12.16: X-Inactivation

The human X chromosome contains over ten times the number of genes as in the Y chromosome. Since males have only one X chromosome, and females have two, one might expect females to produce twice as many of the proteins, with undesirable results.

Instead, in order to avoid this potential issue, female mammalian cells inactivate nearly all the genes in one of their X chromosomes during early embryonic development. In the nuclear envelope surrounding the cell nucleus, the inactivated X chromosome condenses into a small, dense ball called a Barr body. In this state, most of the X-linked genes are not accessible to transcription.

In placental mammals, the inactivated X chromosome—maternal or paternal⁠—is randomly determined (marsupials, however, preferentially inactivate the paternal X chromosome). X inactivation in one cell is also independent of X inactivation in other cells. Thus, about half the embryonic cells inactivate the maternal X copy; the remaining half inactivate the paternal copy, producing a mosaic. When these cells replicate, they produce cells with the same X chromosome inactivated. Notably, Barr bodies get reactivated in cells within the ovaries that become eggs.

X inactivation accounts for the appearance of female tortoiseshell and calico cats. These cats are heterozygous for a gene with alleles for black fur and orange fur located on the X chromosome. Their mottled coats result from random inactivation of the black and orange fur alleles in groups of cells (calico cats also have white fur patches that are caused by a different chromosome). While male tortoiseshell and calico cats exist, they have an extra X chromosome and are generally infertile.

X inactivation reduces the severity of conditions caused by extra X chromosomes. Males with Klinefelter syndrome form Barr bodies to inactivate their extra X chromosome. Females with Triple X syndrome form additional Barr bodies for their excess X chromosome or chromosomes.

In organisms that possess multiple copies of the same chromosome, like females who have two X chromosomes, a genetic compensation process must occur during early development. X chromosome inactivation, or XCI, is the process in which one of the chromosomes in a cell is randomly silenced to prevent the over-expression of the same genes. The inactivated chromosome is condensed into a compact structure, the Barr body, that is inaccessible to transcription.

Near the middle of every X chromosome is a region called the X inactivation center, which contains two complementary sequences for non-coding RNA, called XIST and TSIX, along with other regulatory sequences. XCI is initiated by activators that promote XIST transcription on the chromosome that will be inactivated. The resulting RNA molecules coat the XIST chromosome, the one they're produced from. This step is followed by a complex set of events that includes recruitment of protein partners, reshaping of the DNA, and the production of the Barr body.

TSIX is transcribed in an antisense direction to XIST from the active chromosome, and acts to repress XIST activity by complementary binding. The inactivated chromosome in the form of the Barr body is very stable during the life of the organism and is passed on during every mitotic cell division. For instance, female calico cats get their tortoise shell coat color pattern due to the fact that one of the genes coding for fur color is X-linked, and randomly silenced in cells over different regions of their body.