Thursday, January 27, 2011

How we define the phenotype is critical

The post-doc and I are discussing the following genetics problem, taken from a textbook:
Q.  For a certain gene in a diploid organism, eight units of protein product are needed for normal function.  Each wild-type allele produces five units.
a.  If a mutation creates a null allele, do you think this allele will be recessive or mutant*? 
b.  What assumptions need to be made to answer part a?
*Note: I don't know what the word 'mutant' means here, since we already know that the allele is mutant.  I suspect it's an error so I initially ignored it.

What I originally said:
The mutation is not recessive to the wildtype allele, because the heterozygote has a different phenotype than the wildtype homozygote.  I don't think this conclusion requires any assumptions other than the usual definition of recessive.  
However the postdoc and others have been arguing that mutation should be interpreted as dominant. This requires interpreting the word 'mutant' as an error where 'dominant' was meant, which is not unreasonable.

What I say now (after quite a bit of thinking): 

First, we're told that the mutant allele is a null allele, so the heterozygote is expected to have half the normal amount of protein (5 units instead of 10)  Since 8 units are needed for the normal phenotype, the mutant heterozygote will not be normal.  So the mutant allele certainly is not recessive.

(Here I'm assuming that the defect in one allele doesn't cause the other allele to be upregulated.  That's a possible answer to part b, though I doubt it was what the questioner was looking for, since this question comes from the first chapter on simple Mendelian inheritance.)
We're not told the phenotype of a mutant homozygote, so before considering whether the mutant allele could be dominant to the wildtype allele we need to carefully identify the phenotype in question.  The term 'phenotype' can have different meanings even for a given pair of alleles, depending on what is being observed and how it is being categorized. 

For example, if a pigment is being observed it could be treated qualitatively (red/white; red/pink/white; present/absent) or quantitatively (how much pigment is present).  Phenotypes are usually treated qualitatively in genetics textbooks, with quantitative phenotypes segregated into a special chapter.  But most real phenotypes have gradations, and the observer must decide whether to treat them qualitatively (with 2, 3 or more categories) or qantitatively.

Qualitative categories are usually chosen to reflect the underlying genetic effects.  For example, an observer might initially categorize flower pigment as red/white, and later realize that the 'red' category should be divided into 'red' and 'pink' because this better explained how the colours were being inherited.  If a gene were later discovered that modulated pigment production, the observer might then treat pigment quantitatively.

The problem posed above doesn't give us explicit guidance about whether this phenotype should be treated qualitatively or quantitatively.  Normal is presented as an ordinary word, not flagged as a special term by quotes or italicization, so we could certainly interpret it quantitatively.  However it could be meant qualitatively, although we're not given any clues to what the categories would be (normal/abnormal?  normal/abnormal/severely abnormal?).

If the phenotype is to be treated quantitatively (with 'normal' just taking its ordinary English meaning), then the mutant homozygote is expected to have a more severe abnormality than the heterozygote, so the allele would not be dominant.

But the postdoc argues that it's just as reasonable to treat the phenotype qualitatively with two categories, 'normal' and 'abnormal', and I agree that under this definition the mutant allele would be considered dominant.

However I think that requiring the phenotype to be defined this way is tantamount to making this a 'trick question', because this definition implies that the person posing the question deliberately ignored whatever information might be given by a more nuanced definition (one that considered possible differences between the mutant homozygote and the heterozygote).

Because the wording of the question doesn't favour this interpretation over any other, we should go for interpretations that are more reasonable - qualitative with more than two categories, or quantitative.

Would it be OK to say that the mutant is dominant because the heterozygote and mutant homozygote really do have identical phenotypes under more nuanced definitions (i.e. that they are equally abnormal)?  No, because this would require a biologically unreasonable explanation for the dominance - either the null allele in the heterozygote must completely prevent expression of the normal allele, or the presence of two null alleles in the homozygote must allow them to produce 5 units.  The former is very unlikely though not impossible, and the latter is inconsistent with the meaning of 'null allele'.

Later:  I've heard back from the person who wrote this question.  He indeed meant 'dominant' rather than 'mutant, and his intended answer agrees with that of the postdoc - that all non-normal phenotypes should be lumped together into the 'abnormal' category, which would make the null allele 'dominant'.

 I think this is both scientifically bizarre and pedagogically misleading.  It reinforces the erroneous assumption that alleles must be either dominant or recessive, and requires a very improbable explanation to be treated as typical.  Either question a should give a third option (recessive, dominant or neither) or the question should be framed with "What is wrong with this question?".  Question b can be deleted.


Andy said...

Isn't this just haploinsufficiency?

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