Gene Fusion Analysis in the Battle against the African Endemic Sleeping Sickness

Philip Trimpalis,Sophia Kossida,Vassiliki Lila Koumandou,Evangelia Pliakou,Nicholas P Anagnou

doi:10.1371/journal.pone.0068854

Abstract

The protozoan Trypanosoma brucei causes African Trypanosomiasis or sleeping sickness in humans, which can be lethal if untreated. Most available pharmacological treatments for the disease have severe side-effects. The purpose of this analysis was to detect novel protein-protein interactions (PPIs), vital for the parasite, which could lead to the development of drugs against this disease to block the specific interactions. In this work, the Domain Fusion Analysis (Rosetta Stone method) was used to identify novel PPIs, by comparing T. brucei to 19 organisms covering all major lineages of the tree of life. Overall, 49 possible protein-protein interactions were detected, and classified based on (a) statistical significance (BLAST e-value, domain length etc.), (b) their involvement in crucial metabolic pathways, and (c) their evolutionary history, particularly focusing on whether a protein pair is split in T. brucei and fused in the human host. We also evaluated fusion events including hypothetical proteins, and suggest a possible molecular function or involvement in a certain biological process. This work has produced valuable results which could be further studied through structural biology or other experimental approaches so as to validate the protein-protein interactions proposed here. The evolutionary analysis of the proteins involved showed that, gene fusion or gene fission events can happen in all organisms, while some protein domains are more prone to fusion and fission events and present complex evolutionary patterns.

Highlights

African trypanosomiasis is one of the neglected parasitic diseases which infects both humans and animals in regions of sub-Saharan Africa which cover about 37 countries; more than 60 million people are at risk even today [1]
For all proteins involved in the protein-protein interactions (PPIs) identified by this method, we examine their involvement in crucial metabolic pathways and their evolutionary history
180 fusion events were automatically detected by the SAFE software, from which, only 49 passed the backward BLAST verification step and were thereafter considered for a proposed PPI (Table S1)

Summary

Introduction

African trypanosomiasis is one of the neglected parasitic diseases which infects both humans and animals in regions of sub-Saharan Africa which cover about 37 countries; more than 60 million people are at risk even today [1]. The disease is caused by protozoa of the species Trypanosoma brucei and is transmitted by the tsetse fly, through a bite into the bloodstream. The symptoms are sometimes ignored or at least underestimated, as they include fever and other common symptoms, and behavioral changes, such as anxiety or sleep disorders. The tests used to verify the infection nowadays include painful and complicated procedures such as lumbar puncture, and lymph node aspiration. The available drugs, as effective as they may be, are outdated and can cause severe and often deadly side-effects [2]

Methods

Results

Conclusion