Open AccessTLR4polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans
Author(s) -
Bart Ferwerda,
Matthew McCall,
Santos Alonso,
Evangelos J. GiamarellosBourboulis,
Maria Mouktaroudi,
Neskuts Izagirre,
Din Syafruddin,
Gibson Kibiki,
Tudor Cristea,
Anneke Hijmans,
Lutz Hamann,
S. Leon Israel,
Gehad ElGhazali,
Marita TroyeBlomberg,
Oliver Kumpf,
Boubacar Maïga,
Amagana Dolo,
Ogobara K. Doumbo,
Cornelus C. Hermsen,
Anton F. H. Stalenhoef,
Reinout van Crevel,
Han G. Brunner,
Djin-Ye Oh,
Ralf R. Schumann,
Concepción de la Rúa,
Robert W. Sauerwein,
BartJan Kullberg,
A.J.A.M. van der Ven,
J.W.M. van der Meer,
Mihai G. Netea
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0704828104
Subject(s) - biology , allele , tlr4 , innate immune system , immunology , genetics , immune system , haplotype , genetic variation , gene
Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe. Genetic and functional studies are compatible with a model in which the nonsynonymous polymorphism Asp299Gly has evolved as a protective allele against malaria, explaining its high prevalence in subSaharan Africa. However, the same allele could have been disadvantageous after migration of modern humans into Eurasia, putatively because of increased susceptibility to severe bacterial infections. In contrast, the Asp299Gly allele, when present in cosegregation with Thr399Ile to form the Asp299Gly/Thr399Ile haplotype, shows selective neutrality. Polymorphisms in TLR4 exemplify how the interaction between our innate immune system and the infectious pressures in particular environments may have shaped the genetic variations and function of our immune system during the out-of-Africa migration of modern humans.