Genome complexity: inactivating an X chromosome (Introduction)

by David Turell @, Thursday, November 25, 2021, 15:34 (2 days ago) @ David Turell

Two female X chromosomes in somatic cells must be reduced to one for control:

"While males have both an X and Y chromosome, females have two X chromosomes. As if to avoid a double dose of X chromosome genes, females inactivate one of their two X chromosomes during embryonic development. As for which of the two X chromosomes is inactivated, this appears to be done randomly in each cell. This means that females, unlike males, have two different functional genomes operating in their bodies, making for a fascinating twist to female genetics. That is, in some cells of the female, the first X chromosome is active whereas in the remainder of the cells the other X chromosome is active.

"Exactly how the developing female embryo inactivates one of the X chromosomes has not been well understood. What has been clear is that the story involves a region on the X chromosome itself, and information in that region that codes for a long RNA molecule, known as Xist. The name Xist stands for X-inactive specific transcript, a direct reference to its function of inactivating the X chromosome. But a genetic region that, ultimately, causes the inactivation of the entire chromosome must be handled very carefully. It is present on all X chromosomes but causes inactivation not of the single male X chromosome, and not of one of the two female X chromosomes. Importantly it causes inactivation only of the other female X chromosome.

"In addition to the fact that Xist must be very carefully controlled, new research1 is shedding light on how this single molecule can produce such a significant result. While it seemed that a very large number of Xist molecules must be required to inactivate the much larger X chromosome, the researchers studied mouse embryonic stem cells and found that only about one hundred Xist’s are required. The Xist’s, operating in pairs, recruit a large number of proteins. The result is about 50 complexes, each consisting of two Xist’s and an army of proteins, spaced along the X chromosome. Some of the proteins twist and condense the overall chromosome, compressing it so that most of the genes are close to one of the 50 complexes. Other proteins act to silence those nearby genes, thus essentially inactivating the entire X chromosome. Obviously, there are many important, coordinated, steps in this inactivation process, allowing for a small number of Xist’s to manage this big job. As the paper’s lead author remarked, “It was kind of shocking to us that from just 50 sites, Xist manages to silence a thousand genes.'”

From the paper itself:

"Instead of interacting directly with every gene on the chromosome, Markaki and Plath showed, these Xist pairs act as hubs, or protein magnets, recruiting thousands of proteins to their spots on the chromosome. Then, specialized proteins pull the chromosome into a tightly condensed shape so that every section is in the vicinity of one of these 50 large clouds of proteins. From there, gene silencing proteins within these complexes bind to each gene, shutting it off.

"'The key insight here is that Xist RNA is not acting directly on the X chromosome but is more of an architectural molecule that sets up proteins to do their job," Plath said.

"The team also identified the proteins, called Polycomb group proteins, responsible for twisting the X chromosome into the necessary shape. Without the Polycomb proteins, only those sections of the X chromosome already near one of the 50 Xist sites become inactivated, the researchers found."

Comment: sexual reproduction may bring enhanced evolution potential, but obviously creates problems such as double X's. After seeing this exquisite design, try and tell me a designing mind does not exist.

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