Escape from X chromosome inactivation

Mammals have two sex chromosomes: X and Y. Males have one X chromosome and one Y chromosome and females have two X chromosomes. Since females have two copies of each X chromosome gene, you might expect them to make twice as much gene product as males of the same species. In fact, males and females often make about the same amount of gene product because one of the female X chromosomes is inactivated by a mechanism that causes extensive chromatin condensation.

The mechanism is known as X chromosome inactivation. The phenomenon was originally discovered by Mary Lyon (1925-2014) [see Calico Cats].

It's been known for a long time that some genes are fully repressed by X chromosome inactivation while others are only partially repressed and still others are fully expressed. The three different patterns are illustrated in the figure on the right taken from Figure 1 of a paper by Tukiainen et al. (2017).

The colored bars are genes on the X chromosome of females. Upward pointing arrows indicate that the genes is expressed and upward pointing T's indicate repression. The first pattern is the one that indicates standard X chromosome inactivation where genes on one of the chromosome are transcribed and genes on the inactivated chromosome are repressed. The second pattern is "escape" where homologous genes on both chromosomes are expressed. The third pattern is "variable" and there are a number of subcategories. Sometimes the gene on the "inactivated" chromosome is expressed in only one or two different tissues but repressed in all others. Sometimes the expression of genes on both chromosomes is variable with different levels of transcription in different tissues.

Up until now, it hasn't been possible to fully explore the escape from X chromosome inactivation (XCI) in human tissues because techniques for analyzing all of the human X chromosome genes in multiple tissues weren't readily available. However, the Genotype-Tissue Expression Consotium (GTEx) changed all that. This project looked at RNAs produced in 44 different tissues from 449 recently deceased individuals.

One of the studies examined the expression of 681 X-chromosome genes in males and females (Tukiainen et al., 2017). If the level of RNA produced in female tissues was greater than the level in male tissues, that indicated escape of some sort. Another study looked at expression in subjects who were heterozygous for particular genes. The two alleles could be distinguished by RNA sequencing and thus expression of each allele on different X chromosomes could be monitored. There were 186 genes with allelic differences.

The overall results can be summarized in the figure below based on overall RNA levels. It shows that 15% of the X chromosome genes escape XCI completely and 16% exhibit variable escape. X chromosome inactivation works for 69% of the genes.

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Tukiainen, T., Villani, A.-C., Yen, A., Rivas, M.A., Marshall, J.L., Satija, R., Aguirre, M., Gauthier, L., Fleharty, M., Kirby, A., Cummings, B.B., Castel, S.E., Karczewski, K.J., Aguet, F., Byrnes, A., Lappalainen, T., Regev, A., Ardlie, K. G., Hacohen, N., and MacArthur, D.G. (2017) Landscape of X chromosome inactivation across human tissues. Nature, 550:244-248. [doi: 10.1038/nature24265]