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this post was submitted on 07 May 2024
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Started typing up an answer but don't feel like sourcing it and someone better informed is going to give a better answer eventually, but here's a start...
Whereas the Spanish significantly intermixed with the indigenous populations and created a mestizo (mixed) racial group, the US colonists maintained separation from the native population. In both cases, smallpox/disease reduced the native population by about 90% [relevance to question?]. The long running goal of the decision makers in America was to either force the natives to assimilate or be killed; the reservation was everyone's last choice.
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It should be noted; it wasn't just disease, or rather, disease (as always throughout history and till today) only got far, far worse when natives were also subjected to constant war, violent encroachments, and man-made (American-enforced, rather) famines.
Subject any population- European populations included- to such pressures and their immune systems will be greatly compromised. It wasn't just disease- these went hand-in-hand with systemic policies, ideology, and rhetoric that encouraged disease and killed and terrorized the natives in many other ways, with the end goal of- as you said, assimilation or death (ie. genocide)- and even the question of how much "assimilation" was actually on the table is another matter- they wanted to erase their cultures, religion, livelihoods, rights, etc. yes- but even those who had adopted much of the western customs like the "5 civilized tribes" eventually were driven west in forced marches (the trail of tears- ie. another form of genocide, akin to what was inflicted on the Armenians) despite the US law itself being on their side.
Because no amount of "assimilation"- by natives, by blacks (as one can see with "black Wall Street"/Tulsa, Oklahoma), by other minorities- changed the guiding ethos of the US- if white settler society wanted what you had, or simply wanted you out of the way and saw you as an eyesore to be culled, or wanted you as a slave- one way or another it would take what it wanted through force. And white settler-colonial and imperialist society wants everything the world over and more (and even that would not quench it IMO- because it is a all-devouring, monstrous system that, without new lands to conquer or peoples to subjugate and enslave, would likely collapse in on itself as it is doing now)- still does to this day, as should be clear to anyone sensible as well.
The vast majority of the 90% killed by disease were killed over a hundred years before any of the tribes had ever even heard of a white person or European. Smallpox spread like wildfire since the arrival of the Spanish. The diseases just appeared seemingly out of nowhere and annihilated millions of people without them even knowing what hit them or where it came from.
Stannard, D.E. 1992. "American Holocaust: Columbus and the Conquest of the New World." Oxford University Press.