Effects of Gene Dose, Chromatin, and Network Topology on Expression in Drosophila melanogaster

Abstract

Deletions, commonly referred to as deficiencies by Drosophila geneticists, are valuable tools for mapping genes and for genetic pathway discovery via dose-dependent suppressor and enhancer screens. More recently, it has become clear that deviations from normal gene dosage are associated with multiple disorders in a range of species including humans. While we are beginning to understand some of the transcriptional effects brought about by gene dosage changes and the chromosome rearrangement breakpoints associated with them, much of this work relies on isolated examples. We have systematically examined deficiencies of the left arm of chromosome 2 and characterize gene-by-gene dosage responses that vary from collapsed expression through modest partial dosage compensation to full or even over compensation. We found negligible long-range effects of creating novel chromosome domains at deletion breakpoints, suggesting that cases of gene regulation due to altered nuclear architecture are rare. These rare cases include trans de-repression when deficiencies delete chromatin characterized as repressive in other studies. Generally, effects of breakpoints on expression are promoter proximal (~100bp) or in the gene body. Effects of deficiencies genome-wide are in genes with regulatory relationships to genes within the deleted segments, highlighting the subtle expression network defects in these sensitized genetic backgrounds.

Author Summary

Deletions alter gene dose in heterozygotes and bring distant regions of the genome into juxtaposition. We find that the transcriptional dose response is generally varied, gene-specific and coherently propagates into gene expression regulatory networks. Analysis of expression profiles of deletion heterozygotes indicates that distinct genetic pathways are weakened in adult flies bearing different deletions, even-though they show minimal or no overt phenotypes. While there are exceptions, breakpoints have a minimal effect on gene expression of flanking genes, despite the fact that different regions of the genome are brought into contact and that important elements such as insulators are deleted. These data suggest that there is little effect of nuclear architecture and long-range enhancer and/or silencer promoter contact on gene expression in the compact Drosophila genome.