Translational Biology Approach to Identify Causative Factors for Rare Toxicities in Humans and Animals

Dale      E. Johnson; Sucha      Sudarsanam; Jonathan      Bingham; Subha      Srinivasan

doi:10.2174/157016312799304561

Abstract

Genome-wide RNA splicing (with gene expression) can be used to discover variations that drive specific diseases and / or change the susceptibility in individuals to drug responses including tissue specific toxicities. Evidence linking causative SNPs to individual splicing differences between individuals is emerging and this may lead to a better understanding of susceptibilities related to rare drug-induced toxicities. The development of more sensitive genomics tools is expected to further the study of variations in molecular phenotype from alternative splicing of pre-mRNA. This report highlights a genomics platform developed to measure splicing changes that occur in response to drug exposures, and therefore is applicable for the study of drug-induced toxicity. The platform is applicable for humans, all toxicology species, and specialized model systems. For efficiency, multiple samples can be combined into a single sequencing run and individual sequences can be separated via informatics. Biobanked specimens from clinical trials, toxicology studies, from commercial sources, and/or from public ‘omics’ data resources such as in NCBI are the only sample or non-sample data requirements.

Keywords: ABC transporters, ADME/Tox, Alternative splicing, CD44, CYP450, RNA-seq, Solute carriers, VEGF-A, Genome-wide RNA splicing, toxicology