Dosage compensation

About: Dosage compensation is a research topic. Over the lifetime, 1920 publications have been published within this topic receiving 124589 citations.

Transformation of salivary gland secretion protein gene Sgs-4 in Drosophila: stage- and tissue-specific regulation, dosage compensation, and position effect

Abstract: The Sgs-4 gene of Drosophila melanogaster encodes one of the larval secretion proteins and is active only in salivary glands at the end of larval development. This gene lies in the X chromosome and is controlled by dosage compensation--i.e., the gene is hyperexpressed in males. Therefore, males with one X chromosome produce nearly as much Sgs-4 products as females with two X chromosomes. We used a 4.9-kilobase-pair (kb) DNA fragment containing the Sgs-4d coding region embedded in 2.6 kb of upstream sequences and 1.3 kb of downstream sequences for P-element-mediated transformation of the Sgs-4h underproducer strain Kochi-R. Sgs-4d gene expression was found in all 15 transformed lines analyzed, varying with the site of chromosomal integration. The transposed gene was subject to tissue- and stage-specific regulation. At X-chromosomal sites, the levels of gene expression were similar in both sexes, signifying dosage compensation. At autosomal sites, it was on average 1.5 times higher in males than in females. The results indicate that the transforming DNA fragment contains all sequences necessary for tissue- and stage-specific regulation and for hyperexpression in males.

Sex Chromosome-wide Transcriptional Suppression and Compensatory Cis-Regulatory Evolution Mediate Gene Expression in the Drosophila Male Germline

Abstract: The evolution of heteromorphic sex chromosomes has repeatedly resulted in the evolution of sex chromosome-specific forms of regulation, including sex chromosome dosage compensation in the soma and meiotic sex chromosome inactivation in the germline. In the male germline of Drosophila melanogaster, a novel but poorly understood form of sex chromosome-specific transcriptional regulation occurs that is distinct from canonical sex chromosome dosage compensation or meiotic inactivation. Previous work shows that expression of reporter genes driven by testis-specific promoters is considerably lower—approximately 3-fold or more—for transgenes inserted into X chromosome versus autosome locations. Here we characterize this transcriptional suppression of X-linked genes in the male germline and its evolutionary consequences. Using transgenes and transpositions, we show that most endogenous X-linked genes, not just testis-specific ones, are transcriptionally suppressed several-fold specifically in the Drosophila male germline. In wild-type testes, this sex chromosome-wide transcriptional suppression is generally undetectable, being effectively compensated by the gene-by-gene evolutionary recruitment of strong promoters on the X chromosome. We identify and experimentally validate a promoter element sequence motif that is enriched upstream of the transcription start sites of hundreds of testis-expressed genes; evolutionarily conserved across species; associated with strong gene expression levels in testes; and overrepresented on the X chromosome. These findings show that the expression of X-linked genes in the Drosophila testes reflects a balance between chromosome-wide epigenetic transcriptional suppression and long-term compensatory adaptation by sex-linked genes. Our results have broad implications for the evolution of gene expression in the Drosophila male germline and for genome evolution.

Somatic sexual differentiation in Caenorhabditis elegans.

Abstract: The two sexes of the nematode Caenorhabditis elegans are the self-fertile hermaphrodite (essentially a female with a mixed germ line) and the male, and these differ extensively in anatomy, physiology, and behavior. At hatching, C. elegans larvae of each sex are nearly indistinguishable, differing mainly in the sex-specific death of a handful of neurons. After birth, however, a number of blast cells undergo radically different lineages and differentiation programs in the two sexes, leading to adults in which about one-third of cells are overtly dimorphic. The first C. elegans mutants causing discordance between genetic and phenotypic sex were isolated more than 30 years ago. Since then much progress has been made in uncovering the chromosomal elements and downstream regulatory pathways that control sex determination and sexual differentiation in the worm. The primary signal for sex determination is the ratio of X chromosomes to sets of autosomes, with hermaphrodites normally having two X chromosomes (XX) and males one (XO). The X:A signal is exquisitely dose-sensitive and operates via a group of X-linked regulators acting in opposition to a group of autosomal regulators that compete for the control of the master sex regulator xol-1. The activity of xol-1 coordinately regulates the formation of an active X chromosome dosage compensation complex and the activity of a sex determination regulatory cascade. The sex determination pathway globally controls all sexually dimorphic features by conferring sex specificity on downstream regulatory modules, largely via the action of TRA-1, a Ci/GLI family transcription factor with high activity in hermaphrodites and low activity in males. Much of this regulation involves the imposition of sex-specific activity on general developmental regulators in specific cell lineages. Recent work has answered long-standing questions about the molecular mechanisms controlling the sex determination pathway and shown that some C. elegans sexual regulators have counterparts regulating sexual development in other phyla.

Rethinking sex determination of non-gonadal tissues.

Abstract: Evolution of genetic mechanisms of sex determination led to two processes causing sex differences in somatic phenotypes: gonadal differentiation and sex chromosome dosage inequality. In species with heteromorphic sex chromosomes, the sex of the individual is established at the time of formation of the zygote, leading to inherent sex differences in expression of sex chromosome genes beginning as soon as the embryonic transcriptome is activated. The inequality of sex chromosome gene expression causes sexual differentiation of the gonads and of non-gonadal tissues. The difference in gonad type in turn causes lifelong differences in gonadal hormones, which interact with unequal effects of X and Y genes acting within cells. Separating the effects of gonadal hormones and sex chromosomes has been possible using mouse models in which gonadal determination is separated from the sex chromosomes, allowing comparison of XX and XY mice with the same type of gonad. Sex differences caused by gonadal hormones and sex chromosomes affect basic physiology and disease mechanisms in most or all tissues.

The effect of X-linked dosage compensation on complex trait variation.

Abstract: Quantitative genetics theory predicts that X-chromosome dosage compensation (DC) will have a detectable effect on the amount of genetic and therefore phenotypic trait variances at associated loci in males and females. Here, we systematically examine the role of DC in humans in 20 complex traits in a sample of more than 450,000 individuals from the UK Biobank and 1600 gene expression traits from a sample of 2000 individuals as well as across-tissue gene expression from the GTEx resource. We find approximately twice as much X-linked genetic variation across the UK Biobank traits in males (mean h2SNP = 0.63%) compared to females (mean h2SNP = 0.30%), confirming the predicted DC effect. Our DC estimates for complex traits and gene expression are consistent with a small proportion of genes escaping X-inactivation in a trait- and tissue-dependent manner. Finally, we highlight examples of biologically relevant X-linked heterogeneity between the sexes that bias DC estimates if unaccounted for. Dosage compensation (DC) on the X chromosome has predictable effects on genetic and phenotypic trait variance. Here, the authors use information for 20 quantitative traits in the UK Biobank and across-tissue gene expression to compare X-linked heritability and the effects of trait-associated SNPs between the sexes.