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)?
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 XXXshut 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.
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.
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.]
In the course of writing a paper on women and STEM, I came across articles in the Journal of Sex Research, as one does. [The “related papers” button on PubMed is one of the best ways ever to let a whole day get away from you.] Given that I have just moved to a new area and may dip toes into the dating pool, and I’m a scientist, of course I had to investigate the latest research on dating, sex, and loooooove.
Human ovum (egg). The zona pellucida is a thick clear girdle surrounded by the cells of the corona radiata (radiant crown). Via Wikimedia Commons.
It was September of 2006. Due to certain events taking place on a certain evening after a certain bottle (or two) of wine, my body was transformed into a human incubator. While I will not describe the events leading up to that very moment, I will dissect the way in which we propagate our species through a magnificent process called fertilization.
During the fertilization play, there are two stars: the sperm cell and the egg cell. The sperm cell hails from a male and is the end product of a series of developmental stages occurring in the testes. The egg cell (or ovum), which is produced by a female, is the largest cell in the human body and becomes a fertilizable entity as a result of the ovulatory process. But to truly understand what is happening at the moment of fertilization, it is important to know more about the cells from which all human life is derived.
Act I: Of sperm and eggs
A sperm cell is described as having a “head” section and a “tail” section. The head, which is shaped like a flattened oval, contains most of the cellular components, including DNA. The head also contains an important structure called an acrosome, which is basically a sac containing enzymes that will help the sperm fuse with an egg (more about the acrosome below). The role of the tail portion of sperm is to act as a propeller, allowing these cells to “swim.” At the top of the tail, near where it meets the head, are a ton of tiny structures called mitochondria. These kidney-shaped components are the powerhouses of all cells, and they generate the energy required for the sperm tail to move the sperm toward its target: the egg.
The egg is a spherical cell containing the usual components, including DNA and mitochondria. However, it differs from other human cells thanks to the presence of a protective shell called the zona pellucida. The egg cell also contains millions of tiny sacs, termed cortical granules, that serve a similar function to the acrosome in sperm cells (more on the granules below).
Act II: A sperm cell’s journey to the center of the universefemale reproductive system
Given the cyclical nature of the female menstrual cycle, the window for fertilization during each cycle is finite. However, the precise number of days per month a women is fertile remains unclear. On the low end, the window of opportunity lasts for an estimated two days, based on the survival time of the sperm and egg. On the high end, the World Health Organization estimates a fertility window of 10 days. Somewhere in the middle lies a study published in the New England Journal of Medicine, which suggests that six is the magic number of days.
Assuming the fertility window is open, getting pregnant depends on a sperm cell making it to where the egg is located. Achieving that goal is not an easy feat. To help overcome the odds, we have evolved a number of biological tactics. For instance, the volume of a typical male human ejaculate is about a half-teaspoon or more and is estimated to contain about 300 million sperm cells. To become fully active, sperm cells require modification. The acidic environment of the vagina helps with that modification, allowing sperm to gain what is called hyperactive motility, in which its whip-like tail motors it along toward the egg.
Once active, sperm cells begin their long journey through the female reproductive system. To help guide the way, the cells around the female egg emit a chemical substance that attracts sperm cells. The orientation toward these chemicals is called chemotaxis and helps the sperm cells swim in the right direction (after all, they don’t have eyes). Furthermore, sperm get a little extra boost by the contraction of the muscles lining the female reproductive tract, which aid in pushing the little guys along. But, despite all of these efforts, sperm cell death rates are quite high, and only about 200 sperm cells actually make it to the oviduct (also called the fallopian tube), where the egg awaits.
Act III: Egg marks the spot
With the target in sight, the sperm cells make a beeline for the egg. However, for successful fertilization, only a single sperm cell can fuse with the egg. If an egg fuses with more than one sperm, the outcome can be anything from a failure of fertilization to the development of an embryo and fetus, known as a partial hydatidiform mole, that has a complete extra set of chromosomes and will not survive. Luckily, the egg has ways to help ensure only one sperm fuses with it.
