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UDP-glucuronosyltransferase (UGT) in Pinniped species can be analyzed with the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool to predict pseudogenes in other species
Citation:
Blatz, D., J. Dorne, L. Dellafiora, AND C. LaLone. UDP-glucuronosyltransferase (UGT) in Pinniped species can be analyzed with the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool to predict pseudogenes in other species. SETAC North America 42nd Annual meeting, Portland, OR, November 14 - 18, 2021. https://doi.org/10.23645/epacomptox.17102624
Impact/Purpose:
Presentation to the SETAC North America 42nd Annual meeting November 2021. The US EPA Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool can be used to understand differences in protein sequences across species that may be important for chemical susceptibility. The UDP-glucuronosyltransferase family is a group of metabolizing enzymes which have a great deal of genetic variation which often causes changes to activity and expression of the protein. Specifically, the UGT1A6 protein in the domestic cat has shown to be a pseudogene, or nonfunctioning gene, due to a differing sequence that leads to a lower protein activity when compared to the domestic dog which has a functional UGT1A6 protein. With the SeqAPASS tool, species of interest can be compared at the protein level, to the domestic dog’s functional UGT1A6, thus providing lines of evidence for determining which species may also possess the UGT1A6 pseudogenes and therefore be more susceptible to certain chemicals.
Description:
Differences in xenobiotic metabolism have been identified across species and attributed to the presence or absence of various UDP-glucuronosyltransferase (UGT) isoforms. For example, the domestic cat (Felis catus) is shown to metabolize acetaminophen more slowly than the domestic dog (Canis lupus familiaris) due to a UGT1A6 isoform pseudogene (i.e., non-functional gene). This pseudogene is caused by a premature stop codon in exon 1 of the cat UGT1A6 protein. Recently, the northern fur seal (Callorhinus ursinus) has been shown to have a UGT1A6 pseudogene and similar UGT activity to the domestic cat. To explore UGT1A6 sequence differences across species, the US EPA Sequence Alignment to Predict Across Species Susceptibility tool (SeqAPASS) tool was used. The SeqAPASS tool allows users to rapidly evaluate available protein target sequence and structural similarity at the primary amino acid sequence, conserved domain(s), and individual amino acid residue levels, to understand conservation and therefore predict chemical susceptibility. Through literature review, a case study was developed comparing the functional dog UGT1A6 to Pinniped species with known functional proteins and known pseudogenes. Using the individual amino acid residue comparison feature in SeqAPASS allows for hypothesis generation relative to species-specific predictions of possible UGT1A6 pseudogenes. Specifically, an insertion mutation, resulting in a premature stop codon, at aligned amino acid positions 62-64 in the domestic dog were compared in the example to identify UGT1A6 pseudogenes. This work demonstrates the utility of the SeqAPASS tool to rapidly determine possible pseudogenes in other species and generate research hypotheses as to potential chemical susceptibility. The contents of this abstract neither constitute nor necessarily reflect US EPA policy.
URLs/Downloads:
DOI: UDP-glucuronosyltransferase (UGT) in Pinniped species can be analyzed with the Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool to predict pseudogenes in other species
BLATZ_SETAC UGT POSTER_STICS.PDF (PDF, NA pp, 1011.38 KB, about PDF)