Skip to main content
PMC home page
Genetics logoLink to Genetics
. 2002 Aug;161(4):1599–1607. doi: 10.1093/genetics/161.4.1599

Historical intensity of natural selection for resistance to tuberculosis.

Marc Lipsitch 1, Alexandra O Sousa 1
PMCID: PMC1462208  PMID: 12196403

Abstract

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.

Full Text

The Full Text of this article is available as a PDF (107.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ALLISON A. C. POLYMORPHISM AND NATURAL SELECTION IN HUMAN POPULATIONS. Cold Spring Harb Symp Quant Biol. 1964;29:137–149. doi: 10.1101/sqb.1964.029.01.018. [DOI] [PubMed] [Google Scholar]
  2. Abel L., Casanova J. L. Genetic predisposition to clinical tuberculosis: bridging the gap between simple and complex inheritance. Am J Hum Genet. 2000 Jul 5;67(2):274–277. doi: 10.1086/303033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Altare F., Jouanguy E., Lamhamedi S., Döffinger R., Fischer A., Casanova J. L. Mendelian susceptibility to mycobacterial infection in man. Curr Opin Immunol. 1998 Aug;10(4):413–417. doi: 10.1016/s0952-7915(98)80114-3. [DOI] [PubMed] [Google Scholar]
  4. Bellamy R. Genetics and pulmonary medicine. 3. Genetic susceptibility to tuberculosis in human populations. Thorax. 1998 Jul;53(7):588–593. doi: 10.1136/thx.53.7.588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bellamy R., Ruwende C., Corrah T., McAdam K. P., Thursz M., Whittle H. C., Hill A. V. Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene. J Infect Dis. 1999 Mar;179(3):721–724. doi: 10.1086/314614. [DOI] [PubMed] [Google Scholar]
  6. Bellamy R., Ruwende C., Corrah T., McAdam K. P., Whittle H. C., Hill A. V. Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans. N Engl J Med. 1998 Mar 5;338(10):640–644. doi: 10.1056/NEJM199803053381002. [DOI] [PubMed] [Google Scholar]
  7. Blower S. M., McLean A. R., Porco T. C., Small P. M., Hopewell P. C., Sanchez M. A., Moss A. R. The intrinsic transmission dynamics of tuberculosis epidemics. Nat Med. 1995 Aug;1(8):815–821. doi: 10.1038/nm0895-815. [DOI] [PubMed] [Google Scholar]
  8. Comstock G. W. Frost revisited: the modern epidemiology of tuberculosis. Am J Epidemiol. 1975 May;101(5):363–382. doi: 10.1093/oxfordjournals.aje.a112105. [DOI] [PubMed] [Google Scholar]
  9. Comstock G. W. Tuberculosis in twins: a re-analysis of the Prophit survey. Am Rev Respir Dis. 1978 Apr;117(4):621–624. doi: 10.1164/arrd.1978.117.4.621. [DOI] [PubMed] [Google Scholar]
  10. Davies R. P., Tocque K., Bellis M. A., Rimmington T., Davies P. D. Historical declines in tuberculosis in England and Wales: improving social conditions or natural selection? Int J Tuberc Lung Dis. 1999 Dec;3(12):1051–1054. [PubMed] [Google Scholar]
  11. Ferguson R. G. Some Light Thrown on Infection, Resistance and Segregation by a Study of Tuberculosis Among Indians. Trans Am Clin Climatol Assoc. 1934;50:18–26. [PMC free article] [PubMed] [Google Scholar]
  12. Hoge C. W., Fisher L., Donnell H. D., Jr, Dodson D. R., Tomlinson G. V., Jr, Breiman R. F., Bloch A. B., Good R. C. Risk factors for transmission of Mycobacterium tuberculosis in a primary school outbreak: lack of racial difference in susceptibility to infection. Am J Epidemiol. 1994 Mar 1;139(5):520–530. doi: 10.1093/oxfordjournals.aje.a117035. [DOI] [PubMed] [Google Scholar]
  13. Murray C. J., Styblo K., Rouillon A. Tuberculosis in developing countries: burden, intervention and cost. Bull Int Union Tuberc Lung Dis. 1990 Mar;65(1):6–24. [PubMed] [Google Scholar]
  14. Petersen G. M., Rotter J. I. Genetic and evolutionary implications in peptic ulcer disease. Am J Phys Anthropol. 1983 Sep;62(1):71–79. doi: 10.1002/ajpa.1330620111. [DOI] [PubMed] [Google Scholar]
  15. Rotter J. I., Diamond J. M. What maintains the frequencies of human genetic diseases? Nature. 1987 Sep 24;329(6137):289–290. doi: 10.1038/329289a0. [DOI] [PubMed] [Google Scholar]
  16. Rouillon A., Perdrizet S., Parrot R. Transmission of tubercle bacilli: The effects of chemotherapy. Tubercle. 1976 Dec;57(4):275–299. doi: 10.1016/s0041-3879(76)80006-2. [DOI] [PubMed] [Google Scholar]
  17. Schliekelman P., Garner C., Slatkin M. Natural selection and resistance to HIV. Nature. 2001 May 31;411(6837):545–546. doi: 10.1038/35079176. [DOI] [PubMed] [Google Scholar]
  18. Sousa A. O., Salem J. I., Lee F. K., Verçosa M. C., Cruaud P., Bloom B. R., Lagrange P. H., David H. L. An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13227–13232. doi: 10.1073/pnas.94.24.13227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Stead W. W., Senner J. W., Reddick W. T., Lofgren J. P. Racial differences in susceptibility to infection by Mycobacterium tuberculosis. N Engl J Med. 1990 Feb 15;322(7):422–427. doi: 10.1056/NEJM199002153220702. [DOI] [PubMed] [Google Scholar]
  20. Stephens J. C., Reich D. E., Goldstein D. B., Shin H. D., Smith M. W., Carrington M., Winkler C., Huttley G. A., Allikmets R., Schriml L. Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes. Am J Hum Genet. 1998 Jun;62(6):1507–1515. doi: 10.1086/301867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Wilkinson R. J., Patel P., Llewelyn M., Hirsch C. S., Pasvol G., Snounou G., Davidson R. N., Toossi Z. Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1beta on tuberculosis. J Exp Med. 1999 Jun 21;189(12):1863–1874. doi: 10.1084/jem.189.12.1863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Wilson L. G. The historical decline of tuberculosis in Europe and America: its causes and significance. J Hist Med Allied Sci. 1990 Jul;45(3):366–396. doi: 10.1093/jhmas/45.3.366. [DOI] [PubMed] [Google Scholar]
  23. Wilson L. G. The rise and fall of tuberculosis in Minnesota: the role of infection. Bull Hist Med. 1992 Spring;66(1):16–52. [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES