| Literature DB >> 17925445 |
Bart Ferwerda1, Matthew B B McCall, Santos Alonso, Evangelos J Giamarellos-Bourboulis, Maria Mouktaroudi, Neskuts Izagirre, Din Syafruddin, Gibson Kibiki, Tudor Cristea, Anneke Hijmans, Lutz Hamann, Shoshana Israel, Gehad ElGhazali, Marita Troye-Blomberg, Oliver Kumpf, Boubacar Maiga, Amagana Dolo, Ogobara Doumbo, Cornelus C Hermsen, Anton F H Stalenhoef, Reinout van Crevel, Han G Brunner, Djin-Ye Oh, Ralf R Schumann, Concepcion de la Rúa, Robert Sauerwein, Bart-Jan Kullberg, André J A M van der Ven, Jos W M van der Meer, Mihai G Netea.
Abstract
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.Entities:
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Year: 2007 PMID： 17925445 PMCID： PMC2034238 DOI： 10.1073/pnas.0704828104
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205