Recurring pathway hole

The recurring pathway hole
A biological system such as an enzymatic pathway usually is described as having several components working together. The key to systems reconstruction is to have some mechanism for recognizing each component. When the systems reconstruction for a given system reveals that many different reference genomes appear to be missing the same component, the gap is a recurring pathway hole. Analyses such as Genome Properties and Subsystems can reveal such pathway holes.

Explanations for recurring pathway holes.
Pathway holes are interesting because they may point to a non-orthologous gene displacement, or NOD. However, there are several possible alternate explanations.


 * If a protein is small enough, such as the PqqA gene in the pyrroloquinoline quinone biosynthesis system, the component may be missing because of faulty identification of genes.


 * If a component is identified by its annotation, or through its assignment to a protein family, it may be missing from a systems reconstruction because of faulty annotation or a faulty protein family decision rule.


 * A systems reconstruction may show a hole through false-positive errors in the components assigned as present, rather than a false-negative error for the component left absent.


 * A reconstruction with holes that are not due to annotation error may represent a non-functional system. However, it is more likely to represent a variant form of system. It may be a pathway that starts later, or terminates early, or uses different intermediates.

The art of systems reconstruction requires good selection of branch points in metabolic systems to serve as start and stop points for biochemical pathways. When systems definitions are properly modular, the expectation that most reconstructions should be complete, or completely absent, may be used to validate or adjust annotation methods.

The recurring pathway hole shares some similarities with the orphan marker; in a system with just two components, one found and the other not, they are equivalent. An orphan marker may indicate that a protein with a known molecular function can play a role in a previously unexpected biological process.