Assessing selective pressure in selected Fasciola hepatica gene families
Description
Fasciolosis is caused by liver flukes: F. hepatica, and a sister species – F. gigantica. A growing concern with controlling the disease is resistance to triclabendazole (TCBZ), the only drug shown to kill both adult and immature liver flukes. Currently, F. hepatica mechanism of resistance to TCBZ is not clearly understood and there is no effective commercially available vaccine. Previous work proposed three mechanisms associated with TCBZ mode of action and resistance: tubulin binding activity, drug uptake mechanisms, and drug metabolism mechanism. Exploring evolutionary forces acting on F. hepatica genes associated with TCBZ mode of action and resistance could explain how the parasite develops resistance to the drug, enable identification of potential drug targets, and facilitate development of new drugs. F. hepatica gene family members belonging to each of the three proposed mechanism of action of TCBZ action and resistance, and their trematode orthologous sequences were compiled. The gene families studied include tubulins, ATP-binding cassette transporters (ABC), AC, RAS, ADP ribosylation factor, cytochrome P450 (CYP450), GSTs, and Fatty Acid Binding Proteins (FABPs). Signals indicative of positive selection was identified using Phylogenetic Analysis by Maximum Likelihood (PAML) and McDonald and Kreitman test (MKtest). PAML branch-site model testing identified 1 alpha tubulin, 1 delta tubulin, 5 ABC genes, 9 RAS genes, and 4 ADP ribosylation factor genes with statistically significant sites under positive selection. While the MKtest analysis identified 2 RAS genes and 1 AC genes under positive selection.
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Institutions
- University of Liverpool