Unravelling The Mysteries Of The X-Chromosome- How Sex-Linked Genes Affect The The Health of Men And Women

‘Men are from Mars; Women are from Venus’. While not a literal truth, this tagline became
popularised by Dr John Gray’s 1992 relationship advice book of the same name. However,
this notion had traversed our collective conscience long before then, as the two sexes are
fundamentally viewed as a natural dichotomy, like dark is to light or what war is to peace. In
our more progressive world, this line of distinction has blurred. As many of these tangible
differences can be attributed to social conditioning in addition to inherent physiological
attributes. So, how true is this sentiment in reality? If we entertain the idea that women and
men are on opposing poles of humanity, what comprises the thread that holds them
together? An immediate answer to arise in the minds of professionals and enthusiasts in the
field of biology is simply the ‘X chromosome’. Unlike the socio-political definitions of gender
and sex, the scientific distinction between males and females is seemingly uncomplex. Of
the 23 chromosomal pairs which package most of our DNA, one set is clearly distinguished
as the ‘sex chromosomes'.
On the most basic level, the male is assigned to individuals who possess the XY chromosomal
pairing, whilst females are associated with the XX combination. The terms ‘X’ and ‘Y’
chromosomes are not based on the morphology of the chromosome but on their size and
genomic content. The X is the larger of the two, as it contains the vast majority of the genes
required for normal development and function in both sexes. The Y chromosome is
significantly smaller and uniquely contains the SRY gene, which is affably considered to be a
genetic switch. The gene produces the Y protein, which is critical for male sex development. The
expression of the SRY gene instigates the change to male; a given embryo will mature into a
female in its absence. Therefore, the gene switches the course of development to allow a
biological male to be produced. From this limited information alone, we observe that the
common thread between both sexes is, in fact, the X chromosome. It is a necessity for
survival, as any foetus requires at least one copy to be viable. Of the 867 genes identified,
most of them are required for development, ranging from skeletal, vascular, and neural
tissue to larger structures and organs, such as the retina, ears and skin. Thus, in the same
vein, there are 533 disorders associated with the X chromosome that affect these organs and
tissues, such as haemophilia, red-green colour blindness and Duchenne Muscular
Dystrophy. These conditions are deemed X-linked disorders, as their heritability is based on
their presence on the active X-chromosome. Going back to sex determination, it was
established that females are characterised by the presence of two X chromosomes. In
addition, we have also established that a single copy of this chromosome is required as a
minimum. Despite how it may appear, females do not require both copies due to it being in
dosage equilibrium with males. This essentially implies that one of these chromosomes.
exists in a docile state, which can be attributed to the process of X-inactivation.
The process of X-inactivation is highly complicated, the specific mechanisms of which extend
beyond the scope of this article. Fundamentally, the process involves the silencing of one
copy of the X chromosome in females. It achieves this inactive state by being coated with
the RNA transcribed from the Xist gene on the silenced chromosome. The copy that is
silenced can no longer express genes and is chosen randomly within each cell (however,
there are theories implicating the involvement of non-coding RNAs in selection during early
development). This phenomenon equalises the chromosomal dosage in males and females,
as both now have a single active copy. A lesser-known consequence of this in females is the
mosaicism of their associated genes. While males only have one copy of each allele to
express in their X, females can express one of two potential alleles (the maternal and
paternal gene variants). A classic example of genetic mosaicism in nature is with tortoiseshell.
cats, who present patches of multi-coloured fur. The gene coding the pigment of the
fur is on their X chromosome. Thus, each clump of cells expressing a single pigment creates
the respective patch. In humans, there is little known on the net effect of this
heterogeneity, but some aspects have been elucidated in the context of health. In 2016,
a study by Michaela et al. discovered some interesting trends when they performed 
a genome-wide association study on cancer cell lines in women. As expected, the results 
confirmed that mosaicism was markedly more common in sex chromosomes than those of the
autosomal variety. The novel findings of their research inferred that the frequency of
mosaicism increases with age, and its prevalence is linked to haematological cancers. This
implies that there is potentially a relationship between chronic medical conditions which
become more prevalent with age and increased mosaicism events.
We have addressed how the X chromosomal dosage is standardised between men and
women, so what happens when there are more than expected? Aneuploidy is the term
given for the event where an abnormal copy number of chromosomes exists. In all cell lines,
anything over but two X in females and one in males will significantly impact the health of
the individual. The condition by which an individual has additional or missing chromosomes
are termed aneuploidies, and they affect males and females in different ways. One of the most
notorious abnormalities is Klinefelter’s Syndrome, where the individual has XXY
chromosomes. The consequence of having the extra chromosome is altered physical and
mental development resulting in reduced testosterone, muscle mass and facial hair, and
even reduced intellectual abilities. Most men who exhibit this genotype are infertile, which
seems to be a trend with all males who have a surplus of X chromosomes. A variant of
Klinefelter, XXXY syndrome, results in more severe effects on the individual’s physical and
intellectual state. Women with an extra X are known to possess Trisomy, whose common
effects include developmental delays, tall stature, learning disabilities and other health
conditions such as kidney issues and seizures. As seen with males, additional X
chromosomes exacerbate these problems. Conversely, the XXYY syndrome in males results
in similar symptoms to Klinefelter’s due to the additional genetic material from the X.
Finally, in the case where there the individual only possesses one X chromosome, they will
likely be diagnosed with Turner Syndrome. The typical signs include developmental delays,
resulting in a short stature, ovarian dysfunction and other physical features, such as a
webbed neck. It is still largely unknown which genes cause these symptoms; however, it has
been proposed that lacking the extra copy of the SHOX gene required for bone
development leads to their shorter stature. All these conditions are rare in the population,
but there is hope that further research into them will clarify the many attributes of our sex
The many intricacies of biology make it near impossible to distinguish the sexes in a
definitive way. Researchers will likely continue to gather empirical data in their endeavour
to understand the effects of the X chromosome in health and medicine. In summary, there
is just as much uniting males and females as there is putting them at odds.
Perhaps even more frustratingly, the social differences between the two sexes are equally
as hard to decipher. Regardless of whether you accept or reject the paradigm perpetuated
by Gray and the many who came before and after him, we can all agree that the X
chromosome is the backbone that supports the development and health of all humans.

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