The X chromosome contains hundreds of genes involved in a wide variety of bodily functions beyond determining biological sex. The activity and stability of the X chromosome can change over a person’s lifetime. These alterations can have health implications that emerge later in life.
The Two-Faced X in Females
In females, who have two X chromosomes, a process called X-inactivation, or Lyonization, occurs early in embryonic development. To prevent a toxic double dose of gene products, one of the two X chromosomes in each cell is randomly silenced. This silenced chromosome is compacted into a dense structure, turning off most of its genes.
This random inactivation results in a “mosaic” of cells, where some express genes from the paternal X chromosome and others from the maternal X. This mosaicism explains why female carriers for X-linked conditions may have variable symptoms. If one X chromosome carries a mutation, the presence of the other healthy X in about half of the cells can often compensate.
The pattern of X-inactivation is established early and remains stable for much of an individual’s life, but this can change with age.
The Aging X Chromosome
As individuals age, the stability of the X chromosome can decline. One age-related phenomenon in females is the loss of an X chromosome in a fraction of cells, a process known as aneuploidy. The frequency of X chromosome loss increases with age, and by 65, an estimated 1-2% of a female’s blood cells may have lost an X chromosome, which is associated with a higher risk for certain age-related conditions.
Another change is a shift in the balance of X-inactivation, which can become “skewed” over time. In skewed X-inactivation, a majority of cells preferentially express the genes from one X chromosome. This shift can happen by chance or because cells expressing one X chromosome have a survival or growth advantage.
This skewing can have health consequences, particularly for the immune system. A significant shift can unmask recessive mutations on the preferentially active X, leading to symptoms of a genetic disorder later in life. This has been observed in some autoimmune diseases, where skewed inactivation may disrupt immune tolerance and cause the body to attack its own tissues.
X-Linked Conditions and Late-Onset Manifestations
Changes in the X chromosome with age can influence the presentation of X-linked genetic conditions, causing carriers to show symptoms only in middle or older age. For example, female carriers of the Duchenne muscular dystrophy (DMD) gene are often asymptomatic due to X-inactivation. As they age, some may develop cardiac problems, like cardiomyopathy, because heart muscle cells with the mutated gene become more vulnerable to age-related stress.
Another condition is Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder affecting older male carriers of a “premutation” on the Fragile X gene. These individuals have normal cognitive function in their youth but can develop tremors, balance problems, and cognitive decline later in life. The premutation causes an overproduction of a specific RNA molecule that becomes toxic to brain cells over time.