Evolution of the X and Y Chromosomes
[Note: This was originally published in three parts in August 2007, when it was featured in the Tangled Bank science blog carnival #87. It represents my attempt to represent the state of the research at the time. It has been lightly edited for style and formatting, while remaining true to the original content.]
As we covered in the Development Primer, dosage compensation in humans and mice involves silencing one of the two X chromosomes in XX (typically female) animals. But that isn’t the whole story.
Dosage compensation requires either up-regulation of X expression in cells with one X chromosome, or down-regulation in cells with two X chromosomes. At first, we just compared the two Xs to each other, and saw that one was silenced while the other was expressed. But when we compare expression from the active X chromosome to a normal autosome, we see that the active X is twice as active as any autosome.
Next, consider Turner syndrome (XO women) and Klinefelter’s syndrome (XXY men). These syndromes are caused by a rare event called nondisjunction. Normal human cells are diploid; that is, they have two copies of each chromosome (one from Mom, one from Dad). Gametes (sperm and egg) need to be haploid, having one copy of each chromosome. So as the cell prepares to divide during meiosis, the chromosomes are lined up in the center of the cell and are pulled in opposite directions. Normally, one chromosome of each pair goes to each side. But sometimes nondisjunction occurs; a pair of chromosomes get stuck together, so one gamete gets no copy and the other gets an extra copy (like those old Twix commercials: “Two for me, none for you!”). If those gametes then get to become part of a zygote, then the zygote will have an abnormal number of chromosomes.
If the inactive X chromosome were completely inactive, then we should expect to see no difference between XO and XX females, nor between XY and XXY males. But since Turner and Klinefelter’s are syndromes, the lack of X in the former and extra X in the latter must be doing something.
As it turns out, not all the genes on the inactive X are silenced; some escape inactivation. Recall from the Development Primer that Xist- RNA forms a transcription-free zone in the nucleus, and the inactive X crawls inside. But it seems that, like a loose bundle of yarn stuck hastily in your pocket, some loops of DNA dangle out of this zone, and the genes on those loops get expressed. But which genes, and why?
At this point, we turn to research on X and Y chromosome evolution.
Once upon a time, the Y chromosome used to be just another X chromosome. But at some point, the X-that-would-be-Y (I’ll call it pseudo-Y for now) suffered a major inversion; that is, a big chunk of the chromosome was broken off, flipped around, and stuck back on. This causes a problem with recombination. During meiosis, homologous chromosomes line up and swap pieces of DNA. This can only occur if the pieces being swapped are pretty much the same. Recombination is an important means of swapping around alleles (different versions of genes) and therefore a big player in evolution.
The inversion event threw a wrench into X chromosome recombination. The un-inverted sections could still recombine, but the inverted section couldn’t, and therefore these formerly homologous stretches of DNA diverged, each gradually mutating in different ways. The pseudo-Y experienced a number of other inversion events, each time taking another chunk of the homologous region and rendering it incapable of recombination with X.
How do we know this happened? Because the inversion events left behind fingerprints. We would expect the inverted sections of the pseudo-Y to diverge from the corresponding regions on the X. The more time has passed since the inversion, the more divergence we should expect.
This image is from a 1999 paper by Lahn & Page. They looked at 19 X-linked genes that were known to have homologous sections of DNA on the Y chromosome. For each of these DNA regions, they measured the differences between the X and Y versions. The x-axis in the figure shows location on the chromosome. The y-axis shows the estimated mean number of substitutions per synonymous site. What we see are four main age blocks; genes in Group 1 are more diverged from their Y counterparts than those in Group 2, which suggests the Group 1 region of DNA inverted earlier.
Since then, more refined techniques have distinguished the following evolutionary strata in the X chromosome:
The strata are numbered in order of evolutionary age; S1 is the oldest (in terms of divergence from Y), S5 is the youngest. PAR stands for pseudo-autosomal region. This is a tiny region of DNA that still allows recombination between the X and Y chromosomes; as a result, the PAR retains high homology between the X and Y.
A 2005 paper by Carrel et. al. looked at a whole bunch of genes on the X chromosome, where they were, and whether they escaped X-inactivation. This resulted in the following figure, which shows the amount of escape from inactivation for each stratum:
The red end of the spectrum represents inactivated genes; the purple end represents genes that escape inactivation. Basically, the further away you get from the PAR, the fewer genes you’ll find that have escaped X-inactivation.
It’s important to note that the genes that escape X-inactivation don’t necessarily have high Y-homology themselves; sometimes they just hang out with other genes that have high homology and ride their coattails.
So finally, what does this all tell us about how dosage compensation evolved in mammals? Recall that the active X is hyperactive compared to autosomes. When genes started decaying on the inverted pseudo-Y, the male cells started ramping up expression from their other X chromosome to compensate. But this heightened X expression carried over to females, too. That meant the female cells were getting too much X expression; to compensate, they evolved a mechanism for silencing one of their chromosomes.
Conclusion
We noted that, though dosage compensation in mammals occurs via inactivation of one of the two X chromosomes in XX cells, some genes escape X-inactivation. Furthermore, expression from the active X is twice as great as expression from the autosomes. We wanted to know how this ties into evolution of the X and Y chromosomes.
X and Y homology experiments have demonstrated that the X chromosome can be broken into a pseudo-autosomal region plus five evolutionary strata based on time since divergence from the Y chromosome.
It turns out that genes found in regions with higher Y-homology are more likely to escape X-inactivation. This tells us that gene silencing likely evolved as a response to up-regulation of X expression, which in turn evolved in response to degradation of homologous genes on the pseudo-Y.
This is, of course, a fairly general model. There are exceptions, genes with homology that are silenced and genes without homology that escape silencing. But we still see a profound evolutionary trend. It goes to show that evolution isn’t just about inventing genes for new proteins; it’s also about changing regulation of the genes you already have.