AAMC FL B/B #31

[alyxxs]

I understand the reasoning for their answer but should I assume the father is homozygous (GG) because he doesn't have CF? My thinking was he could be GG or Gg like the mother, in which there would be a 25% chance the child was homozygous for the G mutation.
Looking for some clarification pls.

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[sapientnarwhal]

The two recessive mutations are different.

 

[PNWMedStudent]

You need to pay close attention to which mutation is present in each individual. The mother is heterozygous for the G542X mutation, meaning she can pass one copy of that to the child. The father is heterozygous for the deltaF508 mutation. We know nothing about the fathers G542X status, so we must assume that he is not a carrier nor affected by CF via the G542X mutation (so he has zero copies of G542X). Therefore, the chances the child inherits one copy of G542X from each parent is effectively zero.

 

[mk536]

The key here is to understand that if the father had one G542X allele and one ΔF508 allele, he would have CF. Remember a given allele is a given version of a specific gene, so if the father is heterozygous for ΔF508, he only has one other allele for CFTR, which we assume is the WT since he doesn't have CF. The main issue I have with this question is that they don't clarify that the G542X is a lof mutation.

That said, I still would have selected A even if I weren't vaguely familiar with CFTR mutations. Why? Because in order to reasonably calculate the probability that the offspring is homozygous for G542X if we didn't make the above assumption, we would need to know the frequency of the G542X allele in the population (you can't assume, as you did, that WT and G542X are equally plausible). You did the following math: 0.5*(the probability of homozygous offspring if the father's second allele is WT = 0) + 0.5*(the probability of homozygous offspring if father's second allele is G542X). However the calculation should actually be (1-p)*(0) + p*(0.5), where p is the frequency of the G542X allele in the population. This is not possible to calculate without knowing p, and is beyond the scope of MCAT genetics anyways.

 

[PNWMedStudent]

The key here is to understand that if the father had one G542X allele and one deltaF508 allele, he would have CF. Remember a given allele is a given version of a specific gene, so if the father is heterozygous for deltaF508, he only has one other allele for CFTR, which we assume is the WT since he doesn't have CF. The main issue I have with this question is that they don't clarify that the G542X is a lof mutation.

This isn't necessarily the case. If the individual (the father in your example) has one G542X allele and one deltaF508 allele, he would not have CF based on the passage. It's dictated that individuals homozygous for deltaF508 exhibit CF, however this is not the same as one deltaF508 and one G542X allele. In such a case, the individual would still have one WT allele for each gene, allowing them to be WT for both in their phenotype and not display CF traits. To display CF, either two G542X alleles of two deltaF508 alleles would need to be present.

 

[mk536]

This isn't necessarily the case. If the individual (the father in your example) has one G542X allele and one deltaF508 allele, he would not have CF based on the passage. It's dictated that individuals homozygous for deltaF508 exhibit CF, however this is not the same as one deltaF508 and one G542X allele. In such a case, the individual would still have one WT allele for each gene, allowing them to be WT for both in their phenotype and not display CF traits. To display CF, either two G542X alleles of two deltaF508 alleles would need to be present.

Well, the passage is a bit unclear. However, generally, alleles are versions of a gene. Both of these are alleles of the CFTR gene (ΔF508 is a deletion of three base pairs, G542X is a nonsense mutation). So if the father has ΔF508 on one of his chromosomes, he cannot also have G542X on that chromosome. The closest he could have would be a different allele, containing both a frameshift and premature stop. If he is heterozygous for ΔF508, his other allele could be anything else, whether a mutated version of the gene or WT. However, if that second allele were the G542X mutation, then he would have two non-functional versions of the CFTR protein and would have CF. He therefore does not have the G542X mutation, and so his offspring have 0% probability of being homozygous G542X.