Interplay between copy number, dosage compensation and expression noise in Drosophila

Gene copy number variations are associated with many disorders characterized by high phenotypic heterogeneity. Disease penetrance differs even in genetically identical twins. Can such heterogeneity arise, in part, from increased expression variability of one dose genes? While increased variability in the context of single cell gene expression is well recognized, our computational simulations indicated that in a multicellular organism intrinsic single cell level noise should cancel out and thus the impact of gene copy reduction on organismal level expression variability must be due to something else. To systematically examine the impact of gene dose reduction on expression variability in a multi-cellular organism, we performed experimental gene expression measurements in Drosophila DrosDel autosomal deficiency lines. Genome-wide analysis revealed that autosomal one dose genes have higher gene expression variability relative to two dose genes. In flies, gene dose reduction is often accompanied by dosage compensation at the gene expression level. Surprisingly, expression noise was increased by compensation. This increased compensation-dependent variability was found to be a property of one dose autosomal genes but not X-liked genes in males despite the fact that they too are dosage compensated, suggesting that sex chromosome dosage compensation also results in noise reduction. Previous studies attributed autosomal dosage compensation to feedback loops in interaction networks. Our results suggest that these feedback loops are not optimized to deliver consistent responses to gene deletion events and thus gene deletions can lead to heterogeneous responses even in the context of an identical genetic background. Additionally, we show that expression variation associated with reduced dose of transcription factors propagate through the gene interaction network, impacting a large number of downstream genes. These properties of gene deletions could contribute to the phenotypic heterogeneity of diseases associated with haploinsufficiency.