Submitted by Altranite- t3_11damcv in askscience

So we hopefully know that people can carry some genetic mutation as a heterozygote and have minimal (or no) symptoms, but potential offspring who are homozygous will then show the associated disease with worse symptoms, this is common. But I wonder if there are examples of genetic diseases where the heterozygous condition is actually more severe than the homozygote? Say if a single mutant allele incorrectly activates some pathway relative to wild type, whereas in the homozygote this creates such a large change that the cell responds and the net effect is minimal? Or if two different protein variants interfere with each others’ function, whereas again this potentially does not occur in the wt or homozygote? This could be a loss of function or gain of function effect on the protein. I am not thinking about sex linked genes, only autosomal, or compound mutants where the other allele is affected by a second variant.



You must log in or register to comment.

jubears09 t1_ja8qpu7 wrote

Yes; the best studied mechanism for this is cellular interference.

PCDH19 is the classic human disease example. It's a protocadherin (cell surface protein that affects migration, signaling, etc) on the X chromosome. When both normal and abnormal PCDH19 is present (XX heterozygotes) affected individuals have epilepsy and developmental delay because neurons with different variants behave differently and have trouble forming networks with each other. XY males, regardless of whether there is a mutant or wt allele are normal. XXY males or mosaic males have the same phenotype as heterozygous females.

This is an illustration:

EFNB1 is another example:

OLD paper postulating this:

Edit: I know you said you're not interested in sex chromosomes, but this disease mechanism applies just as easily to autosomal genes. We can predict based on males that a true mutant homozygote would be unaffected while a compound heterozygote would be affected.

The problem with finding an autosomal example is being homozygous outside of a consanguinous situation is exceedingly improbable. Not only do both alleles need to develop a disease causing mutation, but they need to mutate in the same way by chance. Most recessive diseases we see are caused by a compound heterozygous state; which while not wild type, it also not homozygous.


AbouBenAdhem t1_ja95g5v wrote

So if I understand the abstract from the PCDH19 link, the problem isn’t heterozygosity on a cellular level, so much as random X-inactivation causing regions of incompatible homozygous (hemizygous?) cells. Is that correct?


jubears09 t1_ja9kp9y wrote

Sort of. Protocadherins are like address codes in the developing brain. So the problem is having 2 different sets of instructions for migrating neurons. Hence heterozygotes have disease and homozygotes (even if mutant) are normal. even if co-expressed absent mosiacism the prediction would be disease. However, for reasons I mentioned in the original post human examples would be hard to find because the event of 2 identical yet independent mutations would be highly improbable.

In diseases with recurrent mutations there is usually a mechanistic reason (Gain of function in achondroplasia) that wouldn't apply here.

Here is an even older paper describing this before we found any examples.


Droopy1592 t1_jaa720x wrote

This is so damn interesting. I would have never seen anything like this in my normal studies. I never would have thought heterozygous could be worse.


wheatgrass_feetgrass t1_ja9f6vn wrote

This is how I interpreted it as well. The issue is more of the mosiaic distribution of the different tissue. It ends up patchy like a tortoise shell cat's fur.


Germanofthebored t1_ja9gy6e wrote

Oh no, I thought (and taught) that one of the two X chromosomes gets packed away in the Barr body. Do both X chromosomes add to the exogne of the cell, or is the problem an interaction between cells?


za419 t1_ja9jkkw wrote

The problem is in the interaction. If you imagine the "normal" X chromosome (let's call it N), and the "bad" X chromosome (B), then a network of entirely B cells or entirely N cells works fine, since they're all on a standard "protocol" if you will.

However, if you undergo X inactivation in an individual that has BN genetics (one copy of each), then you get some clusters of cells with each type - And at the interface between B and N you get weird, glitchy behavior that can cause symptoms like seizure because they aren't quite fully compatible with one another.

At least, assuming I understood correctly.


MaygeKyatt t1_jaaccl4 wrote

It’s just a problem with the interactions between cells, it sounds like. You’re correct, X Inactivation virtually completely disables one X chromosome, it just happens after cells have divided several times, so some clusters of the developing embryo have one X chromosome while other clusters have the other chromosome.


lituranga t1_ja9kmon wrote

That’s not true, there are many AR conditions with common pathogenic carrier mutations which mean that many affected individuals are absolutely homozygous without any consanguinity.

