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It's widely stated that a large chunk of the Native American population was wiped out by diseases (Notably smallpox) introduced by European colonists to which the natives did not have a resistance. My question is: Exactly what mutations in what genes did Europeans have (Which the natives lacked) that conferred greater resistance to smallpox compared to the native populations?

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First, it is unlikely to be one specific mutation. Such strong selective pressures can lead to many forms of resistance.

Second, even for the mutations we suspect, smallpox is not a heavily studied disease, so definitives are rare.

That said, CCR5 Δ32, a mutation in the CCR5 chemokine receptor protein on immune cells, is believed to be related to smallpox, although the black plague is also a candidate. Today, the mutation is studied because it confers resistance to HIV. We know it was not originally a response to HIV because it showed up long before HIV made the jump to humans.

https://www.pnas.org/doi/10.1073/pnas.2435085100.

Now, of course, for the original contact, the European's normal adaptive immunity from contracting it earlier in life would also come into play, since many Europeans contracted it or the related cowpox during their life. While for the native Americans, it would be a completely new disease, so no one had any adaptive immunity, meaning it could spread like wildfire.

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None, because that's not how immunity works in the case of smallpox.

Most Europeans caught smallpox in childhood (or a variant; discovering that cowpox protected against smallpox led directly to the first vaccine).

A large proportion of those children died (or were blinded). Wikipedia says the death rate was 30%. This was just one of the many reasons that you'd have a large family, because 8 out of 10 children dying before adulthood from now-preventable causes was pretty normal. It's not clear - and it still isn't - whether surviving infectious diseases is down to some "better" genes, better care because of some familiarity with the disease, or simply blind luck.

You therefore have a preselected group of Europeans who, by their survival past childhood, had developed immunity to smallpox. Conversely you have a group of Native Americans who had no immunity and who had no experience caring for people with the disease.

Tribes which survived first contact then also had this immunity, of course. Children continued dying in childhood, but surviving adults were immune after infection.

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    $\begingroup$ that's not how it works in this case ... $\endgroup$
    – Ben Bolker
    Commented Nov 18 at 16:24
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    $\begingroup$ @PasserBy Different things! :) Sickle cell doesn't make you immune to malaria, it just makes it harder for the bug to get into blood cells. Think of sickle cell as putting armour on the blood cells to keep intruders out (which also stops them doing their job properly; it's not a good thing to have!) versus immunity which is like an army of security guards learning how to take down intruders. $\endgroup$
    – Graham
    Commented Nov 18 at 16:26
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    $\begingroup$ That adaptive immunity largely explains Europeans' better smallpox survival rate does not imply there is no such thing as mutations associated with European ancestry and smallpox resistance. Smallpox usually kills in childhood, meaning that any resistance-associated mutations would indeed face significant selection pressure. The question is slightly misguided in focusing on mutations as primarily responsible for differential survival rates, but this answer is slightly misguided in simply dismissing their potential existence: science.org/content/article/smallpox-s-medieval-legacy $\endgroup$
    – Nuclear Hoagie
    Commented Nov 18 at 20:43
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    $\begingroup$ Basically, the fact that European individuals had adaptive immunity and Native Americans didn't does not mean that the European population did not have a genetic advantage after centuries of selective pressure killing off the least smallpox-resistant members of the population at an early age. $\endgroup$
    – Nuclear Hoagie
    Commented Nov 18 at 20:48
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    $\begingroup$ @Graham - That mechanism is really strange. Are you sure that's how sickle cell trait is helpful against malaria? That's very different from most everything I've read. (One source: malariajournal.biomedcentral.com/articles/10.1186/…) Please don't guess at answers, even in comments. $\endgroup$
    – anongoodnurse
    Commented Nov 18 at 22:34

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