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: https://www.ncbi.nlm.nih.gov/books/NBK98182/figure/depienne.f4/

EFNB1 is another example: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605834/

OLD paper postulating this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1686061/

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.

Maybe.

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

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.

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.

http://epilepsygenetics.net/the-epilepsiome/pcdh19-this-is-what-you-need-to-know/

https://www.sciencedirect.com/science/article/pii/S0887899419309269?casa_token=bpHYPTkg5HwAAAAA:DB4d1pgHBXslHmidMxFDYSxDymsUjCJ5_QGpRLIaGsL0Yt7RGZmiYqCmhzMpbnNK1M9YFa7HDkk

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: https://www.nature.com/articles/s41568-018-0076-6

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.

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)

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”.

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.

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.

Yes.

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.

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.

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