Dosage-Dependent Expression Variation Suppressed on the Drosophila Male X Chromosome

DNA copy number variation is associated with many high phenotypic heterogeneity disorders. We systematically examined the impact of Drosophila melanogaster deletions on gene expression profiles to ask if increased expression variability due to reduced gene dose might underlie this phenotypic heterogeneity. Indeed, we find that one dose genes have higher gene expression variability relative to two dose genes. We then asked if this increase in variability could be explained by intrinsic noise within cells, due to stochastic biochemical events, or if expression variability is due to extrinsic noise arising from more complex interactions. Our modeling showed that intrinsic gene expression noise averages at the organism level and thus cannot explain increased variation in one dose gene expression simply. Interestingly, expression variability was related to the magnitude of expression compensation, suggesting that gene dose reduction induced regulation is noisy. In a remarkable exception to this rule the single X chromosome of males showed reduced expression variability, even compared to two dose genes. Analysis of sex transformed flies indicates that X expression variability is independent of the male differentiation program. Instead, we uncover a correlation between occupancy of the chromatin modifying protein encoded by males absent on first (mof) and expression variability, linking noise suppression to the specialized X chromosome dosage compensation system. MOF occupancy on autosomes in both sexes lowered transcriptional noise as well. Our results demonstrate that gene deletions can lead to heterogeneous responses, which are often noisy. This has implications for understanding gene network regulatory interactions and phenotypic heterogeneity. Additionally, chromatin modification appears to play a role in dampening transcriptional noise.

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