(Selected Tables and Figures referenced, but not present in this blog
can be found in their corresponding Science Version blogs)
A process of immense importance in immunology and immunogenomics that involves genetics and embryology is the interesting phenomenon of X chromosome inactivation or XCI. It represents numerous immunologic paradoxes and is a phenomenon we discuss numerous times throughout the book because it affects so many aspects of immunology. This blog will “attempt to explain” the basic embryology and more so, the genetic considerations involved in XCI. They all will be revisited with some frequency in subsequent blog discussions as well.
Among the 46 paired chromosomes in each of the cell in our body, the 23rd pair is called the sex chromosome. Females have 2 X chromosomes as their pairing, while males have one X and one Y chromosome as described in Blog #10. XCI, sometimes termed “lyonization,” named after the British geneticist, Mary Lyon who hypothesized the theory in 1961, proposes that within 5 to 6 days before preimplantation of the embryo, one of the female’s X chromosomes is randomly and permanently inactivated or genetically “silenced” in most, but not all of her cells, with the exception of her lifelong reproductive egg cells which remain with 2 X chromosomes. The XCI process prevents female cells from having twice as many gene products from the X chromosomes as males. It provides the increased potential in females for double protection against certain diseases. But it also introduces the increased risk of negative immunogenic influences (another immune paradox). Add to this the overwhelming abundance of a unique RNA molecule called microRNA or miRNA on the X chromosome and we have one of the most significant paradoxes of the immune system.
The X-chromosome has approximately 155 million base pairs in their DNA which translate to about 900-1400 genes that account for about 5% of the total DNA of a cell versus the Y chromosome at about 70 genes and carries about 58 million base pairs or about 2% of the total DNA of a cell. The protein synthesis we discussed back in Blog #10 of these genes will have dramatic implications in the development of the female’s physical traits, her immune system, risk of autoimmune diseases, and cancers, all to be described in further detail in their respective blogs. The woman’s cells can express X chromosome genes differently (and randomly) from each other. This gives females more diversity than males. Remember, after XCI, the female has more X chromosomes than the male, meaning that females have more genetic options during development and thus, more ways to prevent disease. Again, they represents the bias of females versus males from Blog #4.
Diseases caused by mutations in genes on the X chromosome are called X-linked diseases, that is, genetic diseases in which the disease-causing gene exists on the X chromosome. Males do not experience XCI because they only have one X chromosome. So, if males have a disease-causing gene on their X chromosome, it will be twice more likely to be active and increase the risk of causing an “X-linked” disease. Conversely, XCI helps protect females from X-linked diseases but, given the combinations and permutations created by 900-1400 X chromosome genes, the female is not entirely excluded from their possibility, though rare, as in Rett disease, Turner syndrome, etc..
That MicroRNA or miRNA we mentioned in the first paragraph is a noncoding RNA gene meaning it is not involved in protein synthesis process. It is abundant on the female X chromosome which contains 10% of all miRNAs in the human genome. Estrogens regulate miRNA and further validate a compelling explanation for female predilection towards autoimmune diseases as will be discussed in subsequent autoimmune blogs. It is suggested that about 15% of genes escape the XCI process, all of which recent research has confirmed as primary attributions to the female bias of autoimmune diseases, especially SLE. These “escapees” also play a significant role in oncogenesis or cancer production which we will be discussing in Blog #28.
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