Uncovering the genetic factors that drive X chromosome loss in some cells

2024

Challenge

As females age, it is common for some of their blood cells to lose one copy of the X chromosome, a condition known as mosaic loss of the X chromosome (mLOX). While prior studies found that women with mLOX have an elevated risk of leukemia, no research so far has established risk factors for developing mLOX. Understanding the contributors to, and consequences of, mLOX requires the development of an efficient and sensitive method to detect mLOX in a small fraction of cells, as well as a large, international sample of female research participants.

Advance

In a group of approximately 900,000 women, a refined detection approach found that 12 percent had mLOX. In most of the women with mLOX, less than 2 percent of blood cells lacked the X chromosome. The study also replicated prior findings of an increased risk for leukemia in women with mLOX. Furthermore, the IRP researchers found 42 genetic regions where variation predisposed women to developing mLOX. Finally, the study identified 44 regions on the X chromosome that help determine which of its two copies is more likely to be retained when mLOX occurs.

Impact

This study demonstrates that mLOX is more common than previously expected, especially in older women; however, for most individuals with mLOX, only a small fraction of blood cells are affected. The findings improve our understanding of the relationship between inherited genetic variations and the risk of acquiring chromosomal deletions later in life, such as those commonly seen in cancer.

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