When it reaches the egg, the sperm cell attaches to the surface of the zona pellucida, a protective shell for the egg. For the sperm to fuse with the egg, it must first break through this shell. Enter the sperm cell’s acrosome, which acts as an enzymatic drill. This “drilling,” in combination with the propeller movement of the sperm’s tail, helps to create a hole so that the sperm cell can access the juicy bits of the egg.
This breach of the zona pellucida and fusion of the sperm and egg sets off a rapid cascade of events to block other sperm cells from penetrating the egg’s protective shell. The first response is a shift in the charge of the egg’s cell membrane from negative to positive. This change in charge creates a sort of electrical force field, repelling other sperm cells.
Though this response is lightning fast, it is a temporary measure. A more permanent solution involves the cortical granuleswithin the egg. These tiny sacs release their contents, causing the zona pellucida to harden like the setting of concrete. In effect, the egg–sperm fusion induces the egg to construct a virtually impenetrable wall. Left outside in the cold, the other, unsuccessful sperm cells die within 48 hours.
Now that the sperm–egg fusion has gone down, the egg start the maturation required for embryo-fetal development. The fertilized egg, now called a zygote, begins its journey into the womb and immediately begins round after round of cell division, over a few weeks resulting in a multicellular organism with a heart, lungs, brain, blood, bones, muscles, and hair. It’s an amazing phenomenon that I’m honored to have experienced (although I didn’t know I was until several weeks later).
The Afterword: A note on genetics
A normal human cell that is not a sperm or an egg will contain 23 pairs of chromosomes, for a total of 46 chromosomes. Any deviation from this number of chromosomes will lead to developmental misfires that in most cases results in a non-viable embryo. However, in some instances, a deviation from 46 chromosomes allows for fetal development and birth. The most well-known example is Trisomy 21(having three copies of the 21st chromosome per cell instead of two), also called Down’s Syndrome.
The egg and sperm cells are unlike any other cell in our body. They’re special enough to have a special name, gametes, and they each contain one set of chromosomes, or 23 chromosomes. Because they have half the typical number per cell, when the egg and sperm cell fuse, the resulting zygote contains the typical chromosome number of 46. Now you know how we get half of our genes from our father (who made the sperm cell) and half from our mother (who made the egg cell). Did I just put in your head an image of your parents having sex? It’s the birds and the bees, folks—it applies to everyone!
All text and art except as otherwise noted: Jeanne Garbarino, Double X Science Editor
World Health Organization. “A prospective multicentre trial of the ovulation method of natural family planning. III. Characteristics of the menstrual cycle and of the fertile phase,” Fertil Steril(1983);40:773-778
Allen J. Wilcox, et al. “Timing of Sexual Intercourse in Relation to Ovulation — Effects on the Probability of Conception, Survival of the Pregnancy, and Sex of the Baby,” New England Journal of Medicine, (1995); 333:1517-1521
Poland ML, Moghisse KS, Giblin PT, Ager JW,Olson JM. “Variation of semen measures within normal men,” Fertil Steril (1985);44:396-400
Alberts B, Johnson A, Lewis J, et al. “Fertilization,” Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.
On Mother’s Day this year, we told you why, if you have biological children, those children are literally a part of you for life thanks to a phenomenon called microchimerism. When a woman is pregnant, some of the fetal cells slip past the barrier between mother and fetus and take up residence in the mother. What researchers hadn’t turned up in humans before now was that some of those cells can end up in the mother’s brain. Once there, according to a study published today in PLoS ONE, they can stick around for decades and, the researchers suggest, might have a link to Alzheimer’s disease. Note that is a big “might.”
The easiest way to tell if a fetal cell’s made it into a maternal tissue is to look for cells carrying a Y chromosome or a Y gene sequence (not all fetuses developing as male carry a Y chromosome, but that’s a post for another time). As you probably know, most women don’t carry a Y chromosome in their own cells (but some do; another post for another time). In this study, researchers examined postmortem brain tissue from 26 women who had no detectable neurological disease and 33 women who’d had Alzheimer’s disease; the women’s ages at death ranged from 32 to 101. They found that almost two thirds (37) of all of the women tested had evidence of the Y chromosome gene in their brains, in several brain regions. The blue spots in the image below highlight cells carrying these “male” genes a woman’s brain tissue.
