Sex-chromosome dosage compensation
[2][3] Other lineages equalize the expression of the X- or Z- specific genes between the sexes, but not to the ancestral levels, i.e. they possess incomplete compensation with "dosage balance".
In 1949, Murray Barr and Ewert Bertram published data describing the presence of "nucleolar satellites,[5] which they observed were present in the mature somatic tissue of different female species.
Further characterization of these satellites revealed that they were actually packages of condensed heterochromatin, but a decade would pass before scientists grasped the significance of this specialized DNA.
Building on work done by Ohno and his colleagues, Lyon eventually proved that either the maternal or paternal X chromosome is randomly inactivated in every cell of the female body in the species she was studying,[7] which explained the heterogeneous fur patterns she observed in her mosaic mice.
The fur patterns characteristic of tortoiseshell cats are found almost exclusively in females, because only they randomly inactivate one X chromosome in every somatic hair cell.
Compounding on Lyon's discoveries, in 1962 Ernest Beutler used female fibroblast cell lineages grown in culture to demonstrate the heritability of lyonization or random X-inactivation.
This process involves histone tail modifications, DNA methylation patterns, and reorganization of large-scale chromatin structure encoded by the X-ist gene.
[14] The concept of dosage compensation actually originated from an understanding of organisms in which males upregulated X-linked genes two-fold, and was much later extended to account for the observation of the once mysterious Barr bodies.
[16] Mukherjee and Beermann confirmed this by designing a cellular autoradiography experiment that allowed them to visualize incorporation of [3H]uridine into ribonucleic acid of the X chromosomes.
Thus, the investigators concluded that the two-fold increase in the rate of RNA synthesis in the X chromosome of the male relative to those of the female could account for Muller's hypothesized dosage compensation.
[19] The Male Specific Lethal complex, composed of protein and RNA binds and selectively modifies hundreds of X-linked genes,[20][21] increasing their transcription to levels comparable to female D. melanogaster.
[14] Other species that do not follow the previously discussed conventions of XX females and XY males must find alternative ways to equalize X-linked gene expression among differing sexes.
However, as is the case with the previously discussed mechanisms of dosage compensation, failure to express X-linked genes appropriately can still be lethal.
[26] In these XX organisms, the dosage compensation complex (DCC) is assembled on both X chromosomes to allow for this tightly regulated change in transcription levels.
Because data substantiates the theory that dosage compensation in other species is caused by chromatin-wide modifications, many theorize that the DCC in particular functions similar to the condensin complex in its ability to condense or remodel the chromatin of the X chromosome.
[29] The role of the DCC in this form of dosage compensation was postulated by Barbara J. Meyer in the 1980s, and its individual components and their cooperative function were later parsed out by her lab.
[30] More recently, Meyer's lab has shown that proteins known as X-linked signal elements (XSEs) operate in concert with SDC-2 to differentially repress and activate other genes in the dosage compensation pathway.
[31][33][34] However, reducing the level of more than one XSE in different combinational permutations seems to have an additive effect on ensuring proper sex determination and resultant dosage compensation mechanics.
Few other ZZ/ZW Systems have been analyzed as thoroughly as the chicken; however a recent study on silkworms [39] revealed similar levels of unequal compensation across male Z chromosomes.
The compensated (silenced) genes on Zp resemble a region on the primitive platypus sex chromosome, suggesting an ancestor to the XX/XY system.
[43][44] Thus, the function of the selective silencing may be to spare dosage compensation of genes crucial for sex determination of homologous pairing.
[citation needed] Recent studies are focusing on how epigenetic mechanisms could contribute to dosage compensation in birds, with a particular emphasis on methylation.
This, combined with the portions that are homologous to chicken Z and human 9 chromosomes imply that this level of incomplete silencing may be the ancestral form of dosage compensation.
Additionally, in plant species that lack dimorphic sex chromosomes, dosage compensation can occur when aberrant meiotic events or mutations result in either aneuploidy or polyploidy.
[50] In the XX/XY system of Basiliscus vittatus and multiple neo-sex chromosomes with male heterogamety in the pygopodid gecko Lialis burtonis incomplete compensation without dosage balance were also seen.
[53] In the Florida softshell turtle (Apalone ferox) with ZZ/ZW sex chromosomes, the lack of dosage balance in the expression of Z-linked genes was also found.
Knockout studies in female ES cells and mice have shown that X chromosomes bearing a deletion of the Xist gene are unable to inactivate the mutated X.
Xist RNA accumulates at the morula and blastocyst stages and is shown to be associated with transcriptional silencing of the Xist-coated chromosomal region, therefore indicating dosage compensation has occurred.
[citation needed] Xite and Xist, are both long non-coding RNAs that regulate and facilitate the process of X-inactivation and are important in the silencing of genes within the X chromosome that is being inactivated.
A study using a combination of methods (Hi-C assembly, coverage analysis and ChIp-seq) found that the neo-Z segment exhibits complete dosage compensation which is achieved by increased transcription in ZW females.
