Question about manifestation of an X linked disease (homework help)

Question

I am doing some practice exams and came across this question. Perhaps the answer is a lot simpler than my reasoning, but after discussing it with others, I still disagree why the answer is clearly and simply what it is, based on the information given. I apologise that this is quite long.

-- Question starts below --
During very early development of mammalian females, one of the two X-chromosomes normally present in each somatic cell becomes deactivated. Deactivation is random, with maternal and paternal X-chromosomes equally likely to be deactivated. All cells deriving from this cell carry the same deactivated X-chromosome, creating local patches of tissue with either maternal or paternal features.

Anhidrotic ectodermal dysplasia (AED) is an inherited skin condition caused by the recessive allele (s) of a gene that has its locus on the X-chromosome. In some individuals with this condition, sweat gland distribution is patchy, with some areas lacking glands. In other individuals with this condition, all sweat glands are absent.

Q) Which one of the following is consistent with the information given?

A. Patchy sweat gland distribution is found in males and females but is more likely in males with the condition.

B. Patchy sweat gland distribution is equally likely in both males and females with the condition.

C. Only females with the condition exhibit patchy sweat gland distribution.

D. Only males with the condition exhibit patchy sweat gland distribution.

--/ End of question /--

The correct answer is C.

I would like to know why you should be able to tell that only females will manifest or show patchy sweat gland distribution. My reasoning is, individuals with the condition must have the recessive gene. Since it is an X-linked condition, and females have 2 X chromosomes, they must have 2 copies of the recessive gene (little r) to get this condition. Thus, females must be homozygous recessive, or rr. (Males will be just r)

If we define the phenotype of having the recessive gene, we say that it causes the individual to either have patchy sweat glands or no sweat glands at all. The thing is, they do not tell you under what conditions a person will have patchy sweat glands and when they will have no sweat glands at all.

As an X linked disease, think haemophilia, they should either have the skin condition or they don't: in other words, even though females can be carriers, carrier females will not exhibit the symptoms and the question talks about all humans with the condition (either males or females).

How* the disease manifests isn't made clear, so how are you supposed to know that of those who have patchy sweat glands vs those that have absolutely no sweat glands, females are those who have patchy sweat glands?

*For example: Angelman and Prader-Willi syndromes are both results of errors on the same region of chromosome 15, however, the important how that explains who gets PW and who gets A is, the phenotype depends on whether it was maternal or paternally inherited due to imprinting. By telling you this, if the question told you that males tend to get PWS and females tend to get Angelmann, told you some characteristics of either syndrome, then told you "given that a specific gender is more likely to get a specific symptom", you can determine whether males or females are more likely to have which disorder (PWS or A) based on the symptoms.

The question doesn't have this sort of information. It doesn't tell you how a person tend to get patchy or missing sweat glands and it doesn't tell you anything about incomplete dominance, co dominance, mosaicism etc.

Since both males and females can have the condition but it is X linked, why is it not A, but C? Why can't males have patchy sweat gland distribution too?

One answer I got while discussing this was, the information tells you about random inactivation of the X chromosome. For me, this only further rejects the idea that only females can be patchy: Suppose a female is a heterozygous with XRXr. One X chromosome gets inactivated at random. Let's pretend XR gets inactivated, leaving Xr. This is the recessive gene.

Now, we know the recessive gene produces the skin condition, with could be either patchy or completely absent sweat glands. Sadly, it does not tell you the exact symptoms of the recessive gene, see my point and analogy about PWS and A above. Since it doesn't tell you, I can only assume that like all other X linked diseases, having the recessive gene will cause the individual to show symptoms of that disease, end. of. story.

Usually when you have the recessive gene, you have the disease. Either have or not have. Thus an XRXr female with the first X inactivated will have the recessive disease, and fully show this (no sweat glands at all).

If she was XRXr with the second X inactivated, she would show a normal phenotype and have fully functional in ordinary quantity sweat glands.

Similar case with the males: They either have, or not have the faulty gene due to the fact that they only have 1 X chromosome.

Now, during my discussion with others, someone said, if you assume one copy of AED X (Xr) + one copy of normal X (XR) = carrier, then there is no way to explain how anyone could have patchy glands. They either have normal glands or no glands at all.

