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G3 (Bethesda). 2018 Feb 2;8(2):587-598. doi: 10.1534/g3.117.300400.

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

Author information

1
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
2
Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894.
3
Laboratory of Systems Genetics, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.
4
Department of Genetics and Cambridge Systems Biology Centre, University of Cambridge, CB2 3EH, United Kingdom.
5
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892 briano@nih.gov przytyck@ncbi.nlm.nih.gov.
6
Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894 briano@nih.gov przytyck@ncbi.nlm.nih.gov.

Abstract

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 whether increased expression variability owing to reduced gene dose might underlie this phenotypic heterogeneity. Indeed, we found that one-dose genes have higher gene expression variability relative to two-dose genes. We then asked whether this increase in variability could be explained by intrinsic noise within cells due to stochastic biochemical events, or whether 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. Interestingly, expression variability was related to the magnitude of expression compensation, suggesting that regulation, induced by gene dose reduction, is noisy. In a remarkable exception to this rule, the single X chromosome of males showed reduced expression variability, even compared with two-dose genes. Analysis of sex-transformed flies indicates that X expression variability is independent of the male differentiation program. Instead, we uncovered a correlation between occupancy of the chromatin-modifying protein encoded by males absent on the first (mof) and expression variability, linking noise suppression to the specialized X chromosome dosage compensation system. MOF occupancy on autosomes in both sexes also lowered transcriptional noise. Our results demonstrate that gene dose reduction 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.

KEYWORDS:

CNV; Drosophila; Genetics of Sex; MOF; X chromosome; dosage compensation; expression noise

PMID:
29242386
PMCID:
PMC5919722
DOI:
10.1534/g3.117.300400
[Indexed for MEDLINE]
Free PMC Article

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