CONTENTS
- Upcoming Pathway Tools Tutorial at SRI, January 16-17, 2020
- New Pathway Tools Publication
- The PathoLogic Inference Component of Pathway Tools
Upcoming Pathway Tools Tutorial at SRI, January 16-17, 2020
We will offer a two-day Introduction to Pathway Tools tutorial at
SRI from January 16-17, 2020. The early registration deadline is December 12.
For more information
click here.
New Pathway Tools Publication
The following just-published article describes the many enhancements made to
Pathway Tools during the past four years including multiple extensions to its
metabolic network modeling, omics data analysis, and core database management
capabilities:
"Pathway Tools version 23.0 update: software for pathway/genome informatics and systems biology"
in Briefings in Bioinformatics.
The PathoLogic Inference Component of Pathway Tools
PathoLogic is the computational inference module of Pathway Tools. Here we summarize
the basic operation of PathoLogic as well as some new pathway inference capabilities
coming in our version 23.5 release in the next few weeks.
The current inference capabilities of Pathway Tools are as follows:
- Infer the metabolic reactions catalyzed by the organism
- Infer the metabolic pathways comprised of those reactions
- Infer which genes code for missing enzymes (pathway holes) in those metabolic pathways
- Infer the operons of prokaryotic organisms
From its inception, the reactome and pathway inference components of
PathoLogic have been designed to start with an existing genome
annotation for an organism rather than re-annotating the genome. We
had two rationales for this approach: (1) Building genome annotation
pipelines is a big problem and a hard problem that many other groups
were addressing; we preferred to build on their work rather than
undertake that hard problem ourselves. Furthermore, many groups
perform expert manual oversight and inference during the annotation
process; were we to re-annotate the genome we would be discarding
those manual inferences. In hindsight we feel this strategy has been
validated: genome annotation pipelines have grown even more
sophisticated, e.g., integrating BLAST searches with multiple HMM
libraries and producing a variety of outputs including protein names,
EC numbers, and Gene Ontology terms. Metabolic inference tools that
re-annotate genomes using simple approaches such as BLAST searches
alone will produce inferior annotations and therefore inferior
reactome and pathway inferences.
Since PathoLogic takes as its input the output of genome annotation
pipelines, it must map protein names, EC numbers, and Gene Ontology
terms to reaction assignments. Since the latter two entities are
controlled vocabularies, they are straightforward for PathoLogic to
accept and map to reactions. Enzyme names are much less
straightforward to handle. The core of our approach is to utilize the
enzyme name and reaction associations recorded by curators in the
MetaCyc database. We also supplement those names with additional
enzyme synonyms that we search out using a program that iterates
across the 14,000 genomes in BioCyc and finds the most frequently
unrecognized enzyme names across all of these genomes. Those names
become the highest priorities for curation. Our curators have
recently entered an additional 300 new names from this list so that we
now have a total of 48,000 enzyme names and synonyms available to the
"enzyme name matching" component of PathoLogic. These new names have
significantly boosted reaction inference.
However, some of those enzyme names are ambiguous, either because an enzyme with one name
catalyzes multiple reactions at multiple active sites, or because different enzymes
with the same name catalyze different reactions. In version 23.5, the enzyme
name matcher will use gene names (if available in the genome annotation) to disambiguate
these ambiguous enzyme names. Gene names will also be used to infer reaction mappings
when the enzyme name is not recognized. Although there are occasional errors, our
review of these assignments indicate they are quite accurate. These two strategies further boost
reaction inference.
Version 23.5 will also include several improvements to pathway
inference. MetaCyc pathways now include more extensive use of "key
reaction" definitions, where pathways specify reactions that must have
an enzyme present in the organism to infer that pathway as present.
We also introduce a new pathway field called "key non-reactions",
which prevent inference of a given pathway if a specified reaction
outside that pathway is catalyzed by the organism. In particular
these new rules enable more accurate inference of the appropriate
variants of the TCA cycle and glycolysis pathways. We also added new
rules that result in more accurate inference of super pathways
(pathways built from several smaller pathways).
Another new feature in 23.5 is a new variant of the pathway evidence
report available from the web command Analysis → Reports
→ Pathway Evidence. Previously, this report sorted pathways
by pathway ontology. The new variation of the report sorts
the report by pathway score to speed user review of low-scoring pathways.
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