As we age, our cells accumulate mutations. If a mutation happens in the right place and the right time, it can lead to subpopulations of cells with a slightly different genome, a phenomenon called mosaicism. Most of the time, these mutations are small and do nothing, but on occasion they can lead to biological changes or health problems like cancer. In white blood cells, the most common form of mosaicism is the loss of an X chromosome for individuals who have 2 of them. Despite this common phenomenon, the potential health effects and causes are not known. In a groundbreaking new study, a group of researchers use an enormous population to try to uncover the causes and consequences of this mosaicism.

This team took blood DNA samples from around 880,000 women through a number of international biobanks. They detected a lost X chromosome in around 11% of the women, with an average of 3% of the cells being mosaic. However, this varied widely with age, with over 35% of women over 80 having detectable loss of the X chromosome. Among individuals with higher amounts of X chromosome loss, they found associations with a higher risk for different kinds of leukemia. They also identified mutations that were linked to increased chances of developing mosaicism. Some of these mutations are  related to chromosome stability, but there were also ones affecting immune system function, indicating that mosaic X chromosome loss could be a sign of immune cell dysfunction or possibly even the cause.

In addition to missing X chromosome mosaicism, many other kinds of mosaic chromosomal alterations exist that could possibly affect human health. This groundbreaking study not only revealed the effect mosaicism has on our white blood cells but also provides an important framework for future research looking at similar kinds of mosaicism.

This study was co-led by Yajie Zhao, a human geneticist at the University of Cambridge, Giulio Genevese, a senior computational biologist at the Broad Institute of MIT and Harvard, and Aoxing Liu, a postdoctoral fellow in the lab of Mark Daly at Massachusetts General Hospital.

Corresponding Author: Alex Yenkin

Press Article: Inherited genetic factors may predict the pattern of X chromosome loss in older women (ScienceDaily)

Original Article: Genetic drivers and cellular selection of female mosaic X chromosome loss (Nature)

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