Photo Credit: Chan WFN, Gurnot C, Montine TJ, Sonnen JA, Guthrie KA, et al. (2012) Male Microchimerism in the Human Female Brain. PLoS ONE 7(9): e45592. doi:10.1371/journal.pone.0045592
The researchers also looked at whether or not these blue spots were more (or less) frequent in the brains of women with Alzheimer’s disease compared to women who’d had no known neurological disease. Although their results hint at a possible association, it wasn’t significant. Because the pregnancy history of the women was largely unknown, there’s no real evidence here that pregnancy can heighten your Alzheimer’s risk or that being pregnant with or bearing a boy can help or hinder. As I discuss below, you can end up with some Y chromosome-bearing cells without ever having been pregnant.
Also, age could be an issue. Based on the reported age ranges of the group, the women without Alzheimer’s were on average younger at death (70 vs 79), with the youngest being only 32 (the youngest in Alzheimer’s group at death was 54). No one knows if the women who died at younger ages might later have developed Alzheimer’s.
Indeed, most of this group–Alzheimer’s or not–had these Y-chromosome cells present in the brain. The authors say that 18 of the 26 samples from women who’d had no neurologic disease were positive for these “male” cells–that’s 69%–while 19 of the 33 who had Alzheimer’s were. That’s 58%. In other words, a greater percentage of women who’d not had Alzheimer’s in life were carrying around these male-positive cells compared to women who had developed Alzheimer’s. The age difference might also matter here, though, if these microchimeric cells tend to fade with age, although the researchers did get a positive result in the brain of a woman who was 94 when she died.
Thus, the simple fact of having male-positive cells (ETA: or not enough of them) in the brain doesn’t mean You Will Develop Alzheimer’s, which is itself a complex disease with many contributing factors. The researchers looked at this potential link because some studies have found a higher rate of Alzheimer’s among women who’ve been pregnant compared to women who have not and an earlier onset among women with a history of pregnancy. The possible reasons for this association range from false correlation to any number of effects of pregnancy, childbearing, or parenting.
Nothing about this study means that migration of fetal cells to the brain is limited to cells carrying Y chromosomes. It’s just that in someone who is XX, it’s pretty straightforward to find a Y chromosome gene. Finding a “foreign” X-linked gene in an XX person would be much more difficult. Also, a woman doesn’t have to have borne a pregnancy to term to have acquired these fetal cells. As the authors observe, even women without sons can have these Y-associated cells from pregnancies that were aborted or ended prematurely or from a “vanished” male twin in a pregnancy that did go to term.
In fact, a woman doesn’t even have to have ever been pregnant at all to be carrying some cells with Y chromosomes. Another way you can end up with Y chromosome cells in an XX chromosome body is–get this–from having an older male sibling who, presumably, left a few cellular gifts behind in the womb where you later developed. As the oldest sibling, I can only assume I could have done the same for the siblings who followed me. So, if you’ve got an older sibling and have been pregnant before–could you be a double microchimera?
But wait. You could even be a triple microchimera! This microchimerism thing can be a two-way street. If you’re a woman with biological children, those children already carry around part of you in the nuclear DNA you contributed and all of the mitochondria (including mitochondrial DNA) in all of their cells. Yes, they get more DNA from you than from the father. But they might also be toting complete versions of your cells, just as you have cells from them, although fetus–>mother transfer is more common than mother–>fetus transfer. The same could have happened between you and your biological mother. If so, a woman could potentially be living with cells from her mother, older sibling, and her children mixed in with her own boring old self cells.
The triple microchimera thing might be a tad dizzying, particularly the idea that you could be walking around with your mother’s and sibling’s cells hanging out in You, a whole new level of family relationships. But if you’re a biological mother, perhaps you might find it comforting to know that a cellular part of you may accompany your child everywhere, even as your child is always on your mind–and possibly in it, too.