Wednesday, June 27, 2012

Literal XX Xplainer: How we can live with two X chromosomes

This cat also haz those two chromosomes 
to blame for that splotch on its face.
By Emily Willingham, DXS managing editor

We are "Double X Science" because we target evidence-based information to women, most of whom carry two X chromosomes, although exceptions exist. Some women carry a single X chromosome, and some people can be XY and develop and/or identify as female. That's one reason we mention "the woman in you" here at Double X Science.

But today, I'm writing about those of us who have at least two X chromosomes. You may know that usually, carrying around a complete extra chromosome can lead to developmental differences, health problems, or even fetal or infant death. How is it that women can walk around with two X chromosomes in each body cell--and the X is a huge chromosome--yet men get by just fine with only one? What are we dealing with here: a half a dose of X (for men) or a double dose of X (for women)?

X chromosome
The answer? Women are typically the ones engaging in what's known as "dosage compensation." To manage our double dose of X, each of our cells shuts down one of the two X chromosomes it carries. The result is that we express the genes on only one of our X chromosomes in a given cell. This random expression of one X chromosome in each cell makes each woman a lovely mosaic of genetic expression (although not true genetic mosaicism), varying from cell to cell in whether we use genes from X chromosome 1 or from X chromosome 2.

Because these gene forms can differ between the two X chromosomes, we are simply less uniform in what our X chromosome genes do than are men. An exception is men who are XXY, who also shut down one of those X chromosomes in each body cell; women who are XXX shut down two X chromosomes in each cell. The body is deadly serious about this dosage compensation thing and will tolerate no Xtra dissent.

If we kept the entire X chromosome active, that would be a lot of Xtra gene dosage. The X chromosome contains about 1100 genes, and in humans, about 300 diseases and disorders are linked to genes on this chromosome, including hemophilia and Duchenne muscular dystrophy. Because males get only one chromosome, these X-linked diseases are more frequent among males--if the X chromosome they get has a gene form that confers disease, males have no backup X chromosome to make up for the deficit. Women do and far more rarely have X-linked diseases like hemophilia or X-linked differences like color blindness, although they may be subtly symptomatic depending on how frequently a "bad" version of the gene is silenced relative to the "good" version.

The most common example of the results of the random-ish gene silencing XX mammals do is the calico or tortoiseshell cat. You may have heard that if a cat's calico, it's female. That's because the cat owes its splotchy coloring to having two X chromosome genes for coat color, which come in a couple of versions. One version of the gene results in brown coloring while the other produces orange. If a cat carries both forms, one on each X, wherever the cells shut down the brown X, the cat is orange. Wherever cells shut down the orange X, the cat is brown. The result? The cat can haz calico. 

Mary Lyon (Source)
Cells "shut down" the X by slathering it with a kind of chemical tag that makes its gene sequences inaccessible. This version of genetic Liquid Paper means that the cellular machinery responsible for using the gene sequences can't detect them. The inactivated chromosome even has a special name: It's called a Barr body. The XXer who developed a hypothesis to explain how XX/XY mammals compensate for gene dosage is Mary Lyon, and the process of silencing an X by condensing it is fittingly called lyonization. Her hypothesis, based on observations of coat color in mice, became a law--the Lyon Law--in 2011.

Barr bodies (arrows).
Yet the silencing of that single chromosome in each XX cell isn't total. As it turns out, women don't shut down the second X chromosome entirely. The molecular Liquid Paper leaves clusters of sequences available, as many as 300 genes in some women. That means that women are walking around with full double doses of some X chromosome genes. In addition, no two women silence or express precisely the same sequences on the "silenced" X chromosome. 

What's equally fascinating is that many of the genes that go unsilenced on a Barr body are very like some genes on the Y chromosome, and the X and Y chromosomes share a common chromosomal ancestor. Thus, the availability of these genes on an otherwise silenced X chromosome may ensure that men and women have the same Y chromosome-related gene dosage, with men getting theirs from an X and a Y and women from having two X chromosomes with Y-like genes.  

Not all genes expressed on the (mostly) silenced X are Y chromosome cross-dressers, however. The fact is, women are more complex than men, genomically speaking. Every individual woman may express a suite of X-related genes that differs from that of the woman next to her and that differs even more from that of the man across the room. Just one more thing to add to that sense of mystery and complexity that makes us so very, very double X-ey.

[ETA: Some phrases in this post may have appeared previously in similar form in Biology Digest, but copyright for all material belongs to EJW.]


  1. Naive question that I'm almost embarrassed to ask: How is this different to what happens on all the other chromosomes (that males and females have two of)?

  2. Males and females match up for those, with two copies of each, so that's the "normal" human condition, and no compensation is necessary. It's only the sex chromosomes that are a mismatch in terms of gene complements.

    1. Thanks. For some reason I had in my head that only one copy was used on the non-sex chromosomes too. I should have just thought about eye colour dominance for a counter-example.

  3. Klinefelter syndrome may be a unique window in understanding the role of the X and Y chromosomes and the role of testosterone and other male/female sex steroids in male/female traits even within gender. Klinefelter Syndrome (XXY) is not inherited and is caused by a de novo reproductive error that generates XY or YY sperm mutations in males or XX egg mutations in females.

    KS newborns have a pronounced reduction in the production of testosterone during the first two years of life. KS males are at risk for breast cancer and systemic lupus erythematosus (SLE). The risk in KS for breast cancer and SLE is at the same level of risk seen in adult women. KS is associated with risk for developmental language disorders, cognitive impairment and autism. KS males are described as quiet, sensitive and unassuming. KS males have small testes and a demasculization effect is present featuring reduced sexual motivation and performance.

    Interestingly mice prenatally exposed to alcohol produced the same characteristic features seen in KS, A pronounced drop in neonatal testosterone production, small testes and a reduction in sexual motivation and performance in the treated adult males.