Lung function candidate genes in Drosophila melanogaster

Abstract

RationaleChronic obstructive pulmonary disease (COPD) represents a leading cause of global morbidity and mortality. Genome-wide association studies (GWAS) have implicated numerous genetic variants in lung function impairment, yet confidently identifying the underlying genes and pathways, and translating these findings into mechanistic insight, remains a significant challenge. ObjectivesTo leverage the genetic amenability and high-throughput screening capability of Drosophila melanogaster to determine the role of candidate causal genes in epithelial cell homeostasis. MethodsWe performed a loss-of-function analysis of 60 prioritised lung function candidate causal genes implicated from GWAS in two distinct epithelia: the dorsal thorax and trachea. ResultsWe identified 57/60 tested candidate genes that alter at least one aspect of epithelial morphology and behaviour upon knockdown. With a focus on junctional integrity, cell delamination and tissue growth, we identified 11 genes for further study: Sec6, RpS26, pAbp, Arf102f, Riok1, Sra-1, Inpp5e, CG31759, ssh, eIF6 and Rtf1. Further characterisation found a significant reduction in junctional E-Cadherin levels following Arf102F, Rtf1, RioK1 and Sra-1 knockdown. Following a secondary screen in the Drosophila tracheal system for priority candidates, Sec6 and RpS26 were associated with significant airway defects and a reduction in larval body size. 8/11 priority genes exhibited differential lung gene expression between controls and patients with COPD. ConclusionsThese data demonstrate the amenability of Drosophila melanogaster to perform in vivo functional analyses of candidate causal genes at scale. Initial findings implicate several genes in epithelial homeostasis and integrity, providing new mechanistic understanding and potential therapeutic targets for COPD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=164 SRC="FIGDIR/small/731340v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@dbff6dorg.highwire.dtl.DTLVardef@15e84f0org.highwire.dtl.DTLVardef@69d97aorg.highwire.dtl.DTLVardef@144f47e_HPS_FORMAT_FIGEXP M_FIG C_FIG