It’s not exceedingly improbable at all. Examples off top of my head are delta f 508 for Cystic fibrosis, all the ashkenazi Jewish common AR conditions, SMA, sickle cell disease, alpha thal, beta thal, and I’ve personally seen many patients with other disorders who are affected and homozygous for same pathogenic variant.


jubears09 t1_ja9m58q wrote

Those are exceptions rather than the rule for rare disease. Ashkenazi Jews had a bottleneck effect; SSD is a gain of function, etc. They other thing they have in common is a relatively high allele frequency in the general population.

For interference where a heterozygote would be effected (and therefore selected again) most variants would be de novo; so a homozygous mutant would require simultaneous and identical de novo mutations to occur in the same individual.


lituranga t1_ja9pb51 wrote

Yes fair, just meaning to clarify that the phrase exceedingly improbable is a bit inaccurate since there are a huge amount of examples of disorders that work this way in reality.


iayork t1_ja80u83 wrote


In sheep and pigs, there’s a complex scenario (“polar overdominance”) in which only heterozygotes with a particular mutation show the phenotype:

> A single nucleotide polymorphism in the DLK1-DIO3 imprinted gene cluster alters gene expression … muscle hypertrophy only occurs in heterozygous animals that inherit a normal maternal allele and the callipyge SNP on the paternal allele (+/C).

New insights into polar overdominance in callipyge sheep

The details of how this works don’t seem to be well understood and I’m not going to try to summarize the complicated tentative explanations. In sheep and pigs, the muscular hypertrophy phenotype is at least somewhat desirable, but in humans there may be a similar mutation that, in heterozygotes, is associated with severe obesity.

> In a study sample of 1025 French and German trio families comprised of both parents and extremely obese offspring we found a single nucleotide polymorphism (rs1802710) associated with child and adolescent obesity. Analysis of the allelic transmission pattern indicated the existence of polar overdominance, an unusual mode of non-mendelian inheritance in humans previously known from the callipyge mutation in sheep.

Preferential reciprocal transfer of paternal/maternal DLK1 alleles to obese children: first evidence of polar overdominance in humans


Tus3 t1_ja8cr7j wrote

Your post mentioned overdominance, which made me look up the term on Wikipedia.

That led me to the article for underdominance:

This made me wonder, does one of the examples on that page fit the OP's question?


Jrj84105 t1_ja8gski wrote

This is region so highly conserved. The imprinting of genes on both the maternal and paternal alleles makes any genetic chaos here quite deleterious.


zk3033 t1_ja8ba9s wrote

A bit indirect, but some forms of achondroplasia are so severe that homozygotes are incompatible with live birth, and thus heterozygous (or homozygous would type) are the only observed.

A better example: ABO blood types in terms of blood contaminagion (whether available acceptable blood types, or maternal-fetal hemolytic anemia). Diversity of heterozygous actually works against a “phenotype” of immune acceptance.


AlkalineHound t1_ja8uv38 wrote

This was the first thing I thought of. Another good example is a specific gene for hairlessness in dogs. It's dominant, so Hh would be hairless, but HH zygotes don't make it to birth.


lurkythere t1_ja8s5ye wrote

Yes! PCHDH19-related epilepsy only occurs in heterozygotes. Basically, neurons will express a particular type of cellular junction based on the version of PCDH19 expressed in that cell. If all neurons are mutant, it does not cause problems. But, if there are both variant and wild type neurons present, the mismatch leads to severe epilepsy. This is further complicated by the fact that PCDH19 is on the X chromosome, so males are typically hemizygous (only one copy of the gene) and therefore females are the only ones expected to be affected. This is a reversal of what we typically see in X linked disorders. Homozygous females are also not affected.

Things like Klinefelter syndrome (XXY male), mosaicism, and skewed X inactivation can add even more complexity. But again, it all comes down to whether there are more than one type of PCDH19 being expressed. The fact that males with Klinefelter can have PCDH19 related epilepsy demonstrates that this is not a sex limited disorder, but rather a heterozygote (or mosaic) limited disorder.


Vonspacker t1_ja8eady wrote

Certain cancers (I believe Ras-linked cancers?) Potentially experience this actually.

