Deciphering the Molecular Mechanism Underlying African Animal Trypanosomiasis by Means of the 1000 Bull Genomes Project Genomic Dataset

SIMPLE SUMMARY: Climate change is increasing the risk of spreading vector-borne diseases such as African Animal Trypanosomiasis (AAT), which is causing major economic losses, especially in sub-Saharan African countries. Mainly considering this disease, we have investigated transcriptomic and genomic data from two cattle breeds, namely Boran and N‘Dama, where the former is known for its susceptibility and the latter one for its tolerance to the AAT. Despite the rich literature on this disease, there is still a need to investigate underlying genetic mechanisms to decipher the complex interplay of regulatory SNPs (rSNPs), their corresponding gene expression profiles and the downstream effectors associated with the AAT disease. The findings of this study complement our previous results, which mainly involve the upstream events, including transcription factors (TFs) and their co-operations as well as master regulators. Moreover, our investigation of significant rSNPs and effectors found in the liver, spleen and lymph node tissues of both cattle breeds could enhance the understanding of distinct mechanisms leading to either resistance or susceptibility of cattle breeds. ABSTRACT: African Animal Trypanosomiasis (AAT) is a neglected tropical disease and spreads by the vector tsetse fly, which carries the infectious Trypanosoma sp. in their saliva. Particularly, this parasitic disease affects the health of livestock, thereby imposing economic constraints on farmers, costing billions of dollars every year, especially in sub-Saharan African countries. Mainly considering the AAT disease as a multistage progression process, we previously performed upstream analysis to identify transcription factors (TFs), their co-operations, over-represented pathways and master regulators. However, downstream analysis, including effectors, corresponding gene expression profiles and their association with the regulatory SNPs (rSNPs), has not yet been established. Therefore, in this study, we aim to investigate the complex interplay of rSNPs, corresponding gene expression and downstream effectors with regard to the AAT disease progression based on two cattle breeds: trypanosusceptible Boran and trypanotolerant N’Dama. Our findings provide mechanistic insights into the effectors involved in the regulation of several signal transduction pathways, thereby differentiating the molecular mechanism with regard to the immune responses of the cattle breeds. The effectors and their associated genes (especially MAPKAPK5, CSK, DOK2, RAC1 and DNMT1) could be promising drug candidates as they orchestrate various downstream regulatory cascades in both cattle breeds.