The term “mutation” is a bit loaded, as it implies a defect or deficiency or aberration of some sort. But the value of a particular version of a gene is very much dependent on its context – what might be a defect in one context conveys an advantage in another. And that context means not only the physical and social environment, but the genetic environment as well. Interesting genes rarely have simple stories.
If we are looking for advantageous mutations — I would call them polymorphisms — a good place to start is with infectious disease resistance. Human domestication — our collective decision to become agricultural and sedentary — vastly increased our exposure to infection. Our populations became denser, we lived in intimate contact with animals that serve as disease reservoirs, and we contaminated our food and water with human and animal waste.
The result was an ongoing holocaust of infectious disease death that dominates all of human history. Forget wars, which rarely killed more than a few percent of any given population. Infectious diseases regularly killed 75% of humans up until the late 19th century.
Such relentless selective pressure in agricultural populations led to constant evolution and change in the immune system, particularly in the front-line defenses of the innate immune system. Toll-like receptors enable the immune system to recognize pathogens and mobilize against them. Variants common in European populations reduced susceptibility to smallpox and tuberculosis and typhus. When these diseases were introduced into the western hemisphere, the result was a mass killing of perhaps 90% of the indigenous population. That certainly conferred an advantage to Europeans, who were able to dominate the Americas in the wake of this holocaust.
By Acuna-Soto R1, Stahle DW, Cleaveland MK, Therrell MD. – Emerging Infectious Diseases, April 2002; vol 8 (number 4), pages 360-2, CC0, File:Acuna-Soto EID-v8n4p360 Fig1.png
Cocoliztli disease, long a mystery, has recently been identified as an outbreak of Salmonella enterica Paratyphi C, the cause of paratyphoid fever.
Aside from these polymorphisms, the best candidates for mutations that confer resistance to infection are sickle cell anemia, cystic fibrosis, Tay-Sachs disease, and phenylketonuria.
These are cases where a single gene is responsible for a serious disease when present in two copies, but confers resistance to infectious disease when present in one.
- HBB, the hemoglobin ß-globin gene: mutation causes sickle cell anemia when present in two copies, confers resistance to malaria when present in one
- CFTR: a membrane channel that regulates the movement of chloride and sodium in and out of cells. Mutations cause cystic fibrosis when present in two copies, may confer resistance to cholera when present in one. I’m a little dubious about this claim, at least as a driver for allele spread — cholera did not appear in Europe (where CFTR mutations are most prevalent) until the 1800s. That hardly seems like enough time for them to reach their current frequency in European populations (about 3%).
- HEXA: encodes the alpha subunit of hexosaminidase, an enzyme involved in the turnover of membrane lipids, particularly in nerve cells. Mutations in two copies lead to Tay-Sachs disease, one copy may increase resistance to tuberculosis. In contrast to cholera, TB has been present for millennia, and accounted for a substantial fraction of deaths in European and North American cities.
- PAH: encodes phenylalanine hydroxylase, an enzyme that breaks down the amino acid phenylalanine. Mutations in two copies lead to phenylketonuria, resulting in brain damage. Women carrying a single copy appear to have a reduced rate of abortions associated with fungal infections.
In a world of clean water and antibiotics, but plenty of mosquitoes, only the HBB polymorphisms still confer any advantage. We can expect to see their frequency decline (but not disappear) unless the superbug apocalypse really does hit us.