In 1961, Mary Frances Lyon argued that one of the X chromosomes in females is randomly inactivated during early embryonic development to prevent the overexpression of X-linked genes. Representative illustration.
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In mammals, the females have two copies of the X chromosome while the males carry a single copy. The X chromosome is more significant than for its role in determining sex. Recent genomic studies have shed light on the fundamental biological processes the X chromosome modulates and the genes it encodes. The gathering evidence suggests in fact that it plays a part in a variety of biological functions as well as controls the sex-specific susceptibility to certain diseases.
The human X chromosome encodes around 800 genes, which in turn code for proteins. A loss of function of these genes could thus lead to a variety of genetic diseases. Broadly, the diseases whose onset and/or progression the X chromosome influences can be grouped into three types: (i) X-linked genetic diseases, (ii) diseases influenced by XCI escape, and (iii) those linked to X-chromosome aneuploidy.
There are more than 500 X-linked genetic diseases , and they most affect males. Many of the X-linked traits and diseases are not uncommon in the general population. For example, red-green colour blindness is X-linked, and affects around 8% of males. Duchenne muscular dystrophy, caused by mutations in the dystrophin gene and affecting 1 in every 3,500-5,000 boys born in India and agammaglobulinemia, an immunodeficiency disorder that affects around 1 in 200,000 live births, are also X-linked.
Scientists are also aware of numerical abnormalities — or aneuploidies — of the X chromosome. For example, Klinefelter syndrome is characterised by an extra X chromosome (XXY) and Turner’s syndrome by a loss of one X chromosome in females (X instead of XX).
Inactivation of the X chromosome
In mammalian species, the females typically carry two X chromosomes while males possess one X and one Y chromosome. Each of the X chromosomes is inherited from the parents. In 1961, an English geneticist named Mary Frances Lyon argued that since females have two copies of the X chromosome, one of the X chromosomes is randomly inactivated during early embryonic development, in a process called X chromosome inactivation (XCI), to prevent the overexpression of X-linked genes in females.
In this process, epigenetic changes silence most genes on one X chromosome (epigenetics refers to the processes by which genes are influenced by the environment in which they operate). XCI ensures a balance in the gene expression but scientists are also learning that it plays a role in various genetic disorders. Issues such as incomplete inactivation (a.k.a. escape) or skewed inactivation can lead to the abnormal expression of genes, which contributes to diseases including X-linked disorders, certain cancers, and autoimmune conditions.
Three decades after Dr. Lyon’s hypothesis, researchers unravelled the molecular mechanisms of X inactivation when they discovered Xist, a non-protein-coding RNA. The body deactivates the X chromosome with the help of Xist and another non-protein-coding RNA, called Tsix (reverse of Xist). The differential regulation of these two genes means, in the X chromosome that is to be deactivated, the Xist RNA is overexpressed such that it coats or covers the chromosome.
However, inactivation of the X chromosome is not absolute. As many as a fourth of all genes encoded by the X chromosome could escape inactivation and express themselves, as researchers at the Whitehead Institute, in the U.S., reported in a paper published in the journal Cell Genomics last year.
Autoimmune diseases
Researchers have suggested for a while that a number of immune diseases — including systemic lupus erythematosus, rheumatoid arthritis, and Sjögren’s syndrome — are more common in females than males. Of particular note are autoimmune diseases in which antibodies act against specific proteins.
In a paper published on May 3 in Science Advances, French researchers perturbed the expression of Xist — which triggers XCI — in female mice, and found that previously inactive genes on the inactive X chromosome were reactivated. This was particularly true of genes involved in the Toll-like receptor 7 signalling pathway in immune cells. The result was the spontaneous development of lupus-like inflammatory signs in the female mice, including an increased level of autoantibodies and altered immune cell populations.
The reactivation of specific X-linked genes in response to XCI alteration varies across immune cell types, which is to say diverse molecular pathways are affected. The resulting effects in autoimmune diseases are likely due to a combination of reactivation events in different cell types and global changes in gene expression. The findings reinforce the molecular link between altered XCI and autoimmune diseases, and point the way for possible new drugs to treat them in future.
X and Alzheimer’s disease
Another disease with a sex bias and linked to the X chromosome is Alzheimer’s disease. Women seem to have a higher risk of getting it; worldwide, almost twice as many women have Alzheimer’s as men. In a study published in the journal Cell in October 2022, researchers from Case Western Reserve University in the U.S. suggest a gene called ubiquitin specific peptidase 11 (USP11), involved in a protein modifying process, encourages tau protein to accumulate in the brain. Based on studies of mice brains, the researchers suggested the gene escapes X inactivation and is expressed more in females. This also opens new avenues to develop treatments for Alzheimer’s.
In humans, the Y chromosome has been shrinking over time, so the X chromosome is possibly evolution’s best-bet and thus plays a pivotal role in human health and disease. Its evolutionary genomics and emerging insights into its participation in biological processes illuminate the complex interplay between genetic inheritance, epigenetic modifications, and disease manifestation. Cracking all this to get the full picture could also lead us to new drugs and therapies.
The authors are senior consultants at the Vishwanath Cancer Care Foundation and adjunct professors at IIT Kanpur and Dr. D.Y. Patil Vidyapeeth.
