Probabilistic orthology analysis of the ABC transporters: Implications for the development of multiple drug resistance phenotype.

摘要

Drug transporters are rapidly becoming recognised as central to determining a chemical's fate within the body. This action is a double-edged sword, protecting the body from toxicants, but also potentially leading to reduced clinical efficacy of drugs through multiple drug resistance phenotype. To examine the inter-relationship of this super-family we have constructed phylogenetic trees over an extended evolutionary distance representing each of the seven sub-families. In addition, using protein sequences from species important in the design and evaluation of novel chemicals, namely human, macaque, rat, mouse and dog, we have undertaken probabilistic orthology analysis to examine speciation probabilities within this phylogeny. This data allows us to accurately predict orthologous sequences across these species, an important confirmatory step with implications for cross-species extrapolation of data during drug safety testing. Finally, we present the first complete phylogeny for sub-families within humans constructed utilising the entire coding sequences, at both the DNA and protein levels. We demonstrate for the first time that genes associated with the multiple drug resistance phenotype cluster separately from other genes within the same sub-family, suggestive of a conserved, fundamental, difference in these proteins. Such work may help guide future studies on the mechanisms underlying multiple drug resistance, as well as the development of novel therapeutic approaches to mitigate against its development.