A process of immense importance in immunology and immunogenomics that encompasses genetics and embryology is the phenomenon of X chromosome inactivation (XCI). It represents numerous immunologic paradoxes and is discussed numerous times throughout the book.
This blog will explain the basic embryology and more so, the genetic considerations of XCI and it will be revisited with some frequency in subsequent discussions.
Among the 46 paired chromosomes in each human cell, the 23rd pair is called the sex chromosome. Females have 2 X chromosomes, while males have one X and one Y chromosome as described in Blog #10. XCI or “lyonization” (named after the British geneticist, Mary Lyon who hypothesized the theory in 1961), the lyonization theory proposes that within 5 to 6 days (preimplantation) of the embryo development, one of the 2 X chromosomes in the female is randomly and permanently inactivated (“silenced”) in most (but not all) of her cells, with the exception of her lifelong reproductive egg cells. This process prevents female cells from having twice as many gene products from the X chromosomes as males. It provides the upside potential in females for double protection against certain diseases. But it also introduces the increased risk of negative immunogenic influences. The overwhelming abundance of a unique RNA molecule (microRNA or miRNA) on the X chromosome represents one of the most significant paradoxes of the immune system.
The X-chromosome has approximately 155 million base pairs (nucleotides), 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 transcription and translation of proteins by the genetic code of these genes will have dramatic implications in phenotype (physical traits) development, immunity, autoimmune diseases, and cancers (to be described in their respective blog discussions). Cells can express X chromosome genes differently (and randomly) from each other. This is called cellular mosaicism and it 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.
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 active and more likely to cause disease. Conversely, XCI helps protect females from X-linked diseases but, given the combinations and permutations created by 900-1400 X chromosome genes, cellular mosaicism does not exclude their possibility, though rare (e.g., Rett disease, Turner syndrome).
MicroRNA (miRNA) is a noncoding RNA gene abundant on the female X chromosome that contains 10% of all miRNAs in the human genome. Estrogens regulate microRNAs (miRNA) validating a compelling explanation for a female predilection for autoimmune diseases. It is suggested that about 15% of genes escape the XCI process (called “escapees”), 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 (cancer production) which we will be discussing in Blog #28.
Discussion Questions:
There will be much additional discussion regarding XCI in subsequent blogs, but this introduction explains how it provides females with more X chromosomes than males. Besides the increased risk of autoimmune disease in females from this asymmetrical distribution of X chromosomes, what other positive or negative results (another paradox) might result?
XCI occurs during the first 5 to 6 days (preimplantation) of the embryologic development during pregnancy. Why is it necessary for XCI to occur at this very early stage?
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