X Inactivation and Epigenetics – Etsuko Uno & Drew Berry / WEHI (2012)

Why all calico cats are female?

In all mammals sex is genetically determined by X and Y chromosomes. In Humans females carry two X chromosomes (XX). Males carry both X and Y chromosomes (XY).

The mammalian Y chromosome has began to evolve from the X chromosome at about 170 million years ago. For some strange genetic recombinational quirk that happened in the ancestor of all mammals Y chromosomes lost their ability to exchange information with X. Currently, more than 95% of the human Y chromosome is unable to recombine. This lead to a genetic erosion on Y chromosome. There are 1805 genes on the X chromosome. Regardless of sex all 1805 genes found on X chromosome is needed for healthy development of any Human. Throughout its 170 million year evolutionary history the Y chromosome lost many of its genes and today only 458 genes left in Humans. All 458 genes are essential for male development.

Over the course of its evolution distinct layers and their ages can be seen on the Y chromosome. This is explained wonderfully by Howard Hughes Medical Institute animation:

Evolution of Mammalian Sex Chromosomes – HHMI from Nature Documentaries on Vimeo.

Here in this visualization Walter and Eliza Hall Institute of Medical Research (WEHI) science illustrators Etsuko Uno & Drew Berry show how on of the X chromosomes in females become silenced starting from DNA structure and organization into nucleosomes via histone proteins. Nucleosomes in a sense resemble spools that keep a long string nice and tidy when not in use.

X inactivation is a type of gene dosage compensation. Because females receive two X chromosomes, they inherit two copies of many of the genes that are needed for normal function. Extra copies of genes or chromosomes can affect normal development. Down’s syndrome for instance, is caused by an extra copy of part or all of chromosome 21. In female mammals, X inactivation has evolved to compensate for the extra X chromosome. In X inactivation, each cell ‘switches off’ one of its X chromosomes, chosen at random, to ensure the correct levels of gene expression.

X inactivation is a mandatory process that occurs in all DNA-containing cells of the female body. It represents a useful research model for studying epigenetics. Epigenetics refers to processes that tell our cells how, and when, to read the DNA blueprint. The epigenetic regulation of DNA is critical in both normal development and disease. It is fascinating how a major step in central dogma of biology can be permanently suppressed on a massive scale covering large sections of an entire chromosome.



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