DFLAT: functional annotation for human development

Abstract

BackgroundRecent increases in genomic studies of the developing human fetus and neonate have led to a need for widespread characterization of the functional roles of genes at different developmental stages. The Gene Ontology (GO), a valuable and widely-used resource for characterizing gene function, offers perhaps the most suitable functional annotation system for this purpose. However, due in part to the difficulty of studying molecular genetic effects in humans, even the current collection of comprehensive GO annotations for human genes and gene products often lacks adequate developmental context for scientists wishing to study gene function in the human fetus.DescriptionThe Developmental FunctionaL Annotation at Tufts (DFLAT) project aims to improve the quality of analyses of fetal gene expression and regulation by curating human fetal gene functions using both manual and semi-automated GO procedures. Eligible annotations are then contributed to the GO database and included in GO releases of human data. DFLAT has produced a considerable body of functional annotation that we demonstrate provides valuable information about developmental genomics. A collection of gene sets (genes implicated in the same function or biological process), made by combining existing GO annotations with the 13,344 new DFLAT annotations, is available for use in novel analyses. Gene set analyses of expression in several data sets, including amniotic fluid RNA from fetuses with trisomies 21 and 18, umbilical cord blood, and blood from newborns with bronchopulmonary dysplasia, were conducted both with and without the DFLAT annotation.ConclusionsFunctional analysis of expression data using the DFLAT annotation increases the number of implicated gene sets, reflecting the DFLAT’s improved representation of current knowledge. Blinded literature review supports the validity of newly significant findings obtained with the DFLAT annotations. Newly implicated significant gene sets also suggest specific hypotheses for future research. Overall, the DFLAT project contributes new functional annotation and gene sets likely to enhance our ability to interpret genomic studies of human fetal and neonatal development.

The pathway not taken: understanding ‘omics data in the perinatal context

“…The DFLAT annotation was then validated using both external and internal datasets, so any bias toward internally-produced datasets should be minimal. 22 Other limitations include the difficulties inherent in comparing two resources that have different functional analytic modes and therefore different outputs. We attempted to overcome this limitation by manually categorizing the outputs of the two methods and writing Perl scripts to enable a more direct comparison of the two.…”

“…The derivation and validation of DFLAT has been described in detail in a previous publication. 22 Briefly, DFLAT was created via manual curation from the literature using the Protein2GO curation tool and the methodology of the Gene Ontology Consortium, as well as Gene Ontology Non-Eligible annotations and mouse-to-human ortholog derived annotations. DFLAT was then validated using both external datasets and ones produced by our own laboratory.…”

“…23 We extended the analysis to include gene sets with raw p-values < 0.01, given controversy about adjusting for multiple testing between highly-overlapping gene sets. 22,29,30 …”

“…Members of our group previously have addressed the need for more fetal-focused gene expression analytic tools by adding human-specific, developmentally-relevant annotation to the Gene Ontology (GO) database 21 and maintaining a collection of gene sets tailored for use in studying human development, called “Developmental FunctionaL Annotation at Tufts” or DFLAT (http://dflat.cs.tufts.edu). 22 Using these gene sets in the Gene Set Enrichment Analysis 23 (GSEA/DFLAT), we sought to compare interpretation provided by this publicly-available fetus-specific functional annotation to that of a commercially-available widely-used functional analytic tool, Ingenuity Pathway Analysis (IPA).…”

The Amniotic Fluid Transcriptome as a Guide to Understanding Fetal Disease

“…The Developmental FunctionaL Annotation project at Tufts (DFLAT) (see http://dflat.cs.tufts.edu/data .htm, Wick et al 2014) is gene ontology annotation specific to the developing human fetus. This database can be used with GSEA to identify developmental processes and functions associated with the observed differential gene expression.…”