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

chromosomes.

 

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.