Resolving the homology—function relationship through comparative genomics of membrane-trafficking machinery and parasite cell biology

Abstract

With advances in DNA sequencing technology, it is increasingly common and tractable to informatically look for genes of interest in the genomic databases of parasitic organisms and infer cellular states. Assignment of a putative gene function based on homology to functionally characterized genes in other organisms, though powerful, relies on the implicit assumption of functional homology, i.e. that orthology indicates conserved function. Eukaryotes reveal a dazzling array of cellular features and structural organization, suggesting a concomitant diversity in their underlying molecular machinery. Significantly, examples of novel functions for pre-existing or new paralogues are not uncommon. Do these examples undermine the basic assumption of functional homology, especially in parasitic protists, which are often highly derived? Here we examine the extent to which functional homology exists between organisms spanning the eukaryotic lineage. By comparing membrane trafficking proteins between parasitic protists and traditional model organisms, where direct functional evidence is available, we find that function is indeed largely conserved between orthologues, albeit with significant adaptation arising from the unique biological features within each lineage.

An evolutionary balance: conservation vs innovation in ciliate membrane trafficking

“…Thus, a mechanistic understanding of membrane trafficking in ciliates, to complement the body of research primarily in animal and fungal (also Opisthokonta) cells, would allow one to compare different cell biological outcomes achieved over enormous evolutionary intervals. This is true for protists in general since unicellular organisms represent most of the diversity in Eukarya . However, ciliates have an advantage in that, for several species, there are already well‐developed experimental toolkits facilitating a wide range of approaches for functional studies.…”

“…This is true for protists in general since unicellular organisms represent most of the diversity in Eukarya. [26][27][28] However, ciliates have an advantage in that, for several species, there are already welldeveloped experimental toolkits facilitating a wide range of approaches for functional studies. These tools are most advanced for Tetrahymena thermophila and Paramecium tetraurelia, but molecular studies are also feasible in Oxytricha trifallax and Stentor coereleus ( Figure 1).…”

Regulation of early endosomes across eukaryotes: Evolution and functional homology of Vps9 proteins

“…Comparative genomic and phylogenetic analyses have demonstrated the presence of Rab5, Rab21 and Rab22 subfamily members across the breadth of eukaryotes 1,2 indicating that these Rabs were likely present in the Last Eukaryotic Common Ancestor (LECA). This is confirmed by the characterization of Rab5 orthologues in diverse eukaryotes representing each of the 5 eukaryotic supergroups, 3 and highlights the importance of this particular Rab protein and its functions to eukaryotic cells in general.…”

Evolution of protein trafficking in kinetoplastid parasites: Complexity and pathogenesis

“…Many of the major groups of trafficking proteins are paralogous, including Rab and ARF GTPases, SNAREs, tethers, coats and adaptins . In general, functions are well conserved between orthologs across eukaryotes, for example Rab7 is almost always functionally associated with late endocytic/pre‐lysosomal transport . This enables the prediction of transport routes with an acceptable and useful level of accuracy, albeit precise functions and interactions for specific proteins are somewhat harder to ascertain.…”