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)

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