Gene set enrichment analysis of microarray data from Pimephales promelas (Rafinesque), a non-mammalian model organism

Methods for gene-class testing, such as Gene Set Enrichment Analysis (GSEA), incorporate biological knowledge into the analysis and interpretation of microarray data by comparing gene expression patterns to pathways, systems and emergent phenotypes. However, to use GSEA to its full capability with non-mammalian model organisms, a microarray platform must be annotated with human gene symbols. Doing so enables the ability to relate a model organism's gene expression, in response to a given treatment, to potential human health consequences of that treatment. We enhanced the annotation of a microarray platform from a non-mammalian model organism, and then used the GSEA approach in a reanalysis of a study examining the biological significance of acute and chronic methylmercury exposure on liver tissue of fathead minnow (Pimephales promelas). Using GSEA, we tested the hypothesis that fathead livers, in response to methylmercury exposure, would exhibit gene expression patterns similar to diseased human livers.

We describe an enhanced annotation of the fathead minnow microarray platform with human gene symbols. This resource is now compatible with the GSEA approach for gene-class testing. We confirmed that GSEA, using this enhanced microarray platform, is able to recover results consistent with a previous analysis of fathead minnow exposure to methylmercury using standard analytical approaches. Using GSEA to compare fathead gene expression profiles to human phenotypes, we also found that fathead methylmercury-treated livers exhibited expression profiles that are homologous to human systems & pathways and results in damage that is similar to those of human liver damage associated with hepatocellular carcinoma and hepatitis B.

This study describes a powerful resource for enabling the use of non-mammalian model organisms in the study of human health significance. Results of microarray gene expression studies involving fathead minnow, typically used for aquatic ecological toxicology studies, can now be used to generate hypotheses regarding consequences of contaminants and other stressors on humans. The same approach can be used with other model organisms with microarray platforms annotated in a similar manner.