Explain allelic complementation at molecular level

Question

I know that Allelic complementation is a phenomenon where two recessive loss-of-function allele generate a functional gene product by compensating each others' defect. But I don't get how do they compensate each others' defect.

Answer 1

As Matej said, mutations in two different genes (or even a gene and a non-coding regulatory element) can lead to complementation and as they pointed out, the complementation test is designed to check if mutations are on separate genes or not.

Molecular mechanisms that may lead to complementation (apart from Matej's example):

• The double mutation in two enzymes in a pathway basically that does not alter the metabolic flux. Lets assume the pathway is linear i.e. no branches. The net flux would be limited by the slowest enzyme in the pathway. If a mutation increases activity of the rate limiting enzyme-1 while another mutation reduces the activity of enzyme-2 then the net flux may not change.
• If a regulatory gene acts on another gene by some kind of molecular recognition (protein-DNA, protein-RNA, RNA-DNA, RNA-RNA, protein-protein), then the effect of a mutation in the recognition domain in the regulator can be complemented by another mutation in the target such that the binding affinity is preserved. For e.g. a miRNA regulating a mRNA. If a mutation in miRNA, A→G, is compensated by a mutation, U→C, in the target, then there may be no change in the molecular phenotype. This logic also applies for two gene products that function as a heterodimer.

However, different mutations in the same gene may also lead to complementation like effect. I cannot cite an example but there is a theoretical possibility. Therefore this answer is speculative. There can be two cases here:

1. Two different mutations in the same allele
2. Two different mutations in two different alleles

For case-1 you can imagine a situation in which the activity of the gene product depends on intramolecular interactions (secondary and tertiary structures). Two mutations can preserve the intramolecular interaction in a manner similar to the case of intermolecular interactions discussed above.

For case-2 you can imagine a gene-product that functions as a homodimer. If the two mutations preserve the intermolecular interactions in the dimer then you would see complementation. Case-2 can also be observed in a situation when the mutations occur in two different functional domains of two different alleles such that finally the dimer is still capable of carrying out its activity.

Answer 2

The main principle is that the loss-of-function mutations have to be on different genes and recessive. Source

I wouldn't say they compensate each other. If either of them was in homozygous conformation, their effect would be full-shown.

The thing on the molecular level is that often less than 50 % of the gene product is necessary for the gene to "work", to fulfill its function. (in other words, the loss-of-function mutation is recessive and one functional allele is sufficient to show its effect). If the individual is recessive homozygot for the mutation in the gene, there isn't enough functional product to fulfill the function.

However, sometimes, mutations in two different genes can result in the same phenotypic outcome (e.g. one gene making colorless precursor of stain, the other one making protein which turns it into the actual coloring molecule). If there is a homozygous conformation for mutation in either of these two genes, the molecule of stain won't be produced and the flower will be colorless.

However, if two individuals aaBB and AAbb (both colorless) pair, the offsprings will all have colorful phenotype (AaBb) because there will be some of the stain precursor and some of the enzyme that makes stain molecule from the precursor, hence there will be some stain. This event is called complementation.

This was actually used in the past to determine, whether some recessive-trait-carrying individuals had mutation on one gene or on two.