Sex chromosomes are responsible for more than just sex determination, study finds

Human sex chromosomes come from a pair of autosomes, the ordinary or non-sex chromosomes that contain the majority of our genome and occur in identical pairs. This ancestral pair of autosomes diverged to become two different chromosomes, X and Y. Although X and Y moved away from each other and assumed unique functions, namely determining sex and causing sex differences between men and women, they also retain common functions. functions inherited from their common ancestor.

New research led by Whitehead Institute member David Page, also a professor of biology at the Massachusetts Institute of Technology and a medical researcher at Howard Hughes, and postdoctoral fellow in his lab Adrianna San Roman, sheds light on the shared role of sex chromosomes as influential genetic regulators.

The research, published in Cellular genomics on December 13, shows that genes expressed from the X and Y chromosomes impact cells throughout the body – not just the reproductive system – by increasing or decreasing the expression of thousands of genes found on d other chromosomes.

Additionally, the researchers found that the pair of genes responsible for about half of this regulatory behavior, ZFX and ZFY, found on the X and Y chromosomes, respectively, have essentially the same regulatory effects as each other. This suggests that ZFX and ZFY inherited their role as influential genetic regulators from their common ancestor and maintained it independently, even though their respective chromosomes diverged, because this regulatory role is essential for human growth and development. Genes regulated by ZFX and ZFY are involved in all kinds of important biological processes, showing that sex chromosomes contribute extensively to functions beyond those related to sexual characteristics.

Page and San Roman measured how the X and Y chromosomes affected overall gene expression by graphing how the expression of each gene changed in cells based on the number of X or Y chromosomes present. For this work, they used tissue samples from people with a naturally occurring variation in their number of sex chromosomes: people born with one to four X chromosomes and zero to four Y chromosomes. These sex chromosome variations are found in the the entire human population and cause various health disorders but, unlike duplications of most other chromosomes, are compatible with life.

“Using the natural variation in sex chromosome composition in the human population, we were able to mathematically model the impact of the number of X and Y chromosomes on gene expression in a way that has never been done before “By taking this approach, we gained new insights into the massive impact of genes X and Y across the entire genome,” says San Roman.

For this project, researchers looked at two types of cells that they chose for ease of sample acquisition – lymphoblastoid cells, a type of immune cell, and fibroblasts derived from skin cells, which help form our tissues. connectives – and measured how gene expression changed. in each cell type with each additional X or Y.

They found that thousands of genes changed their expression levels in response to changes in the number of X and/or Y chromosomes present. The effects evolved linearly, meaning that each additional X or Y chromosome changed gene expression to the same extent. Which genes were affected, and to what extent, were different for each of the cell types, suggesting that each cell type in the body may have a unique response to gene regulation by genes on the X and Y chromosomes.

However, for a given gene in a given cell type, the effect of an additional X tended to be similar to the effect of an additional Y. This was a surprising finding for the researchers, who expected that differences in how genes on X and Y regulate other genes might help explain some of the observed sex differences in health and illness. For example, men and women have different risks of developing certain diseases, different symptoms if they develop the same disease, and different reactions to certain medications.

There are many differences between male and female cells that are not yet explained, and genetic regulators on X and Y that change gene expression throughout the body appear to be promising candidates for contributing to these differences.

Instead, Page and San Roman focused on the gene pair ZFX and ZFY as being responsible for about half of the effect of X and Y on widespread gene expression, and the pair appears to be functionally equivalent, although ZFX sometimes had a slightly stronger effect. than ZFY. Other genes on X and Y are likely also widespread genetic regulators, making up the other half of the effect.

These other genetic regulators may, like ZFX and ZFY, be XY pairs playing essentially equivalent roles. After all, gene regulation is an important function, and the regulatory roles that X and Y inherited from their common ancestor might need to be carried out in exactly the same way for fetal viability, regardless of how X and Y interact. separate.

However, researchers suspect that certain X and Y genes must change gene expression in different ways, or to different degrees, in order to explain the many sex differences observed in male and female cells. The challenge is that because the largest effect of X and Y on generalized gene expression is shared, it will be more difficult for researchers to determine how the two chromosomes affect gene expression differently. .

“The effects on the genome that may explain sex differences are more subtle than we predicted,” says San Roman. “An interesting point for future studies is that although we found that X and Y had highly correlated effects on gene expression, we observed larger effects with the copy number of of Y, which could contribute to gender differences.”

Rethinking sex chromosomes: inactive X versus active X

One subtlety that hasn’t been addressed so far is that when Page and San Roman think about sex chromosomes, they no longer think about X the way most people think. Their work convinced them that our current understanding of sex chromosomes is imprecise. Although human sex chromosomes are defined as X and Y, there are actually two types of X chromosomes, and only one of them differs between typical males and females. Every human being in the world has an active “X” chromosome. This chromosome is, like an autosome, universally present and its presence therefore has no impact on sex.

What differs between typical men and women is which chromosome pairs with the active X: typical men have a Y chromosome and typical women have an “inactive X” chromosome, which is genetically identical with active X but the majority of its genes are transformed. disabled. In people who have atypical sex chromosome compositions, any extra X chromosome will always be an inactive X chromosome. So when the researchers measured the effect of adding extra X chromosomes, they were actually measuring the effect of adding extra inactive X chromosomes.

The inactive X and Y, rather than the X and Y, are more specifically the sex chromosomes that researchers believe change widespread gene expression. Additionally, Page and San Roman discovered that inactive X and Y both regulate the expression of many genes on the active X chromosome, just as they do on all autosomes. (This expands on earlier work by Page and San Roman that focused on the relationship between the inactive X and the active chromosome.) In summary, the active function as both sides of the X chromosome. the same piece, both as sex chromosomes and as genetic regulators.

“These chromosomes have always been known as ‘inactive’ X chromosomes and ‘gene-poor’ Y chromosomes, and have received little attention beyond how they contribute to sexual differentiation. He told us “So it was amazing to see how extensive their network of influence was,” Page says. “These chromosomes contain genes like ZFX and ZFY that are global genetic regulators, and I think as we learn more about them, it will completely change the way we think about the genetics of the human X and Y chromosomes.”