Dynamic Spatial-temporal Expression Ratio of X Chromosome to Autosomes but Stable Dosage Compensation in Mammals

In the evolutionary model of dosage compensation,per-allele expression level of the X chromosome has been proposed to have twofold up-regulation to compensate its dose reduction in males(XY)compared to females(XX).However,the expression regulation of X-linked genes is still controversial,and comprehensive evaluations are still lacking.By integrating multi-omics datasets in mammals,we investigated the expression ratios including X to autosomes(X:AA ratio)and X to orthologs(X:XX ratio)at the transcriptome,translatome,and proteome levels.We revealed a dynamic spatial-temporal X:AA ratio during development in humans and mice.Meanwhile,by tracing the evolution of orthologous gene expression in chickens,platypuses,and opossums,we found a stable expression ratio of X-linked genes in humans to their autosomal orthologs in other species(X:XX1)across tissues and developmental stages,demonstrating stable dosage compensation in mammals.We also found that different epigenetic regulations contributed to the high tissue specificity and stage specificity of X-linked gene expression,thus affecting X:AA ratios.It could be concluded that the dynamics of X:AA ratios were attributed to the different gene contents and expression preferences of the X chromosome,rather than the stable dosage compensation.

The evolution of sex chromosome dosage compensation in animals

The evolution of heteromorphic sex chromosomes shall lead to gene expression dosage problems,as in at least one of the sexes,the sex-linked gene dose has been reduced by half.It has been proposed that the transcriptional output of the whole X or Z chromosome should be doubled for complete dosage compensation in heterogametic sex.However,owing to the variability of the existing methods to determine the transcriptional differences between sex chromosomes and autosomes(S:A ratios)in different studies,we collected more than 500 public RNA-Seq data set from multiple tissues and species in major clades and proposed a unified computational framework for unbiased and comparable measurement of the S:A ratios of multiple species.We also tested the evolution of dosage compensation more directly by assessing changes in the expression levels of the current sex-linked genes relative to those of the ancestral sex-linked genes.We found that in mammals and birds,the S:A ratio is approximately 0.5,whereas in insects,fishes,and flatworms,the S:A ratio is approximately 1.0.Further analysis showed that the fraction of dosage-sensitive housekeeping genes on the X/Z chromosome is significantly correlated with the S:A ratio.In addition,the degree of degeneration of the Y chromosome may be responsible for the change in the S:A ratio in mammals without a dosage compensation mechanism.Our observations offer unequivocal support for the sex chromosome insensitivity hypothesis in animals and suggest that dosage sensitivity states of sex chromosomes are a major factor underlying different evolutionary strategies of dosage compensation.

Masculinizer gene controls sexual differentiation in Hyphantria cunea

The Masculinizer gene,Masc,encodes a lepidopteran-specific novel CCCHtype zinc finger protein,which controls sex determination and dosage compensation in Bombyx mori.Considering the potential application of it in pest control,it is necessary to investigate the function of Masc gene in Hyphantria cunea,a globally invasive forest pest.In the present study,we identified and functionally characterized the Masc gene,HcMasc,in H.cunea.Sequence analysis revealed that HcMASC contained the conserved CCCH-type zinc finger domain,nuclear localization signal,and male determining domain,in which the last was confirmed to be required for its masculinization in BmN cell line.However,expression data showed that unlike male-biased expression in B.mori,Hc-Masc gene expresses in main all developmental stages or tissues in both sexes.Clustered regularly interspaced palindromic repeats(CRISPR)/CRISPR-associated protein 9-based disruption of the common exons 1 and 3 of the HcMasc gene resulted in imbalanced sex ratio and abnormal external genitalia of both sexes.Our results suggest that the HcMasc gene is required for both male and female sexual differentiation and dosage compensation in H.cunea and provide a foundation for developing better strategies to control this pest.

Re-evaluation of the function of the male specific lethal complex in Drosophila

A set of proteins and noncoding RNAs, referred to as the male specific lethal （MSL） complex, is present on the male X chromosome in Drosophila and has been postulated to be responsible for dosage compensation of this chromosome -- the up-regulation of its expression to be equal to that of two X chromosomes in females. This hypothesis is evaluated in view of lesser known aspects of dosage compensation such as the fact that metafemales with three X chromosomes also have equal expression to normal females, which would require a down-regulation of each gene copy Moreover, when this complex is ectopically expressed in females or specifically targeted to a reporter in males, there is no increase in expression of the genes or targets with which it is associated. These observations are not consistent with the hypothesis that the MSL complex conditions dosage compensation. A synthesis is described that can account for these observations.