How the second X chromosome in females gradually becomes inactive?

X chromosome: how genetics becomes egalitarian.


According to cell biology, men have an X chromosome whereas women have two (XX). But, how can we get around this difference?

Scientists at the University of Geneva (UNIGE), Switzerland conducted a study dating from the 1960s to sequence skin and blood cells one by one. Their main objective was to determine how the second X chromosome in females gradually becomes inactive in order to avoid an overdose of genes encoded by the X.

For their study, scientists investigated the arbitrary inactivation of one of the two X chromosomes in women, which was found in 1960 by Mary F. Lyon. The British scientist was the primary individual to show that women have two X chromosomes, in contrast to men, and that one of them remains quiet through a system for adjusting the quality measurements, making up for the nearness in ladies of an additional duplicate of the qualities situated on the X chromosome.

During the 1990s, nonetheless, researchers found that a few qualities in the inactivated X chromosome stayed away from this inactivation. In any case, how?

Expression of genes subjected to X chromosome inactivation. © UNIGE
Expression of genes subjected to X chromosome inactivation. © UNIGE

To figure out the answer, scientists sequenced 935 skin cells and 48 blood cells from five different women so they could analyze the phenomenon in more detail.

Federico Santoni, a former researcher in the Department of Genetics said, “We first individualized the cells and ascertained the genes expressed in each cell. Then we sequenced the genome of the five women and with bioinformatics, we were able to identify which X chromosome in each cell was activated and which was silent.”

Until recently, experimental techniques did not have the sensitivity needed to precisely measure the gene expression rates that escape inactivation. Now, however, thanks to the experimental and bioinformatic approach developed by UNIGE, the geneticists have identified 55 of these genes, including five that were still unknown.

Professor Antonarakis said, “Our main discovery was that no X chromosome in all the cells analyzed is 100% inactive; the rate varies from cell to cell. This gene produces small RNA molecules that surround one of the two X chromosomes, forcing the genes on this chromosome to stay silent.”

“We’ve shown that the more XIST RNA molecules there are on this inactivated chromosome, the more silent its genes are and vice-versa. The expression of this gene explains the variable level of inactivation between the cells.”

Borel said, “XIST is, therefore, the key gene for the inactivation of one of the two X chromosomes in women’s cells. But it isn’t the only one. For the first time, we uncovered five other genes that play an important role in the X chromosome inactivation mechanism.”

“This will help us understand what happens at the molecular level during inactivation. Even more importantly, it means we can expand our investigations to learn more about the differences between men and women across a range of diseases.”

Antonarakis said, “There are many diseases that are caused by genes located on the X chromosome, such as hemophilia, intellectual disability syndromes, and developmental disorders. During our research, we also discovered that X chromosome inactivation varied according to the different life phases of a cell and according to cell type. This could account for the differences seen in the severity of certain diseases between patients, the age of onset of and why some tissues are targeted by diseases.”

You can read all about the results in the journal PNAS.


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