Genetics question - If you could help me out here, you'd be my new best friend.

[Phloston]

Could someone please clarify as to the difference between the "null allele effect" and the "dominant negative effect"?

Please give examples!!

USMLE Rx uses osteogenesis imperfecta for dominant negative effect to illustrate that the collagen product from the mutant allele directly enervates (i.e. "damages") the collagen structure.

For some reason, I had had the perception that osteogenesis imperfecta demonstrates the null allele effect, not the dominant negative effect, in the sense that it is not the abnormal gene product that directly induces the actual damaging effect, but instead it's the mere lack of normal product that results in structural weakening.

It appears as though internet sources say both, which obviously isn't helpful.

Regardless, if someone could comment on OI with respect to the null vs dominant negative effect and/or also give an example of each, that's be so great!

~Phloston

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[ijn]

If it were the mere lack of a normal type I collagen that caused the most commmon type of OI, then you wouldn't see the disease unless the kid had two defective alleles. In general one allele is sufficient to produce enough normal gene product unless the defective product is a dominant negative.

I'm guessing you're seeing both dominant negative and null effect in searches because OI isn't due to a single gene defect. Based on wiki there are at least eight different types of OI. Most of the eight are autosomal dominant, but two of them are autosomal recessive. Correct me if I'm wrong, but from what I can tell dominant negatives only happen in autosomal dominant conditions. One defective gene product is sufficient to prevent the phenotypic expression of the functional gene. I'd consider most autosomal recessive conditions to be examples of the null effect, where you'd need two defective genes to fail to display a normal phenotype.

 

[AndyRSC]

Correct me if I'm wrong, but from what I can tell dominant negatives only happen in autosomal dominant conditions. One defective gene product is sufficient to prevent the phenotypic expression of the functional gene. I'd consider most autosomal recessive conditions to be examples of the null effect, where you'd need two defective genes to fail to display a normal phenotype.

It would appear so on the surface, but it's not the case. The autosomal dominants can be both null allele or dominant negative, depending on the translational defect in the collagen. In OI type I, mRNA instability of the defective gene product merely causes the collagen precursors to be cut in half. This isn't compensated for by the wild-type allele production, thus it's AD. In OI types II-IV, mutations cause the normal Gly-X-Y sequence to be disrupted, which screws up procollagen folding, secretion, and function of the proteins that are secreted. In this way, the defective gene affects the wild-type product.

The autosomal recessive pathogenesis, which occurs in OI type VII and rarely in type III, isn't outlined, except the mention that it's multigenetic/multifactorial.

Source: http://www.ncbi.nlm.nih.gov/books/NBK1295/

 

[Phloston]

I mean, this article is from the American Journal of Human Genetics:

It's titled, "Osteogenesis imperfecta type I is commonly due to a COL1A1 null allele of type I collagen."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682712/

There are quite a few articles in PubMed that say type-ONE is null allele.



The reason I'm confused is because I'm 92% finished with USMLE Rx at the moment, and a question I just answered happens to have mentioned in one of the unrelated explanations that OI is dominant negative, however I swear I had encountered a question about a month ago specifically asking about what type of mutation OI is, and the answer was null mutation. Then, in the answer explanation for dominant negative effect, which in this question was incorrect, it said an example would be a mutation that prevents a transcription factor from binding. However I specifically remember that the answer was "null mutation" for OI and that only ~15% got it right. Now, I'm encountering an explanation that says the opposite. Rx isn't helping out here.

 

[Phloston]

It would appear so on the surface, but it's not the case. The autosomal dominants can be both null allele or dominant negative, depending on the translational defect in the collagen. In OI type I, mRNA instability of the defective gene product merely causes the collagen precursors to be cut in half. This isn't compensated for by the wild-type allele production, thus it's AD. In OI types II-IV, mutations cause the normal Gly-X-Y sequence to be disrupted, which screws up procollagen folding, secretion, and function of the proteins that are secreted. In this way, the defective gene affects the wild-type product.

The autosomal recessive pathogenesis, which occurs in OI type VII and rarely in type III, isn't outlined, except the mention that it's multigenetic/multifactorial.

Source: http://www.ncbi.nlm.nih.gov/books/NBK1295/

That helps, thanks. What would be even more helpful is if someone could give examples of a condition for each that's not OI!

 

[scarshapedstar]

Is there any meaningful difference between

null vs. dominant negative

and

haplosufficient vs. haploinsufficient?

