Advantage, females! — X chromosome makes women genetically more rich than men
Most of us know the simple rule of genetics in reproductive biology: if you inherit a X and a Y chromosome from your parents, you are a biological male (XY); if you receive only X chromosomes from both parents, your assigned biological sex is female (XX).
According to the National Genome Research Institute, the Y chromosome only has 55 protein coding genes while the X chromosome is the home of around 900 genes. Besides determining biological sex, many of these X-derived genes are involved in the development of vital organs such as the brain, bone, heart blood, etc.
So, it begs the question: are women superior to men in their genetic abundance?
The short answer is, yes! But it is not because of women carrying more X chromosomal genes than men.
A random epigenetic process is the key!
To ensure a fair distribution of genes between both sexes, one of the female X chromosomes is silenced at the very early stage of life. This is a random epigenetic process known as the X chromosome inactivation (XCI).
This s is also termed as “Lyonization” in honor of its discoverer Mary Frances Lyon, a 20th century British geneticist.
XCI not only equalizes gene level between two sexes but also ensures smooth embryonic development in female. Double dosage of X chromosomes may cause embryonic death.
So, the puzzle remains — how are women genetically more diverse or superior than men — if both sexes contain only one active X chromosome?!
The trick lies in ‘cellular mosaicism’. What happens is that not every cell turns off the same X chromosomes in females. Most often, XCI happens in 50:50 manner i.e. half of the cells shut down paternal X chromosomes while the other half shut down maternal X chromosomes. Hence, females are ‘mosaic’ in their genetic composition. Males, on the other hand, only possess one type: maternal!
Exception: The chances of silencing only one type of X (either paternal or maternal) is extremely low (1 in 2²⁰). We do not know for sure whether it happens in human, but it happens in mice and marsupial mammals like kangaroos, where all the paternal X chromosomes are inactivated. This is known as imprinted X inactivation.
This mixed distribution of paternal and maternal X chromosomes provides female with more genetic diversity as well as protection from X-linked disorders such as red-green color blindness, hemophilia, etc.
‘It’s not easy being male’
Since men only inherit one maternal X chromosome, mutation of genes in that chromosome means high chance of developing X-linked diseases. However, ‘mosaic’ females can compensate the effect of mutations in the genes in paternal X chromosome by healthy copies of the same genes of its maternal X chromosome.
Unsurprisingly, male suffers more from X-linked diseases than women.
For example, men are four times more likely to suffer from autism — a developmental disorder. X chromosomes has a large amount of brain genes which means it plays very important role in defining human cognition/behavior. Mutation in the autism-causing genes in the male X chromosome cannot be offset by a healthy copy of those genes.
Hemophilia (a blood clotting disorder) and color blindness also mostly affect men for similar reasons.
Because of this mosaicism, women also have the ability to produce stronger immune response which may explain why women tend to better job fighting off infectious diseases than men do.
There are around 500 X-linked disorders and men bear the brunt of them!
(Sometimes) a double-edged sword for women!
Inheriting a ‘mosaic’ genetic content comes with some liabilities too. For example, since female immune system can recognize more antigens, it also increases the risk of developing autoimmune disorders in women.
Plus, the inactive X chromosome can occasionally become active at older age due to environmental triggers which are yet to be identified. The reactivation makes cells to become cancer prone. This may explain why women suffer more from certain type of blood cancers in the latter stages of their life.
Besides, some genes on the X chromosomes manage to escape the inactivation which may cause additional diseases in women.
XCI research is underway, long way to go
Despite some dark sides, random XCI gives women more protection from X-linked diseases than men. Research attempting to uncover the mechanism is ongoing and there have been some striding progress in the last two decades.
Understanding how and when each cell decides to silence one of its chromosomes will not only help fighting X-linked disorders, it will also pave the way for decoding other undiscovered cellular communication.
However, as of now, complete understanding of the mechanism and potential therapeutic interventions for hundreds of X-linked disorders are still quite a far way.
For now, it’s advantage, females!
