Genome-wide analysis reveals novel regulators of growth in Drosophila melanogaster

Abstract

Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA) analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity.\n\nAUTHOR SUMMARYGenetic studies in Drosophila have elucidated conserved signaling pathways and environmental factors that together control organismal size. In humans, hundreds of genes are associated with height variation, but these associations have not been performed in a controlled environment. As a result we are still lacking an understanding of the mechanisms creating size variability within a species. Here, under carefully controlled environmental conditions, we identify naturally occurring genetic variants that are associated with size diversity in Drosophila. We identify a cluster of associations close to the kek1 locus, a well-characterized growth regulator, but otherwise find that most variants are located in or close to genes that do not belong to the conserved pathways but may interact with these in a biological network. Many of these genes have a conserved role in humans. We validate 33 novel growth regulatory genes that participate in diverse cellular processes, most notably cellular metabolism and cell polarity. This study is the first genome-wide association analysis of natural variants underlying size in Drosophila and our results complement the knowledge we have accumulated on this trait from mutational studies of single genes.