Finding detailed relationships between proteins specific to phenotypes among microbial organisms Daniel Park Molecular Biology Institute, UCLA Yeates lab SoCalBSI August 24, 2006

OUTLINE Phylogenetic profiles Ternary logic analysis Building COG & phenotype profiles Results of logic analysis

OUTLINE Phylogenetic profiles Ternary logic analysis Building COG & phenotype profiles Results of logic analysis

PHYLOGENETIC PROFILES Turning an earlier question on its side: From, “What proteins are found in a genome?” To, “What genomes contain a given protein?”

VARIATIONS OF PHYLOGENETIC PROFILES Relationships between protein families Relationships between protein family profile and given target ‘phenotype’ profile

OUTLINE Phylogenetic profiles Ternary logic analysis Building COG & phenotype profiles Results of logic analysis

COMPLEXITY OF CELLULAR PROCESSES

HIGHER ORDER RELATIONSHIPS: TERNARY LOGIC ANALYSIS A B

8 LOGIC TYPES FOR PHYLOGENETIC PROFILE TRIPLETS

MEASURING MUTAL INFORMATION BETWEEN TWO PROFILES Where U is the uncertainty coefficient relating profiles x and y H is the Shannon entropy of the probability distributions Range of U : [0,1]Ex. U = 0.88  88% decrease in uncertainty High value of U indicates high mutual information between x and y

MEASURING MUTAL INFORMATION AMONG THREE PROFILES U(c | f(a,b)) where f(a,b) is the logical combination of a and b Constraints: U(c|a) < x U(c|b) < x U(c|f(a,b)) > y

OUTLINE Phylogenetic profiles Ternary logic analysis Building COG & phenotype profiles Results of logic analysis

COGs: CLUSTERS OF ORTHOLOGOUS GROUPS Set of orthologous proteins from at least three different lineages Cluster  Functional group

COMBINATIONS OF COG PROFILES MATCHING A PHENOTYPE

ASSOCIATING MORE GENOMES WITH COGS

` BUILDING COG PROFILES 81,480 proteins 354 bacterial genomes 4,613 COGs

BUILDING PHENOTYPE PROFILES

OUTLINE Phylogenetic profiles Ternary logic analysis Building COG & phenotype profiles Results of logic analysis

Cumulative no. of protein triplets recovered at an uncertainty coefficient score greater than a given threshold

Frequency for each of the eight logic function types observed

CORRELATIONS WITH PHENOTYPES: TEMPERATURE RANGE For U > 0.8, one relationship between proteins was found: Hyperthermophilicity = and( COG0432, !COG0225 ) U ( Hyp. | COG0432 ) = 0.26 U ( Hyp. | COG0225 ) = 0.29 U ( Hyp. | and ( COG0432, !COG0225 ) ) = 0.71 [S] COG0432: Uncharacterized conserved protein [O] COG0225: Peptide methionine sulfoxide reductase

LOGICAL COMBINATION OF COG PROFILES MATCHING A PHENOTYPE PROFILE c = hyperthermophilicity f = and( COG0432, !COG0225 ) a = COG0432(Uncharacterized conserved protein) b = !COG0225(Peptide methionine sulfoxide reductase)

CONCLUSIONS There may be a correlation between the absence of methionine sulfoxide reductase and the presence of an uncharacterized conserved protein in hyperthermophiles.

CONCLUSIONS –Classified ~80,000 proteins from 354 bacterial genomes into ~4,600 COGs –Built COG and phenotype profile matrices for 354 fully sequenced bacterial genomes –Support that ternary relationships among COGs are biologically significant –Support that some logic types are seen in biology more than others:1 (and) 5 7 (xor)

FUTURE DIRECTIONS Build a richer database of phenotype profiles Investigate relationships at lower cutoffs Experimentally characterize the unknown COG0432 by crystallography

ACKNOWLEDGEMENTS Todd Yeates Matteo Pellegrini Yeates lab Morgan Beeby Brian O’Connor Rest of the lab SoCalBSI 2006 Jamil Momand Wendie Johnston Sandra Sharp Nancy Warter-Perez Ronnie Cheng Fellow participants