Monday, September 25, 2006
X Chromosome Inactivation
That cute kitten is Copycat or CC – the first cloned cat. She is genetically identical to her “mom” (to the right) but phenotypically different. The reason is because of the peculiar phenomenon called X-chromosome inactivation (XCI) that occurs in all the female cells in mammals.
In mammals sex is determined by differential inheritance of the sex chromosomes. Females are XX while males are XY. To compensate for having an extra dosage of X chromosome genes that might be developmentally fatal, the cells in the female embryo randomly select one X chromosome and shut it off (transcriptionally silence it). This “silent” state is maintained throughout life in the female cell. Since the phenomenon is random (each cell independently decides its fate), mammalian females are essentially mosaics. CC is different from her progenitor because the gene for coat color lies on the X chromosome and is randomly silenced in the clone, giving it it’s unique calico pattern.
The phenomenon is evolutionarily conserved in the mammalian lineage – since there is preliminary evidence to suggest that XCI occurs in Prototherians (egg laying mammals) who arose 200-300 million years ago and also in Metatherains (marsupials). Since X and Y differentiation also occurs in these lineages, it is likely that XCI arose as a way of dosage compensation.
How is it done? The random X chromosome inactivation has been linked to a region on the X chromosome, called Xic (X- inactivation center). What is so unique about this region is that all the genes characterized so far are non- coding genes – they make the RNA but this RNA is never used to make a cellular protein. The ncRNA (non coding RNA) from this region are responsible for counting the number of X chromosomes present in the cell, marking one for silencing and maintaining the silenced state. The most talked about transcript from this region is Xist which is essential for the silencing step.
The mechanism of how the ncRNA form Xist or other mapped locus do the inactivation is not yet known. It is most likely that transcription of these genes help to bring in chromatin remodeling factors (things that signal that the chromosome is silenced). Since Xist transcription would take about 30 minutes, during which the RNA is physically attached to the X chromosome, this explanation seems plausible. The unraveling of the mechanism would help us understand another dosage compensation mechanism (that of imprinting) but that is another blog.