Finding detailed relationships between proteins specific to phenotypes among microbial organisms

Daniel ParkMolecular Biology Institute, UCLA

Yeates labSoCalBSI

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

)(/)],()()([)|( xHyxHyHxHyxU

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) < xU(c|b) < xU(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

No. of fully sequenced bacterial genomes over the last 9 years

66

354

70

50

100

150

200

250

300

350

400

1997 2003 2006

Years

No

. o

f b

acte

rial

gen

om

es

`

BUILDING COG PROFILES

• 81,480 proteins• 354 bacterial genomes• 4,613 COGs

BUILDING PHENOTYPE PROFILES

http://www.ncbi.nlm.nih.gov/genomes/lproks.cgi

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 = hyperthermophilicityf = 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)

57 (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