Historical intensity of natural selection for resistance to tuberculosis.

Infections have long been thought to exert natural selection on humans. Infectious disease resistance is frequently invoked as a mechanism shaping human genetic diversity, but such hypotheses have rarely been quantitatively evaluated with direct measures of disease-related mortality. Enhancement of genetically determined resistance to tuberculosis by natural selection has been proposed as a factor explaining the decline of tuberculosis in Europe and North America in the period 1830-1950 (before the advent of antimicrobial chemotherapy) and the apparently reduced susceptibility of Europeans and their descendants to tuberculosis infection and/or disease. We used Swedish vital statistics from 1891 to 1900 to estimate that individuals who escaped mortality from pulmonary tuberculosis (PTB) during the European tuberculosis epidemic would have enjoyed a fitness advantage of 7-15% per generation compared to individuals who were susceptible to PTB mortality; individuals with 50% protection would have had a selection coefficient of 4-7%/generation. Selection during the peak of the European TB epidemic could have substantially reduced the frequency of already rare alleles conferring increased susceptibility to PTB mortality, but only if the phenotypic effects of these alleles were very large. However, if resistant alleles were rare at the beginning of this period, 300 years would not have been long enough for such selection to increase their frequency to epidemiologically significant levels. Reductions in the frequency of rare susceptibility alleles could have played at most a small part in the decline of the epidemic in the century preceding 1950. Natural selection by PTB deaths during the European TB epidemic alone cannot account for the presently low level of TB disease observed among Europeans and their descendants just prior to the appearance of antibiotic treatment.