Some heterozygote advantages in humans are:

  1. People with sickle-cell trait are resistant to malaria, but people with sickle-cell disease tend to die young.
  2. Depending of the source we believe, people with one copy of a cystic fibrosis allele are immune to tuberculosis, or cholera, or typhoid fever (or two of them or all the three!) (it has been debunked).
  3. People with one copy the CCR5-delta 32 allele are resistant to AIDS, when they have two copies, they are immune to AIDS, but they are at higher risk for West Nile virus disease complications.

So, I wonder what would a heterozygote advantage against influenza in humans look like. I ask because I am writing a story with an influenza pandemic that devastated humanity (and other ape species) à la Spanish Flu.

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    $\begingroup$ Should note that CCR5-delta 32 only confers immunity to HIV when homozygous. Heterozygosity confers resistance only. Similarly, people with one allele for sickle-cell are not immune to malaria, but are more resistant to the infection. $\endgroup$
    – jdunlop
    Sep 18 '21 at 19:01
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    $\begingroup$ people with both sickle cell alleles tend to die because they can't form functional red blood cells. so that's all you need something contextually beneficial when heterozygous and lethal if homozygous. $\endgroup$
    – John
    Sep 18 '21 at 19:37

Come at it from the story.

You got me thinking about this. What inherited thing could protect from flu? Maybe IL-4 deficient persons would have less severe flu? Those people might be more susceptible to parasitic infection, and asthma, and maybe have poorer memory, and maybe be more sensitive to pain. But how to make that into an interesting story? The fact that your characters struggle with hookworms is hard for me to hook to the engine of a narrative.

A lot of heterozygote advantaged persons have no particular phenotype - for example sickle cell trait. Not a lot different about those people. It is not until they get together and have a homozygote baby that you see the phenotype manifested more - sick babies. I guess sick babies give a story some energy.

So the story: I picture your story like Stephen King's The Stand: everyone dying of flu except his few characters, who do not get sick. In your story, the people who do not die might know how they are different or maybe not. Maybe they are all descended from Latvian immigrants. Maybe they are a bunch of random folks who share in common a propensity for asthma or sensitivity to pain or poor memory. But really they can be whatever you want - after the flu apocalypse the survivors are unlikely to be doing molecular biology to elucidate the basis for their resistance.

Some phenotypes will be more helpful for your story than others. Flu is so complicated that if you assert these folks are resistant and are different in other ways (that you choose) and leave it at that, that will be good enough. If, for example, you assert they are deficient in IL-4 and try hard to get into those weeds I think (having just done that!) it will be a distraction from your effort to write a compelling story.

It occurs to me that instead of molecular biology, the basis for resistance could be something very different. Not a receptor or a cytokine but something more than that. Maybe something fundamental about the interface between human and world. And when the first homozygote baby is born it is not sick; not at all. But it is even more different than the parents. It is the next step in human evolution after the flu bottleneck.


This is Deeply Unlikely

Influenza is not nearly as monolithic an infection as HIV (two dominant strains) or malaria (a very weird parasite). There are hundreds of strains of influenza that work in marginal but genetically significant different ways.

As such, it's deeply unlikely that any one allele (as in these other cases) would confer resistance to all, or even most, influenza strains. Genetic makeup causes natural variation in how a given strain infects a population anyway, without the unusual limited-gene behaviour seen in certain other diseases, as you listed.

The most likely mutation to confer greater survivability to a population ravaged by flu would be something that makes pneumonia less likely, as that's the most common cause of death from an influenza infection. In turn, this would probably mean a mutation (not likely to be a single gene, but best not to get too far into the weeds) that reduces inflammation in its bearers.

Someone with this genetic disorder would be more prone to infection and blood poisoning from mundane cuts and abrasions. They would also be less likely to suffer from seasonal allergies to the same degree as others.


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