Dosage Compensation

Dosage Compensation

The presence of different numbers of X chromosomes in males and females presents a special problem in development. Because females have two copies of every X-linked gene and males possess one copy, the amount of gene product (protein) from X-linked genes would normally differ in the two sexes: females would produce twice as much gene product as males. This difference could be highly detrimental because protein concentration plays a critical role in development. Animals overcome this potential problem through dosage compensation, which equalizes the amount of protein produced by X-linked genes in the two sexes.

Dosage Compensation

In fruit fly Drosophila melanogaster, dosage compensation is achieved by a doubling of the activity of the genes on the X chromosome of the male (XY) .

In the round worm Caenorhabditis elegans hermaphrodites (XX), , it is achieved by a halving of the activity of genes on both of the X chromosomes. Note (males XO)
In Placental mammals i.e., human females (XX), one X chromosome is inactivated (X-inactivation).

Drosophila melanogaster

Caenorhabditis elegans

Barr Body

In 1961, Murray Barr and Ewart G. Bertram observed condensed, darkly staining bodies in the nuclei of cells from female cats this darkly staining structure became known as a Barr body/ Sex Chromatin Body Mary Lyon proposed in 1961 that the Barr body was an inactive X chromosome; her hypothesis (now proved) has become known as the Lyon hypothesis. She suggested that, within each female cell, one of the two X chromosomes becomes inactive; which X chromosome is inactivated is random. If a cell contains more than two X chromosomes, all but one of them is inactivated

Barr Body

The Lyon hypothesis states that in cells with multiple X chromosomes, all but one are inactivated during mammalian embryogenesis Further, once inactivation has occurred, all progeny cells have the same X-chromosome inactivated. The inactivation of an X chromosome into a Barr body is somctimes referred to as Lyonization.
In humans this body can be easily demonstrated in female cells derived from the buccal mucosa (cheek cells) or in fibroblasts (undifferentiated connective tissue cells), but not in similar male cells.

Barr Body

This highly condensed structure is about 1m in diameter, lies against the nuclear envelope of interphase cells. It stains positively in the Feulgen reaction. a cytochemical test for DNA.

X-inactivation

X-inactivation (also called lyonization) is a process by which one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging into transcriptionally inactive heterochromatin. X-inactivation occurs so that the female, with two X chromosomes, does not have twice as many X chromosome gene products as the male, which only possess a single copy of the X chromosome.

The choice of which X chromosome will be inactivated is random in placental mammals such as mice and humans, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell. Unlike the random X-inactivation in placental mammals, inactivation in marsupials applies exclusively to the paternally derived X chromosome.

Two alleles at this locus: X, which produces non-orange (usually black) fur, and Xo, which produces orange fur. Males are hemizygous and thus may be black (XY) or orange (XoY) but not black and orange. (Rare tortoiseshell males can arise from the presence of two X chromosomes, XXoY.) Females may be black (XX), orange (XoXo), or tortoiseshell (XXo).
Female calico cat

Mechanism of X- inactivation

Exactly how an X chromosome becomes inactivated is not completely understood either, but it appears to entail the addition of methyl groups (CH3) to the DNA. The X-inactivation center (XIC) on the X chromosome is necessary and sufficient to cause Xinactivation. The XIC contains two non-translated RNA genes, Xist and Tsix, which are involved in X-inactivation.

The XIST (for X inactive-specific transcript) gene, located on the X chromosome, is required for inactivation. Only the copy of XIST on the inactivated X chromosome is expressed, and it continues to be expressed during inactivation (unlike most other genes on the inactivated X chromosome). Interestingly, XIST does not encode a protein; it produces an RNA molecule that binds to the inactivated X chromosome. This binding is thought to prevent the attachment of other proteins that participate in transcription and, in this way, it brings about X inactivation.

The Tsix (Transcription silencing inactivation of X gene) encodes a large RNA, theTsix RNA is transcribed antisense to Xist. Tsix is a negative regulator of Xist; X chromosomes lacking Tsix expression (and thus having high levels of Xist transcription) are inactivated much more frequently than normal chromosomes. Like Xist, prior to inactivation, both X chromosomes weakly express Tsix RNA from the Tsix gene. Upon the onset of X-inactivation, the future Xi ceases to express Tsix RNA (and increases Xist expression), whereas Xa continues to express Tsix for several days.