2 all
homologs ecoli-hinf 138 566 13 33 ecoli-bsub 8
9 322 8 8 ecoli-mjan 10 30 1 2 probable
orthologs ecoli-hinf 105 482 11 28 ecoli-bsub
34 168 4 4 ecoli-mjan 12 33 1 2
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Genome Alignments - Statistics
Breakdown of genes in the genome
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Genome Alignments - Statistics
Fraction of the genome in conserved gene strings
- from template-anchored alignments Minimum Synec
hocystis sp. 5 Aquifex aeolicus 10 Archaeoglo
bus fulgidus 13 Escherichia coli 14 Treponema
pallidum 17 Maximum Thermotoga
maritima 23 Mycoplasma genitalium 24
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Context-Based Prediction of Protein Functions
A Novel Translation Factor (COG0536)
L21
L27
GTPase?
GTP-binding translation factor
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Context-Based Prediction of Protein Functions
A Novel Translation Factor (COG0012)
TGS domain containing GTPase?
Peptidyl-tRNA hydrolase
GTP-binding translation factor
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