The inactivation of the X chromosome (Lyonization)

Sex Chromosomes (X and Y Chromosomes)

Genetic information in organisms is stored in chromosomes within the nucleus of cells. Humans have 23 pairs (46 in total) of chromosomes, inheriting 23 chromosomes from each parent. Among the 46 chromosomes, 22 pairs (44 in total) are autosomes, carrying numerous genes. The remaining 1 or 2 are sex chromosomes, which also contain genes related to sex determination. Humans have two types of sex chromosomes: X and Y chromosomes.

In humans, females have two X chromosomes (XX), while males have one X and one Y chromosome (XY). The region called "SRY" on the Y chromosome plays a crucial role in expressing genes necessary for male development.

Lyonization

The Y chromosome, responsible for determining male sex, contains around 50 genes, primarily involved in sex determination. In contrast, the X chromosome carries over 1000 genes, including many crucial for organismal function.

So, are there differences in the amount of protein produced from genes on the X chromosome between females with two X chromosomes and males with only one X chromosome?

The answer is "No."

It's known that females with two X chromosomes produce proteins from the X chromosome nearly as efficiently as males. If genes essential for life maintenance were more expressed on the X chromosome in females, there might have been greater differences between males and females.

Actually, one of the two X chromosomes in females is functionally inactivated, effectively allowing only one X chromosome's worth of function, similar to males. This inactivation mechanism of the X chromosome is called "lyonization" (derived from Mary Lyon, a British geneticist who proposed this hypothesis in the 1960s).

In "lyonization," which X chromosome gets suppressed is determined at birth in each cell, so if there are differences in the function of the two X chromosomes, each cell will exhibit a mosaic state with different characteristics.

Example of Lyonization: Mechanism of Calico Cats

Understanding the concept of "lyonization" from a general explanation might be difficult, but a familiar example where you can understand its mechanism is "calico cats."

You often see calico cats around you, with fur colors of white, black, and brown. The gene that determines whether the fur is brown (O) or black (o) exists on the X chromosome (X). In female cats, if both X chromosomes have the "OO" gene, the entire body will be a brown fur cat, and if both have the "oo" gene, the entire body will be a black fur cat. So, what color will the fur be if the combination of genes is "Oo" with one brown and one black gene?

According to the mechanism of "lyonization," it seems that the function of one X chromosome is suppressed, so it appears that only one color, either brown or black, will appear. However, as mentioned earlier, since which X chromosome is suppressed is determined cell by cell at birth, cells of brown and black will mix randomly in a mosaic state. Therefore, the fur mixes brown and black, creating a calico cat.

Male calico cats are rare.
So far, the explanation of calico cats has assumed female cats with two X chromosomes.
Then, are there male calico cats?

Since males have only one X chromosome, they can only possess either a black or brown gene. Therefore, calico cats are basically not born.
However, when chromosomal abnormalities occur and the sex chromosome becomes "XXY" and three, "lyonization" may occur, and it may become a calico cat. It is said that the probability of a male calico cat occurring due to chromosomal abnormalities becoming "XXY" is about one in 30,000, and it is considered to be very rare.

This chromosomal abnormality becoming "XXY" is the cause of a genetic disease called "Klinefelter syndrome," and I will explain it in detail later.

Genetic Abnormalities of Sex Chromosomes

There are many reported genetic diseases caused by abnormalities of sex chromosomes, but here we will introduce some representative diseases, and consider how "lyonization" is involved in these diseases.

Klinefelter Syndrome (XXY, XXXY, etc.)

Genetic diseases caused by having more than two X chromosomes, such as "Klinefelter syndrome" with "XXY" as an example, are called "Klinefelter syndrome." This is a disease that occurs in males with a Y chromosome, and the frequency is considered to be about 500 to 1000 people per person.

There are more than one X chromosome, but due to "lyonization," excessive X chromosome function is suppressed, so it does not become a fatal genetic abnormality. Also, symptoms are often mild, and it is considered that many people have been discovered for the first time by visiting because of infertility, and living without knowing that they are a syndrome.

However, the appearance of symptoms such as testicular atrophy and azoospermia is still a problem, because there are genes on the X chromosome that do not undergo "lyonization" called "pseudoautosome regions" and more genes on the X chromosome than usual are expressed.

For more information on symptoms and treatment, please refer to this site.

Turner Syndrome (XO)

"Turner syndrome" is also a disease related to abnormal sex chromosomes, but it refers to a series of syndromes that occur in women with only one X chromosome (XO). The frequency is seen in about 2,500 people per person.

Even in normal women with two X chromosomes (XX), due to "lyonization," one is functionally inactivated, so it seems that there is little difference in the function of one X chromosome with Turner syndrome, which has only one X chromosome. Certainly, Turner syndrome is not a fatal genetic abnormality like Klinefelter syndrome, but Turner syndrome has fewer genes in the "pseudoautosome region" not subject to inactivation on the X chromosome, compared to normal, and clinical symptoms such as short stature and amenorrhea are shown.

Conclusion

"Lyonization" is an important mechanism that regulates gene expression by inactivating one of the two X chromosomes in women with two X chromosomes. It is involved in the occurrence of calico cats and plays an important role in diseases related to sex chromosome abnormalities such as Klinefelter syndrome and Turner syndrome. "Lyonization" is considered to alleviate symptoms compared to other chromosomal abnormalities, contributing to the mild nature of these diseases.