All of that discussion related to chromosomes, dominance, recessiveness, etc. got me thinking about sex-linked inheritance. It’s a common subject taught in high school biology, and it is something I discuss in my biology textbook. However, X-inactivation seemed (in my mind) to contradict something that is routinely taught in most high school biology courses. I searched the web for an answer to this apparent contradiction, but to no avail. No matter what kinds of keywords I used, I couldn’t find an article that addressed this particular problem.
As a last resort, I ended up E-MAILing my sister-in-law. My wife is brilliant, and she comes from a family of brilliant people. Her oldest sister is not only an accomplished molecular biologist, she is also a dedicated college professor. I knew she would have the answer to this question, but I hate to bother people who are busy doing such productive things. Nevertheless, I really wanted an answer, so I broke down and sent her the question. Not surprisingly, she answered it straightaway. I thought I would blog about it, mostly so I would remember it later on.
WARNING: If you thought what I have posted before was geeky, you probably won’t like what appears below the fold!
To set up the question, remember that for autosomes (chromosomes that have nothing to do with gender), humans have two of each. Thus, there are two of each “gene” that you find on autosomes. Technically, each gene on an autosome is called an “allele,” and the proper technical phrase is that there are two alleles for each autosomal gene.
When it comes to the sex chromosomes, however, things are different. Women have two X chromosomes, so they have two alleles for every gene on the sex chromosomes as well. However, men have one X chromosome and one Y chromosome. As a result, they do not have two alleles for every gene on the sex chromosomes.
In standard Mendelian genetics (which doesn’t always apply but is a nice starting point), an allele can be dominant or recessive. If you have even one dominant allele, you will express the dominant trait. In order to express the recessive trait, you must have two recessive alleles. A common example is the height of a pea plant. Pea plants tend to be tall or short, but nothing in between. There is a single autosomal gene that governs this, and the allele that produces a tall plant is dominant. So every plant has two alleles for height. If even one allele is the dominant one, the plant will be tall. The only way the plant can be short is for it to have two shortness alleles.
If a gene is on the X chromosome, however, only women have two alleles for that gene. Men have just one allele for the gene. As a result, it is much more likely for men to express the trait associated with the recessive allele if the gene is on the X chromosome. After all, a woman has to have BOTH alleles recessive in order to express the recessive trait. A man, however, has only one X chromosome, so if he inherits just one recessive allele, he will express the recessive trait.
Once again, there is a standard example for this. Hemophilia is a blood disorder in which the blood does not clot well. A person with hemophilia can lose a lot of blood and even die from a small cut, because his or her blood doesn’t clot well. It turns out that this disease is governed by a single gene, which is located on the X chromosome. The recessive allele leads to a gene that cannot produce an important protein in blood clotting. The dominant allele leads to a gene that does produce the protein.
So…according to the general story in a freshman biology book, women are significantly less likely to be hemophiliacs than men. After all, they must receive TWO recessive alleles in order to be unable to make the necessary protein, while a man needs to get only one. Indeed, consider the case where a man without hemophilia marries a woman with hemophilia. Both of the woman’s X chromosomes carry the recessive allele. The man’s single X chromosome, however, carries the dominant allele. All daughters from this marriage will get an X chromosome from the father and an X chromosome from the mother. Since the father’s X chromosome carries the dominant allele, the daughters will never have hemophilia. However, the sons get only one X chromosome, and it MUST come from the mother. The father MUST give them the Y chromosome in order for them to be male. Thus, all the sons will be hemophiliacs, because they will all have the recessive allele on their only X chromosome.
That’s the setup. If a woman has one dominant X allele and one recessive X allele, she will always express the dominant trait.
But wait one darn minute. A woman always has one X chromosome inactivated! Consider the daughters mentioned above. They each have one X chromosome with the dominant allele and one with the recessive allele. What happens if the X chromosome with the dominant allele is inactivated? Doesn’t that mean the only active allele will be the recessive one? Doesn’t that mean that unlike the standard biology book tells me, a marriage between a hemophiliac woman and a non-hemophiliac man can, indeed, produce a hemophiliac daughter?
My sister-in-law provided the missing piece of the puzzle that allows me to understand why X-inactivation does not contradict the story given in every biology textbook. The key questions are, “When does X-inactivation occur, and how does it occur?”
According to my sister-in-law, X-inactivation occurs 16 days after fertilization. At that point, the embryo is composed of about 500 to 1,000 cells. When X-inactivation occurs, it is random on a PER CELL basis. So about half of the cells will inactivate one of the X chromosomes, while the other half of the cells will inactivate the other X chromosome. At that point, then, the embryo is composed of cells that have two different active genomes. In roughly half the cells, the mother’s X chromosome is active, and in the other half of the cells, the father’s X chromosome is active.
Those cells begin reproducing and spreading their specific active genome. So roughly speaking, from day 16 on, the daughter will be “half-n-half.” As a result, half her cells will be able to produce the protein needed for blood clotting. Since not much of that protein is needed for good blood clotting, the half that can make the protein will produce sufficient amounts.
She tells me that this is why tortoiseshell cats look the way they do. The fur color of orange or black is based on a gene that resides on the X chromosome. So male cats in many breeds are generally all shades of orange or all shades of black, because they can have only one of the alleles. However, a female can have both alleles, and since half of her cells have one turned off and the other half have the other turned off, she will usually have spots of orange fur and spots of black fur.
The more I learn about genetics, the more I stand in awe of its Designer!