Citation:

LaLone, C. Informatics to advance cross species extrapolation. Unilever Meeting, Sharnbrook, Bedfordshire, UK, February 28, 2020.

Impact/Purpose:

The SeqAPASS tool allows users to compare protein similarity across species. This is important because chemicals act on protein targets. Therefore, by understanding how similar proteins are across species, the SeqAPASS tool can produce predictions of chemical susceptibility across hundreds of species rapidly. This presentation will be an overview of the challenges in extrapolating toxicity data/knowledge across species and a description of the functionality of the tool itself using case study examples to highlight features.

Description:

The Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool was first released in January of 2016. It was created to address challenges the Agency faces in extrapolating chemical toxicity data/knowledge generated from model organisms or surrogate species to all species of concern. SeqAPASS was designed to take advantage of existing information regarding chemical-protein interactions in sensitive species and allows for comparisons to protein sequences across species at different levels of specificity, moving from primary amino acid sequence to consideration of critical amino acids. Each level of sequence comparison in the SeqAPASS evaluation is intended to add a line of evidence toward protein conservation (or lack thereof) to identify species with a given chemical target. The major assumption is that if other species possess a similar protein target compared to a known sensitive species, then there is a greater likelihood that a chemical could act on that target in the other species rendering it susceptible to chemical perturbation. The SeqAPASS analysis has been developed in partnership with significant input from Program Offices and Regions regarding needs and attributes of the tool and relative to methodology and functionality that would make the tool fit for a variety of purposes and decision-making needs. Recent improvements to the tool have focused on features requested by Program Office partners including data visualization, automated predictions of susceptibility at all levels of the analysis, integration of summary and settings reports, interoperability with other EPA tools, and guidance for identification of appropriate query proteins and literature to support critical amino acid residue comparisons. The methods, features, and functionality of the SeqAPASS tool from version 1.0 (2016) to 4.0 (2019) have made the tool operable, consistent, and streamlined, providing chemical susceptibility predictions of yes or no for hundreds to thousands of species rapidly. However, the tool is designed to evolve as the science surrounding protein sequence and structural comparisons advances. That is why, current research is exploring the utility of homology modeling and molecular docking as a means to take this evaluation of species similarity to the protein structural level to yield predicted binding affinity across species. Parallel to developing a pipeline that considers structural similarity, case studies are created to demonstrate the utility of these new approaches relative to understanding conservation of proteins important for bioaccumulation and toxicity of chemicals of concern to EPA.

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