Dosage compensation and demasculinization of X chromosomes in Drosophila

Abstract

The X chromosome of Drosophila shows a deficiency of genes with male-biased expression, whereas mammalian X chromosomes are enriched for spermatogenesis genes expressed premeiosis and multicopy testis genes. Meiotic X-inactivation and sexual antagonism can only partly account for these patterns. Here, we show that dosage compensation (DC) in Drosophila may contribute substantially to the depletion of male genes on the X. To equalize expression between X-linked and autosomal genes in the two sexes, male Drosophila hypertranscribe their single X, whereas female mammals silence one of their two X chromosomes. We combine fine-scale mapping data of dosage compensated regions with genome-wide expression profiles and show that most male-biased genes on the D. melanogaster X are located outside dosage compensated regions. Additionally, X-linked genes that have newly acquired male-biased expression in D. melanogaster are less likely to be dosage compensated, and parental X-linked genes that gave rise to an autosomal male-biased retrocopy are more likely located within compensated regions. This suggests that DC contributes to the observed demasculinization of X chromosomes in Drosophila, both by limiting the emergence of male-biased expression patterns of existing X genes, and by contributing to gene trafficking of male genes off the X.

Figure 1

A. The two-step model of MSL targeting to the X chromosome. I. The MSL complex (red circles) targets specific high affinity chromatin entry sites (HAS) on the X-chromosome in a sequence-dependent manner. HAS represent a subset of the MSL-bound regions in wildtype Drosophila that also recruit the MSL complex under more stringent conditions (such as when inserted into an autosome, or when integral subunits of the MSL complex are missing). II. After initial targeting, the MSL-complex spreads along in cis from the entry sites (shown by blue arrows), and predominantly binds to the 3′ end of actively transcribed genes. MSL-binding causes acetylation at histone H4 and results in a global change of the chromatin structure, facilitating a two-fold transcriptional up-regulation of X-linked genes in males (green line). B. Models of sex-biased expression versus dosage compensation in Drosophila. I. Direct interference of the dosage compensation machinery with male-biased expression. Binding of the dosage compensation complex, changes in chromatin structure, and global hyper-transcription of X-linked genes may interfere with subsequent transcriptional modifications and up-regulation of X genes in males (green circles). Genes further away from a HAS (or those not bound by the MSL complex) are more likely to be up-regulated in males. II. Indirect effects of dosage compensation on sex-biased gene expression. Genes further from a HAS will less likely be compensated in males, resulting in female-biased expression for genes further away from a HAS.

Figure 2

A. Distance to nearest HAS for X-linked genes. X-linked genes are categorized according to their MSL-binding profile [20], expression bias [29] or patterns of retroposition [31]. Genes targeted by the MSL complex (bound) are significantly closer to a HAS than genes not bound (unbound). Genes with male-biased expression are significantly further away from a HAS compared to female- and un-biased genes. Parental genes that have a retrocopy in the genome are significantly closer to a HAS than genes not having a duplicate retrocopy. B. Sex-biased expression versus distance to HAS. Plot of gene expression sex ratio (log₂ female/male ratio) for each X-linked gene in D. melanogaster against distance to its closest HAS. The lines are regression highlighting the trends: Red, female-biased genes; blue, male-biased genes; grey, unbiased genes. The black line describes the trend of all data. C. Fraction of dosage compensated genes. X-linked genes are categorized according to their expression bias [1], their change in sex-biased gene expression on the D. melanogaster lineage [29], or patterns of retroposition [31]. Genes with male-biased expression are significantly less likely to be bound by the MSL complex. Parental genes with a retrocopy are significantly more likely to be MSL-bound than genes not having a retrocopy.

Figure 3

A. Fraction of sex-biased genes across Drosophila chromosomes. The percentages of genes with male-biased (blue) or female-biased (red) expression are shown. X-linked genes are divided into those bound by the MSL complex (X_b) or not bound (X_u). Male-biased genes bound by the MSL complex are significantly underrepresented on the X. B. Sex-biased expression ratios across Drosophila chromosomes. Comparison of the extent of male and female biased gene expression ratios for each chromosome in D. melanogaster. Sex-biased gene expression is significantly lower for male-biased genes on the X relative to autosomes. The absolute value of the log₂ expression ratio is plotted on the y-axis. Bold horizontal bars are the median value, the box is the inter-quartile range, and the whiskers is the 95% confidence interval.