According to a ground-breaking study, sex chromosomes—particularly through the genes ZFX and ZFY—play a crucial role in controlling the expression of genes throughout the human body, upending preconceived notions about their purpose.
The autosomes, also known as the ordinary or non-sex chromosomes that make up the majority of our genome and are found in identical pairs, are the source of human sex chromosomes. After diverging, the ancestral pair of autosomes split into the X and Y chromosomes. In addition to developing distinct roles—namely, identifying sex and influencing sex differences in males and females—X and Y also continue to perform shared roles that they inherited from their common ancestor.
Novel Studies on Gene Regulation
The shared function of the sex chromosomes as significant gene regulators is clarified by new study by Whitehead Institute Member David Page, a postdoc in his lab Adrianna San Roman, and a biology professor at the Massachusetts Institute of Technology. David Page is also a Howard Hughes Medical Investigator. The study, which was published on December 13 in the journal Cell Genomics, demonstrates how thousands of genes located on other chromosomes are expressed differently depending on how the X and Y chromosomes are expressed, affecting cells not only in the reproductive system but throughout the body.
Essential Gene Regulators: ZFX and ZFY
Moreover, the researchers discovered that ZFX and ZFY, the gene pair located on the X and Y chromosomes, respectively, which account for around half of this regulatory behaviour, essentially have the same regulatory effects as one another. Given how important this regulatory function is to human growth and development, it is possible that ZFX and ZFY independently preserved the important gene regulatory role that they inherited from their common ancestor, even after their individual chromosomes separated. The genes governed by ZFX and ZFY are implicated in numerous significant biological processes, indicating that the sex chromosomes play a significant role in functions that extend beyond those associated with sexual traits.
Sex Chromosomes’ Effect on Global Gene Expression
By plotting the changes in each gene’s expression in cells according to the amount of X or Y chromosomes present, Page and San Roman were able to determine the impact of X and Y chromosomes on global gene expression. They used tissue samples from individuals that naturally vary in the number of sex chromosomes they have, i.e., individuals who can be born with zero to four Y chromosomes and one to four X chromosomes. Unlike duplications of most other chromosomes, these changes in sex chromosomes are common throughout the human population and cause a range of health issues, but they are compatible with life.
We were able to create a previously unheard-of mathematical model of how the number of X and Y chromosomes affects gene expression by utilising the natural variance in sex chromosomal composition in the human population. We were able to learn more about the profound effects that the X and Y genes have on the entire genome by using this method. Says San Roman.
For this project, the researchers examined two cell types—skin-cell derived fibroblasts, which aid in the formation of our connective tissues, and lymphoblastoid cells, a type of immune cell—and measured how gene expression changed in each cell type with each additional X or Y.
They discovered that variations in the quantity of X and/or Y chromosomes present caused thousands of genes to alter in expression. Gene expression was altered by an equal amount with each extra X or Y chromosome due to the effects’ linear scaling. Each type of cell in the body may respond differently to the control of genes by X and Y chromosomal genes, as evidenced by the different genes that were affected and the degree of that effect for each type of cell.
We were able to learn more about the profound effects that the X and Y genes have on the entire genome by using this method. Says San Roman.
Exposing Unexpected Parallels and Divergences in Gene Regulation
Nonetheless, the effect of an extra X tended to resemble the effect of an extra Y for a given gene in a particular cell type. The researchers were taken aback by this discovery as they had anticipated that variations in the way X and Y genes control other genes would contribute to the explanation of some of the sex differences observed in health and illness. For example, the chances of contracting specific diseases, the symptoms experienced when an illness manifests, and the responses to specific medications vary between men and women. Male and female cells differ in a number of ways that remain unexplained, and gene regulators on X and Y that modify gene expression throughout the body appear to be good candidates to be contributing to these differences.
Instead, Page and San Roman focused on the gene pair ZFX and ZFY, which they found to represent roughly half of the influence of X and Y on widespread gene expression. Although ZFX occasionally had a slightly bigger effect than ZFY, the combination appears to be functionally similar. The other half of the influence is probably due to broad gene regulators on other genes on X and Y.
Similar to ZFX and ZFY, these additional gene regulators could be X-Y pairings with nearly identical functions. Gene regulation is, after all, a crucial job. Regardless of how else X and Y grow apart, the regulatory tasks that they received from their common ancestor may need to be fulfilled in exactly the same way for foetal viability.
To explain the numerous sex differences observed in male and female cells, the researchers believe that some X and Y genes must alter gene expression in distinct ways or to varying degrees from one another. The problem is that it will be more difficult for researchers to identify the ways in which the two chromosomes influence gene expression differentially because the largest effect of X and Y on widespread gene expression is shared.
“The effects on the genome that could account for differences in sex are more nuanced than we initially thought,” adds San Roman. Although we found that X and Y had strongly correlated impacts on gene expression, we found that X had larger effects than Y copy number, which may account for sex differences. This is an area of interest for future research.
Reevaluating X-linked chromosomes: Inactive vs. Active
A nuance that hasn’t been mentioned up to this point is that Page and San Roman think of X differently than most people do when they consider the sex chromosomes. They have been persuaded by their research that the way we now comprehend sex chromosomes is inaccurate. There are two types of X chromosomes, and only one of them differentiates between typical males and females, despite the fact that the human sex chromosomes are designated as X and Y. There is one “active X” chromosome in each and every human being. This chromosome has no effect on sex because, like autosomes, it is uniformly present.
Typical males have the Y chromosome, whereas typical females have the “inactive X” chromosome, which is genetically identical to the active X but has most of its genes switched off. This is what separates normal males and females from each other. Any more X chromosomes in individuals with abnormal sex chromosomal compositions will always be inactive X chromosomes; therefore, when the researchers examined the impact of adding more X chromosomes, they were really examining the impact of adding more inactive X chromosomes.
The X and Y are not the sex chromosomes that the researchers discovered to be influencing widespread gene expression; rather, it is the inactive X and Y. Moreover, Page and San Roman discovered that, similar to all autosomes, the inactive X and the Y both control the expression of several genes on the active X chromosome. (This builds on earlier research by Page and San Roman concerning the connection between the active and inactive X.) In conclusion, the Y and inactive X chromosomes work as gene regulators and sex chromosomes, respectively, whereas the active X chromosome functions like an autosome.
“It was astonishing to us to see how wide their network of influence was,” says Page. “These chromosomes have historically been known as the ‘inactive’ X and the ‘gene-poor’ Y chromosomes, and given little attention beyond how they contribute to sex differentiation.” “We’re going to completely change our understanding of the genetics of the human X and Y chromosomes as we learn more about these chromosomes, because they contain genes like ZFX and ZFY that are global gene regulators.”
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