I think it was an in vitro study where overactive Ras was studied in homozygous WT, heterozygous, and homozygous mutant, while growth of cell populations was observed. They actually found that heterozygous conditions exhibited more severe progression of the disease.

It's thought that certain cancerous signals operate within a sweet spot, where their results are not so severe that feedback mechanisms halt them, but are severe enough to cause a diseased phenotype.

I'll take another look at my notes and double check the details of this because it was really a quite fascinating example of this exact phenomenon you're asking about.

If you're interested as to why - Ras at normal levels induces normal proliferation. Certain mutations to Ras are able to push this into excessive proliferation. However beyond this, even more proliferative signaling through Ras induces senescence instead and causes cells to age and effectively die. Hence there is a 'sweet spot' possible where some mutant Ras is present but the signaling is not so excessive that cancer cells die.

EDIT: After going to my notes to check it was in fact mutation of Ras which alters it's nucleotide binding such that it is constitutively active.

If you want to read more about it, the paper describes it as the 'sweet spot' model here:

It seems there is some nuance to do with the signaling power of given mutations which might contribute to oncogenesis as well, so perhaps not a perfect model of heterozygosity being more pathogenic than homozygosity, however the concept is still somewhat there I think.


evolutionista t1_ja9x81w wrote

In vivo I think this will require consanguinity to produce someone who has homozygous ras mutations as these are fairly rare disorders with severe effects in heterozygotes. Also, they aren't concentrated in particular endogamous populations as far as I know.

In vivo we have to additionally ask if a fetus would be viable with homozygous ras pathogenic variants. Heterozygosity may reduce viability of fetuses with related genetic diseases.


Vonspacker t1_jaa1jy6 wrote

You might be interested in this paper:

Outlines in vivo studies in mice showing how Ras zygosity effects tumour identity differently based on the type of mutation they've got. While Ras knockouts seem to make fetuses unviable, Ras Gain-of-function seems to still permit viability, but also confers shorter lifespans because of tumours.

A lot of Ras mutations are acquired from what i know, with different mutations being linked more to certain organs because of the nature of carcinogens that organ is exposed to. So I don't know if it's super worth looking deeper into heredity of this sort of thing, even if its very cool.


WildZontar t1_ja9dsab wrote

Yes, this can happen and is known as underdominance and is a specific type of epistasis (which is a more complex, but more realistic view of the interaction between alleles than the simple dominant/recessive model that is taught in intro biology). The thing is, if the disease is severe, then selection will be very strong against heterozygotes. If the population is otherwise freely mixing, whichever allele is less common would pretty quickly get removed, so such examples will never be common. If the alleles segregate among sub-populations that don't mix freely, then this kind of thing is likely a contributing factor to speciation (see the Dobzhansky–Muller model, though if you want to look at the most current research on this idea, "cryptic variation" is the umbrella term that you should use)


North-Pea-4926 t1_ja8pz1x wrote

I can’t find examples of particular diseases, but there are situations where heterozygous individuals have lower fitness than homozygous individuals. Try searching for disruptive selection or underdominance. Or causes for low hybrid fitness.

In plants there is “hybrid necrosis” as a result of incompatible immune systems. Mammals have “hybrid sterility”.


DurianBig3503 t1_ja8q9ko wrote

Theoretically, if;

  1. Both alleles are transcriptionally active.
  2. It forms a homopolymer.
  3. Both forms are functional.

Then it could happen that either homozygote functions better than the heterozygote. I have never seen it.


Doobledorf t1_ja8lk4q wrote

What I can think of:

There are some genetic diseases where if you are a homozygote, it is a guarantee stillbirth. Cats with the bobcat tail, for example, are heterozygotes for a disorder which would have caused them to be stillbirths had they been homogeneous for it.


tamarakalule t1_ja9gmi6 wrote


Not particular to your question, but genetic combinations determining sex categorisation- ideally one turns out either phenotypically male or female in regards to a particular species in sexually reproducing organisms and this takes place at some point during fertilisation & early developmental stages(in vitro of maternal parent).

