genetics - Can difference in the expression potential of alleles lead to dominance?

Several hour ago I was in thoughts what allele dominance really means on molecular level. As we know from basic genetics, if the organism had Aa type of some gene so trait is controlled by this gene would be equal to AA case. And we see it only when our organism is growing up. I'd like to know, how it works on molecular level, why Aa = AA in phenotype? I suggest, that expression level of A locus is greater than a locus and if so, why? Is that because of chemical structure of dominance allele that RNA polymerase interact with it more frequent?

Please, help me to understand. Thanks.

P.S. I don't consider different gene interactions as epistasis etc. just give you simplest example to describe what I want to know, but any useful considerations are appreciated.

Answer

Dominance is not commonly known to occur because of higher expression level, per se of one of the alleles. It can certainly be a factor but usually dominance is mostly known to arise because of a slight difference in function (or in other words activity) of the gene product (which may be a protein or an RNA).

Note that a change of function doesn't mean the alleles would have a totally different function. It just means that the alleles can be different in the way they function. For example two variants of an enzyme may have slightly different kinetic properties (such as V_max K_m and k_cat). While change of activity may generally refer to V_max (maximum enzyme activity), mutations can also change the other constants. Some mutations can make the enzyme sensitive to temperature by affecting the stability of the overall structure. The extreme would be a functional allele and a non-functional allele.

While concentration of the product does affect its activity, it does not change its specific activity, which may change in the presence of a mutation.

Moreover, even if one allele is actually has a higher expression than the other, the resultant trait can be differentiated from that of the aa homozygote only if the two alleles have slightly different functions or if the difference in expression level between of the gene product in Aa and aa is great enough to elicit different biological effects. In the second case there would be no change in the gene function and the effect of dominance is purely based on gene dosage. This review by Veitia and Birchler (2010) explores the possibility of stoichiometric alterations of macromolecular complexes or cellular networks being responsible for dominant phenotypes*.

Now, how can a mutation lead to a difference in expression level without changing the activity of the product?

There are three cases here:

1. The mutation is in the expressed region (exonic) but doesn't lead to change in activity (for e.g. synonymous mutations)


2. The mutation is in the transcribed region but in the intron.


3. The mutation is in the non-transcribed DNA regions such as promoter/enhancer etc. Exceptions: certain downstream promoter elements are actually transcribed.

Only mutations in the promoters/enhancers can affect transcription by affecting the recruitment of RNA-polymerase. However, you should note that mutations in the non-transcribed regions, especially in the distal regulatory elements are not considered a part of the gene in consideration. Since, such complex modes of regulation were unknown during the time of Mendel, the classical genetics does not explain these effects. Hence, these mutants would not be called alleles of the considered gene.

Mutations in the transcribed regions may affect the elongation rate of polymerase (especially if it leads to formation of stable DNA secondary structures). This is just a theoretical possibility and I have not come across any study that has reported something like this.

However, mutations in the untranslated regions of the mRNA can change the expression of the protein. These mutations may affect post-transcriptional regulation of the protein expression or even the RNA localization.

Synonymous mutations in the coding region can affect the rate of translation and hence the protein concentration.

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*_{(quoted verbatim)}