Sequence-based functional annotation: what if most of the genes are unique to a genome?

The genomes of trypanosomatids are distantly related to other eukaryotes, with significant numbers of hypothetical or conserved hypothetical trypanosomatid-specific genes, whose functions cannot be determined using homology-dependent annotation methods. Here, we describe homology-independent methods to infer biological functions of genes based solely on their sequences. These approaches are not limited to trypanosomatid genomes and provide grounds for analysis of genomes of Plasmodium falciparum and other parasites associated with neglected tropical diseases. A critical evaluation of the current state of annotation of parasitic genomes endorses the need to exploit homology-independent computational methods, which can identify protein functions, potentially including essential genes, and provide a plethora of valuable information on interaction networks and regulatory elements.