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“Inactive” X Chromosome Plays Bigger Role in Sex Differences Than Once Thought

A rendering of X chromosomes in purple.
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Research from the Whitehead Institute at the Massachusetts Institute of Technology (MIT) has thrown new light on the influence of the X chromosome on sex differences. The study, published in Cell Genomics, illustrates that the inactive X chromosome can regulate gene expression on the active X chromosome, potentially contributing to differences between the sexes in health and disease.

XY or XX What’s in a letter?

Our sex chromosomes are typically XY in men and XX in women, and these chromosomes were once believed to only contribute to sex determination. Recent research has, however, shown that the sex chromosomes also influence a variety of other genes, leading to sex differences in health and disease. These differences present in a myriad of ways, such as increased risks of getting a certain disease, experiencing different disease symptoms and responding to the same drug differently. 

Our sex chromosomes have evolved to have one of the chromosome pair “activated”. In men, the Y chromosome, which has lost most of its genes over time, is paired with an active X chromosome; and in women, one of the X chromosomes is active and the other is inactive. On the inactive chromosome, most of the genes aren’t expressed.

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“Everybody on the planet carries one active X chromosome, so that first X chromosome really does not contribute, we think, to differences between males and females,” said Dr. David Page, professor of biology at MIT and senior author of the paper. “If we transition from saying that females are XX and males are XY, to saying that females are Xi (have an inactive X) and males are Y, that really focuses the question.”

Although research has shown that approximately a quarter of the genes on the inactive X chromosome are expressed, this is often overlooked as more research has focused on the more active partner chromosome.

How silent is the inactive X chromosome?

The new study aimed to understand how the inactive X chromosome contributes to gene expression and thus sex differences.

To do so, the team focused on the genetics of people with unusual combinations of sex chromosomes. A whole host of different sex chromosome combinations exist outside of the typical XX and XY combinations, from having just one X chromosome with no counterpart to XXXXY. Individuals with unusual combinations of sex chromosomes often have health issues, including heart defects, infertility, hearing impairments and more.

When there are multiple copies of an X chromosome, all but one are inactive. The researchers could therefore measure changes to gene expression when there are multiple inactive X chromosomes.

One might expect the expression level of the sex chromosome genes that are active on the inactive X chromosome to change proportional to the number of inactive X chromosomes present, and those that are inactive to not change at all.

However, the research team found that having additional inactive X chromosomes increased and decreased the expression of 38% of X chromosome genes by varying amounts. In some cases, even if the only active copy of a gene was on the active X chromosome with no expression coming from the inactive X the presence of additional inactive X chromosomes changed the expression level of the gene.

This led the team to conclude that genes on the inactive X chromosome can modulate the expression of the genes on the active X.

A new way of thinking

Page and his team hope that these findings highlight the importance of the inactive X chromosome in sex differences in health and disease, providing a new lens through which to view sex differences.

The team also hopes that a greater understanding of the role of inactive X chromosome genes and their interactions with the active X chromosome will provide new insights into the health issues faced by those with an unusual combination of chromosomes.

They have already identified a “top 10” list of X chromosome genes that they hypothesize have a distinct effect on sex differences and on the health issues associated with atypical chromosome arrangements.

“This is a new way of thinking about how the X chromosome is expressed and how it might be impacting our biology,” said Dr. Adrianna San Roman, first author of the new paper. “This top ten list will be really interesting to consider in the future in terms of how the level of expression of these genes affects cells and tissues in very fundamental ways.”


Reference: San Roman AK, Godfrey AK, Skaletsky H, et al. The human inactive X chromosome modulates expression of the active X chromosome. Cell Genomics. 2023;3(2):100259. doi: 10.1016/j.xgen.2023.100259

This article is a rework of a press release from the Whitehead Institute. Material has been edited for length and content.