An individual that turns out with an in-between combination of the two (Hermaphrodite) is likely sterile/infertile, may have low function in the less developed organ system which may or not be a problem except there’re associated urinogenital complications, and in humans puberty is affected by two sets of hormone cycles that synergistically have regressive effects on the individuals body physiology and overall development curve(mental retardation & stunted physical growth are also witnessed in certain severe cases)

It presents with different allele-combinations and is a very rare condition because plenty times the zygote is not viable at all. Do all individuals with this suffer the above traits? Realistically speaking, we’re not in a position to form an opinion of that as a fact- they seemingly can lead normal lives but that’s only the lesser part of an already small case group.


marieterna t1_jaasxym wrote

Fatal Familial Insomnia (FFI) is a genetic disorder caused by a mutation in the PRNP gene. The PRNP gene codes for the prion protein, thought to be involved in copper signaling and cell adhesion. For the mutation itself, at position 178, asparagine (N) replaces the wild type aspartic acid (D); D178N is the correct notation. However, what determines if someone shows the pathology of FFI or familial Cruetzfeldt-Jakob (fCJD), depends on another position on the mRNA that’s translated. The D178N mutation must be coupled with a methionine at position 129; this site is the valine/methionine polymorphism site.

Homozygotes at codon 129 show a shorter disease duration, more severe insomnia, and the disease is mostly restricted to the thalamus.

Heterozygous at codon 129 show a longer disease course and other symptoms, such as ataxia and dysarthria; the disease is not restricted to the thalamus, and can spread to other parts of the brain, such as the cerebral cortex.


[deleted] t1_ja7y91i wrote



fingawkward t1_ja8foyo wrote

It was my understanding that being heterozygous for sickle cell confers advantage in resistance to malaria while homozygocity causes sickle cell disease.


sparky_1966 t1_ja8p8n1 wrote

You are correct, heterozygous provides some protection from malaria and homozygous causes sickle cell. The heterozygotes are still not normal and are less healthy than normal people, but the negative pressure from malaria is strong enough that it's a net gain.


sa2bcity t1_ja8x9in wrote

You are right. In this case, however, the sickle-cell allele is the one that confers the advantage.


TestTubeRagdoll t1_ja8pmnk wrote

> There are some disorders where the normal allele in heterozygotes confers some advantage, such as with Huntington's disease. Wexler, N. S., et al. (1987). Homozygotes for Huntington's disease. Nature, 326(6109), 194–197.

Just wanted to point out that this is a pretty outdated reference (from before the causative gene for HD was actually identified - they had a rough idea of the locus based on linkage analysis in HD families). As far as I am aware, there isn’t any strong evidence that the normal allele in heterozygotes confers an advantage in HD - and the article you linked actually states that homozygotes and heterozygotes appear to have the same phenotype, suggesting a true dominant condition, rather than one where heterozygosity is advantageous. There is a caveat that homozygotes for HD are quite rare, so studies involving them can be somewhat small.


sa2bcity t1_ja8wljh wrote

Yes, there are flaws with the article I referenced. There are other articles that suggest a more negative clinical course for homozygotes.

Squitieri, F., et al. (2003). Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. Brain, 126(4), 946–955.


TestTubeRagdoll t1_ja92zob wrote

Yes, this study makes the point better, although it's still small (n=8 homozygotes), and relies on retrospective analysis of clinic records.

Based on that study, it does look like there could be faster progression in homozygotes, although I don't know if there's enough data to argue that the normal allele is specifically conferring an advantage, as opposed to simply a dose effect of having 2 copies of the mutant allele.

It's also worth noting that not all studies show this same trend. For example, a 2019 Neurology study (, which was somewhat larger (n=28 homozygotes) and used patients who are part of the EHDN Registry Database (ie using standardized data collection protocols for clinical data) did not see a difference in disease progression between homozygotes and heterozygotes.


[deleted] t1_ja86obm wrote



doogie1993 t1_ja8an8c wrote

Completely wrong and useless answer in this context. Almost certain this is assuming the homozygous has two normal alleles, which isn’t what OP was asking.


HermitAndHound t1_ja8bd1a wrote

Depends on where the age cutoff is. Some of those have a greatly reduced life expectancy. At 40 years of age the heterocygotic people have more symptoms compared to the dead ones.

Don't trust the AIs further than you can throw them.


iayork t1_ja8eaa5 wrote

This is why r/AskScience doesn’t allow AI-generated answers, and bans people who provide them.