 

[ijn]

It would appear so on the surface, but it's not the case. The autosomal dominants can be both null allele or dominant negative, depending on the translational defect in the collagen. In OI type I, mRNA instability of the defective gene product merely causes the collagen precursors to be cut in half. This isn't compensated for by the wild-type allele production, thus it's AD. In OI types II-IV, mutations cause the normal Gly-X-Y sequence to be disrupted, which screws up procollagen folding, secretion, and function of the proteins that are secreted. In this way, the defective gene affects the wild-type product.

The autosomal recessive pathogenesis, which occurs in OI type VII and rarely in type III, isn't outlined, except the mention that it's multigenetic/multifactorial.

Source: http://www.ncbi.nlm.nih.gov/books/NBK1295/

What's an example of an AD disease that is due to a null effect that can appear on STEP 1? For OI I doubt they're going to get into minutae of the subtypes. If there isn't one, then I think AD = dominant negative, AR = null effect suffices to correctly answer anything they may throw at you.

 

[AndyRSC]

The reason I'm confused is because I'm 92% finished with USMLE Rx at the moment, and a question I just answered happens to have mentioned in one of the unrelated explanations that OI is dominant negative, however I swear I had encountered a question about a month ago specifically asking about what type of mutation OI is, and the answer was null mutation.

I'd chalk it up to question writers jumping to simplicity and overlooking the variation in pathogenesis of such conditions - same as the cholera toxin bull****. My strategy would be to review the differences between the classical type I and types II-IV and to answer accordingly, should that question ever pop up on boards.

I think you mentioned you have a ****-ton of resources, so I'm guessing you have the Kaplan videos. I'd look at the genetics lectures for examples, as I recall the lecturer giving good examples of each. A polygamist-looking bloke - Reichenbecher, I think.

 

[Phloston]

The conclusion I've come to:

Osteogenesis imperfecta type-I (the most common type) is null-allele effect.

USMLE Rx asked a question on OI a while ago. Given that the sub-type was not given, it was implicit that type-I was what had been referred to. Therefore, null allele was in fact the correct answer to that question, as Rx had stated.

Subsequently, USMLE Rx asked a question about an entirely unrelated topic, and negative dominant effect was an answer choice. In the explanation for this answer choice, it was cited that osteogenesis imperfecta is an example of a dominant negative effect. This is also true, but not for type-I; this is true for types II-IV. USMLE Rx had left out the specifics of the sub-type, when in fact it should have been stated considering not citing one suggests type-I.

Therefore, OI is both null allele and dominant negative effect, with the most common sub-type demonstrating the former.

 

[Star Fox]

Yes you are right. OI can be either depending on subtype. Hopefully the real deal is more specific.

Null allele = you get less product since the null allele product is nonfunctional.

Dominant negative = you get no functional product since the dominant neg mutation will screw everything completely.

 

[AndyRSC]

What's an example of an AD disease that is due to a null effect that can appear on STEP 1?

Well, osteogenesis imperfecta. At a glance, Marfan's syndrome and Williams syndrome are also.

 

[ijn]

Well, osteogenesis imperfecta. At a glance, Marfan's syndrome and Williams syndrome are also.

Wiki says that Marfan's is a dominant negative. I can't find anything definitive with William's, except that its related disorders (supravalvular aortic stenosis) are dominant negative.

 

[AndyRSC]

Wiki is not a reliable source if you're going to contest something.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC295860/?page=2

Very beginning of page 2.

 

[ijn]

Wiki is not a reliable source if you're going to contest something.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC295860/?page=2

Very beginning of page 2.

Fine.

http://emedicine.medscape.com/article/946315-overview#showall

Production of abnormal fibrillin-1 monomers from the mutated gene disrupts the multimerization of fibrillin-1 and prevents microfibril formation. This pathogenetic mechanism has been termed dominant-negative because the mutant fibrillin-1 disrupts microfibril formation though the other fibrillin gene encodes normal fibrillin. This proposed mechanism is evinced by the fact that cultured skin fibroblasts from patients with Marfan syndrome produce greatly diminished and abnormal microfibrils.

 

[AndyRSC]

Eh, I dunno, I'm not convinced. The Medscape article seems to base this claim on the fact that defective gene product causes abnormal microfibrils, whereas published studies say that the microfibrils produced are normal but diminished.

All in all, I doubt something so ill-defined would ever be the hinging point of a step I question. Just stick to what's in FA.

 

[Star Fox]

Robbins says 70-85% of Marfan syndrome is due to dominant negative inheritance, so I would go with this. The rest are due to mutations such as the null mutation in the paper you cited, which was a study about a specific family that had this mutation, so while yes it happens I think we should count this as predominantly dominant negative. I am getting more confused myself the more I read this thread haha