The body contains a number of digestive enzymes known as proteases which break down proteins into their component amino-acids. These are on the whole confined to the digestive tract and other places where they are needed, but they do to some extent get through into the blood plasma, where they tend to break down the tissues of the body indiscriminately. This tendency is counteracted by the presence in the plasma of a protein which functions as a protease inhibitor. This exists in a large number of forms controlled by a set of alleles, and having different degrees of inhibitory activity. There is one with extremely low activity, and there also probably exists an amorph gene which produces no activity at all.()
Individuals with two low-activity or amorph genes for the protease inhibitor (Pi) system suffer from one or more diseases characterized by protein breakdown. They invariably have some degree of pulmonary emphysema, with breakdown and running together of the alveoli, the little air sacs of the lungs. They also often have a form of liver cirrhosis, and sometimes duodenal ulcers. They are probably also more than normally liable to a number of other diseases.
The protease inhibitor or Pi variants certainly vary considerably in frequency in different populations and one might expect that, for instance, low or absent Pi activity would suffer negative selection in populations where pulmonary function is particularly important, such as high altitudes, but so far no such functionally based population studies appear to have been done.
As with so many pathogenic genes, it is problematic how the harmful genes of the Pi system persist with substantial frequencies in most populations. One suggestion is that their harmful effects are balanced by a selective advantage in that the spermatozoa of males with these genes, containing little or no protease inhibitor, can without inhibition break down the proteins present in solution in the fluids of the female reproductive tract, and so penetrate these fluids more easily, and that such males are therefore more fertile than normal.