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.
Highlights
Recent 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
Functional analysis of expression data using the Developmental FunctionaL Annotation at Tufts (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
Summary
A major contribution of the DFLAT project has been to capture critical information about developmental context to further characterize literature-derived functional annotation. DFLAT’s impact on the analyses of many different developmental stages is likely due to the introduction of the orthology-derived annotation, but it may reflect the fact that some genes with known roles in fetal development may continue to play similar roles after birth. DFLAT is well suited for gene set and pathway analysis on human fetal and neonatal expression data. Using DFLAT-derived gene sets in gene set enrichment analyses provides a larger number of enriched functions, but provides results that are more likely to be confirmed in the literature Even those that have not yet been confirmed tend to implicate more specific molecular processes, leading to the development of novel, focused hypotheses about the molecular mechanisms behind specific pathologies. All authors read and approved the final manuscript
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call