The marvels of female DNA

8th March 2020 – Colette Christiansen

For all the cat lovers out there, have you ever wondered why there are female calico cats with beautiful tortoiseshell coats, but no male calico cats? You may be surprised to find that human females also have a mosaic pattern – we just can’t see it.

We have 23 pairs of chromosomes which contain instructions – genes – for making what our body needs to develop and maintain itself. One chromosome of each pair is inherited from our mother and one from our father. One of these pairs is what determines whether we are male or female. This sex chromosome pair has two X chromosomes for females and one X and one Y chromosome for males.

If females have two copies of an X chromosome, this means that they have twice the number of copies of genes that are on the X chromosome than males do.  For all other chromosome pairs having two copies of each gene is normal and necessary and both males and females have these.  However, when it comes to the X chromosome this is a special exception.  As can be seen from males, who are XY rather than XX, two copies of X are not needed.

Does having extra instructions matter though? We know from conditions like Down’s Syndrome where people have three copies of chromosome 21 rather than two that extra chromosomes do affect how we develop. Three copies of a larger chromosome with more genes leads to Patau’s Syndrome which is generally fatal in the first weeks of life.  Women might not be able to survive with two fully working X chromosomes.

As ever, biology has an answer. When females are just a small collection of cells in the womb, one of the X chromosomes is inactivated. This is a random process, so the result is that around half the cells inactivate one X and the other half inactivate the other. As these original cells go on to divide into many more and create you, the result for females is a pattern which varies throughout.

The instructions for fur colour in calico cats are contained in the X chromosome, which is how some parts end up different colours from others, depending on which X chromosome is active in which patch.  If instructions for human skin colour was also on the X chromosome, human females could also have patterned skin.

So the next time you admire the beautiful coat of a calico cat, make sure you admire also the wonder that is you or the women in your life.

Chromosome X marks the spot

25th November 2019 – by Paz Garcia

The X chromosome in women shows up differently in different parts of the body, according to new research published today in Nature Communications.

This means that women may not benefit from technologies that predict health risks based on genes on the X chromosome.

The team, led by researchers from the Department of Twin Research & Genetic Epidemiology, also found that age affects the patterns of X chromosomes, through a process known as “X inactivation”.

Further research is needed to understand the impact of different patterns of X inactivation on healthy ageing in women and how it can be taken into account when developing genetic tools that predict health risks.

What is X inactivation?

Chromosomes are lengths of DNA that contain genes on them.

Males have both an X and a Y chromosome, and females have two X chromosomes (XX). Humans only need one dose of the genes on the X chromosome however, so in females one of the X chromosomes in every cell is “switched off” so they don’t get double the dose. This process is known as X inactivation.

Which of the two X chromosomes is switched off is random, leading to roughly equal levels of each in the body.

Evidence suggests however that in some body parts in women, one X chromosome is much more likely to be inactivated than the other, leading to skewed patterns of X inactivation across different body parts.

What did they do?

The team, led by Dr Kerrin Small and Antonino Zito, studied whether the skew of X chromosome inactivation is linked to genetics, age, smoking and autoimmune diseases.

The researchers studied blood, fat and skin samples from almost 800 twins, including 8 pairs where one twin had rheumatoid arthritis – an autoimmune condition – and the other twin did not.

What did they find?

Blood, fat and skin have different X chromosome inactivation patterns. These patterns become more skewed with age and smoking. In addition, genetics affect the skewed patterns in the blood, but not in fat or skin.

The team also found that twins who have autoimmune conditions have more skewed patterns of X chromosome inactivation in the blood than their co-twins without the condition.

What does this mean?

Researchers will need to take into account the differences in X inactivation throughout the body in females.

First author Antonino Zito explained:

“It’s important to note that X inactivation patterns in the blood are not a reliable indicator of X inactivation in other parts of the body. We need to take this into account when designing genetic tools to predict health risks, which often rely on specialised blood tests. Otherwise, it may be that future genetic health tests are less reliable for older women, as the dose of X chromosome genes in the blood sample is different to that found elsewhere in the body.”

Senior author Dr Kerrin Small added:

“Our results indicate an association between X inactivation patterns and genetics, age, smoking and autoimmune conditions. We will need to carry out further research to understand the relationship between these features, and the implications of skewed X inactivation for healthy ageing in women.”

Zito A, Davies MN, Tsai PC, Roberts S, Andres-Ejarque R, Nardone S, Bell JT, Wong CCY and Small KS. Heritability of skewed X-inactivation in female twins is tissue-specific and dependent on age. Nature Communications (2019)

Why do more women develop lupus than men?

15th May 2019 – by Paz Garcia

Photograph of Selena Gomez
Singer and actor Selena Gomez has spoken publicly about living with lupus

King’s College London researchers have identified a new gene which may explain why so many more women develop lupus than men.

Systemic lupus erythematosus – known as SLE or lupus – is an autoimmune condition where the immune system mistakenly attacks the joints, skin and other organs, leading to inflammation.

It’s thought to affect about 65,000 people in the UK. 9 out of every 10 people with the condition are female.

The team included Dr Amy Roberts and Dr Kerrin Small from the Department of Twin Research and Genetic Epidemiology.

The paper was published today in Nature Communications.

Why did they do this research?

Previous research suggests that the X chromosome plays a role in lupus.

Chromosomes are lengths of DNA that contain certain genes on them.

Males have both an X and a Y chromosome, and females have two X chromosomes (XX). Humans only need one dose of the genes on the X chromosome however, so in females one of the X chromosomes in every cell is “switched off” so they don’t get double the dose.

Evidence suggests however that some genes on the switched off X chromosome escape this inactivation.

The team therefore decided to investigate suspect genes on X chromosomes, to see if there were any links with lupus.

What did they find?

The team analysed genetic information and cells collected as part of a number of existing research programmes, including from TwinsUK.

The researchers identified a gene on the X chromosome called CXorf21 as the likely culprit.

They found that the gene was closely linked to another gene known to play a role in lupus which also escapes inactivation in switched off X chromosomes.

The team also found that activity in this gene could be increased in a number of different ways. These included when the gene was not inactivated in switched off X chromosomes and when exposed to immune system molecule interferon – both classic hallmarks of lupus.

What does this mean?

We now have a better understanding of the genetics behind lupus, and why it affects so many more women than men. This could help us develop new screening strategies to pick up new diagnoses sooner, and ultimately help us develop treatments for the condition.

Dr Amy Roberts, who co-led the research, explained:

“It is not understood why females are more at risk than males for developing lupus, or indeed most other autoimmune diseases. Historically this has been attributed to hormonal differences.

However, genes encoded on the X chromosome are good candidates because these are the only chromosomes that are different between the sexes. We examined once such gene, CXorf21, which creates a protein of unknown function. We found that females have more of the CXorf21 protein than males.

Our study supports the idea that males and females have different risks for autoimmune conditions due to genetics. More work is now needed to fully understand the function of this protein, which ultimately could lead to both a better understanding of the disease and potential for improved treatments.”

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