But I think this is exactly the point. The question doesn't ask you how anyone could have either patchy or totally absent sweat glands. Why does patchy glands exist? Where is the condition of its existence? It's not told to you in the question. The normal train of thought (at least for me) is therefore, a female either has it or they don't. No where does the text mention anything to do with mosaicism. IF the question TOLD you that AED is inherited the way it is etc, then stated that females have patchy sweat glands while males have none at all, and asked you "what is the most likely reason for this", then you can say mosaicism.

This direction of reasoning would work much more logically.

Otherwise I just don't see this.

Would appreciate input from someone specialising in genetics.

Answer 1

If the disorder was an autosomal recessive disorder (and follows the Mendelian dominant/recessive pattern), then your reasoning is correct. Both men and women would either have the disease or not have it at all. If a person has a heterozygous genotype, then they will not have the disease. Only if they have a homozygous recessive genotype will they show any characteristics of the disorder. This is clear for an autosomal recessive disorder. However, for X-linked disorders, things are a bit more complicated. For men, there is no concept of recessive/dominant alleles. They either have the gene or they don't. For women, we need to consider X-inactivation.

When we talk about X-inactivation, the main thing is that it is random. That means that approximately half the cells in the body will contain one copy while the other half will contain the other copy. Some cells will have the recessive allele and some cells will have the dominant allele. In the case of color-blindness, this means that approximately half the cone cells will be defective and the other half will not be. Most of the time, the brain learns to ignore the signals from the defective cells. However, there are cases when the number of defective cells are more than the number of normal cells (due to random inactivation), and the woman experiences Tetrachromacy. You cannot compare these disorders to Angelman and Prader-Willi syndromes because those are on autosomal chromosomes and these are on the sex-chromosomes. You are right that the textbook does not mention anything about which individuals have patchy sweat glands and which do not have them at all. However, the textbook states that the recessive allele on the X-chromosome causes the condition. This means that we can assume both of these things:

• The trait is not a polygenic trait - That is, it is only caused by the gene on the X-chromosome
• The trait follows Mendelian dominant/recessive pattern

Although we cannot be extremely sure of either of those, we can assume it for sake of this problem. Since the allele is able to cause a complete loss of sweat glands, we can arrive at the conclusion that the recessive gene causes the loss of sweat glands. The reason some women have patchy sweat glands is because of X-inactivation, and the areas in which the recessive copy is activated will have no sweat glands. On the other hand, the areas where the dominant copy is activated will have normal sweat glands. I think that the source of confusion here are the terms dominant and recessive. Although we say that the trait is "recessive", there is no concept of dominance and recession for X-linked traits. For women, half the cells are deactivated whether or not they contain recessive traits. For men, the X-chromosome is used whether or not they contain recessive traits. This means that the even if a dominant gene (in the X-chromosome) was recessive, it would have no consequences on the phenotype. In women, the phenotype (for X-linked traits) is always random (or rather, it's different for each cell - some sweat glands have one phenotype while others have a different phenotype).

Regarding your question on why men can't have patchy sweat glands, consider this. A man would either have the defective copy of the gene or a normal copy of the gene. Normal copy would result in normal sweat glands, so we have to deduce that the defective copy would result in patchy sweat glands. However, this would mean that women with homozygous recessive would still have patchy sweat glands. Hence, nobody would have complete loss of sweat glands. Since the question clearly states that some people have patchy sweat glands while others have a loss of sweat glands, we have to assume that the defective allele causes a complete loss of sweat glands. This makes sense as men would have no sweat glands, homozygous recessive women would still have no sweat glands, and heterozygous women would have patchy sweat glands. Because this is the only answer that makes sense, this must be the correct answer.

Like you said, this isn't guaranteed to be true, especially if the trait is polygenic. However, it's the most plausible answer (and the other three are definitely false), so I think that the question is put in a fairly good manner. Since they have mentioned the trait to be X-linked "recessive" (like I mentioned before, there really isn't a concept of recession for X-linked traits), we can assume that it follows the Mendelian pattern, and making this assumption, arrive at the right answer.

Hope I answered your question!