A novel hypothesis-unbiased method for Gene Ontology enrichment based on transcriptome data

PLoS One. 2017 Feb 15;12(2):e0170486. doi: 10.1371/journal.pone.0170486. eCollection 2017.

Abstract

Gene Ontology (GO) classification of statistically significantly differentially expressed genes is commonly used to interpret transcriptomics data as a part of functional genomic analysis. In this approach, all significantly expressed genes contribute equally to the final GO classification regardless of their actual expression levels. Gene expression levels can significantly affect protein production and hence should be reflected in GO term enrichment. Genes with low expression levels can also participate in GO term enrichment through cumulative effects. In this report, we have introduced a new GO enrichment method that is suitable for multiple samples and time series experiments that uses a statistical outlier test to detect GO categories with special patterns of variation that can potentially identify candidate biological mechanisms. To demonstrate the value of our approach, we have performed two case studies. Whole transcriptome expression profiles of Salmonella enteritidis and Alzheimer's disease (AD) were analysed in order to determine GO term enrichment across the entire transcriptome instead of a subset of differentially expressed genes used in traditional GO analysis. Our result highlights the key role of inflammation related functional groups in AD pathology as granulocyte colony-stimulating factor receptor binding, neuromedin U binding, and interleukin were remarkably upregulated in AD brain when all using all of the gene expression data in the transcriptome. Mitochondrial components and the molybdopterin synthase complex were identified as potential key cellular components involved in AD pathology.

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Databases, Nucleic Acid*
  • Gene Expression Regulation, Bacterial*
  • Gene Ontology*
  • Humans
  • Salmonella enteritidis / genetics*
  • Salmonella enteritidis / metabolism
  • Transcriptome*

Grants and funding

MF was supported by PhD divisional scholarship of The University of Adelaide. EE was partially supported by NHMRC APP1061006 in the Alzheimer’s Disease Genetics Laboratory, School of Biological Sciences. We acknowledge funding from Nectar to host the web and database server of this study. Nectar is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.