Upvote:7
I think you're overthinking this.
As I understand it, immunity or susceptibility is on a bell curve. After generations of exposure to any specific disease, those who were most susceptible to the disease and variants vanish from the reproductive pool. Native Americans had not had the benefit of that exposure so the susceptible individuals were still alive.
Guns Germs and Steel explains that urbanization selects for individuals with stronger immune systems generally. Those with weaker or less adaptive immune systems don't reproduce. Native Americans had a lower level of urbanization so statistically speaking their immune systems were less adaptive.
It isn't about a specific gene (although I'm sure there are genes that influence the strength and adaptability of the immune system), it is about the expression of the immune system - individuals who are exposed to multiple disease vectors during the crucial period of childhood when the immune system is being trained develop stronger immune systems.
The Hygiene Hypothesis1 would seem to confirm this. At every horse barn I've visited, some wag has posted a reference to the study that shows that children kept in an overly clean/sanitary environment grow up to be more sickly adults, while children who play in the mud grow up healthier. The more disease vectors you're exposed to when your immune system is training, the more likely your immune system will have a relevant antibody when you're exposed later.
Yes, I'm aware that sources would improve this answer - I will yield to and upvote anyone who can provide sources.
1 Hat tip and a double tot to @called2voyage.