TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans
Edited by Richard A. Flavell, Yale University School of Medicine, New Haven, CT, and approved August 28, 2007
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.
Acknowledgments
We thank Garrett Hellenthal (University of Oxford, Oxford, U.K.) for kindly proving a modified version of msHOT. This work was supported by a Vidi Grant of The Netherlands Organisation for Scientific Research (to M.G.N.) and an FP6 European network of Excellence (BioMalPar) fellowship (to M.B.B.M.). The Servicios Generales de Investigacion/Ikerkuntzarako Zerbitsu Orokorrak-Servicios Generales-Ikerkuntza (SGI/IZO-SGIker) UPV/EHU (supported by the National Program for the Promotion of Human Resources within the National Plan of Scientific Research, Development and Innovation–Fondo Social Europeo, McyT, and the Basque Government) is gratefully acknowledged for generous allocation of computational resources.
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© 2007 by The National Academy of Sciences of the USA.
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Received: May 23, 2007
Published online: October 16, 2007
Published in issue: October 16, 2007
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Acknowledgments
We thank Garrett Hellenthal (University of Oxford, Oxford, U.K.) for kindly proving a modified version of msHOT. This work was supported by a Vidi Grant of The Netherlands Organisation for Scientific Research (to M.G.N.) and an FP6 European network of Excellence (BioMalPar) fellowship (to M.B.B.M.). The Servicios Generales de Investigacion/Ikerkuntzarako Zerbitsu Orokorrak-Servicios Generales-Ikerkuntza (SGI/IZO-SGIker) UPV/EHU (supported by the National Program for the Promotion of Human Resources within the National Plan of Scientific Research, Development and Innovation–Fondo Social Europeo, McyT, and the Basque Government) is gratefully acknowledged for generous allocation of computational resources.
Notes
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0704828104/DC1.
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The authors declare no conflict of interest.
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