Trypanosoma brucei causes both Human African Trypanosomiasis and Animal African Trypanosomiasis. These diseases are transmitted by tsetse flies through saliva infected with T. brucei as the vector feeds on a blood meal. One strategy of controlling disease transmission is disrupting the life cycle of T. brucei in the tsetse fly. Ongoing studies on Sodalis glossinidius have provided the proof-of-concept that tsetse endosymbionts may be used to interfere with pathogen transmission through the vector. This strategy, however, relies on the knowledge of trypanosome biology, especially the developmental events that take place in the tsetse fly vector to allow for its survival. This study aimed at constructing a gene co-expression network to predict key genes in T. brucei development in the tsetse fly, the functional roles which these genes are associated with, and also predict 3' untranslated region motifs for gene clustering together in the network. RNA-seq counts data generated from the developing T. brucei parasite in the tsetse fly was used in this study. The expression levels of T. brucei genes were obtained by running the RNA-seq data through the RNA-seq pipeline. Using the T. brucei gene expression data, the weighted gene co-expression network analysis approach was used to construct and analyze the network. Twelve (12) out of 27 functionally enriched gene modules (clusters) of the co-expression network were obtained from the network analysis. The enriched functional roles for the clusters were associated with cell cycle, cell signaling, mitochondrion, protein biosynthesis, and cell surface and highlight important functional processes during the parasite’s development on tsetse fly. The hub (key) genes for the 12 modules encoded proteins such as RBP6, Inner arm dynein 5-1 protein, and BARP protein, that have previously been proven crucial in T. brucei development in the tsetse fly. The hub genes may be involved in key processes that enable the parasite develop and complete its life cycle in tsetse fly. Other hub genes encoded proteins whose functional roles are still unknown and could serve as candidate genes for further studies. The 3’ untranslated region motif prediction for genes clustered together identified 10 significantly enriched motifs that could provide insights into gene regulation during parasite’s development in tsetse. The results of this study provide a resource for network-based data mining to identify candidate genes for functional studies. The knowledge obtained from co-expression analysis will provide novel insights on the role of genes in development and T. brucei molecular processes that may be targeted by trypanocidal products.

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