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

Abstract

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.\n\nAuthor SummaryGene copy number variations are associated with many human disorders characterized by high phenotypic heterogeneity and understanding the effects of gene copy alterations is essential if we wish to understand factors influencing disease heterogeneity. While heterogeneous responses to reductions in gene dosage can be attributed in part to genetic background differences, we found that responses to dosage reduction vary, even in identical genetic backgrounds. Heterogeneities are not restricted to reduced dosage genes, but propagate through gene networks to affect downstream genes with normal copy number. We also found that reduction in gene dosage is associated with the introduction of expression variation or noise. Expression noise was also observed to propagate across the gene network, further contributing to the heterogeneous response to gene deletion. Through the use of computational simulation, we showed that the majority of the increased noise we observed is most likely due to extrinsic rather than intrinsic sources. Irrespective of the source of the observed noise, we propose that the presence of expression noise and its propagation through gene networks is likely to contribute to the heterogeneity of disease phenotypes observed in humans.