title: TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans.
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.
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.forename: Matthew B B
authors.initials: MB
authors.lastname: McCall
authors.forename: Santos
authors.initials: S
authors.lastname: Alonso
authors.forename: Evangelos J
authors.initials: EJ
authors.lastname: Giamarellos-Bourboulis
authors.forename: Maria
authors.initials: M
authors.lastname: Mouktaroudi
authors.forename: Neskuts
authors.initials: N
authors.lastname: Izagirre
authors.forename: Din
authors.initials: D
authors.lastname: Syafruddin
authors.forename: Gibson
authors.initials: G
authors.lastname: Kibiki
authors.forename: Tudor
authors.initials: T
authors.lastname: Cristea
authors.forename: Anneke
authors.initials: A
authors.lastname: Hijmans
authors.forename: Lutz
authors.initials: L
authors.lastname: Hamann
authors.forename: Shoshana
authors.initials: S
authors.lastname: Israel
authors.forename: Gehad
authors.initials: G
authors.lastname: ElGhazali
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.forename: Oliver
authors.initials: O
authors.lastname: Kumpf
authors.forename: Boubacar
authors.initials: B
authors.lastname: Maiga
authors.forename: Amagana
authors.initials: A
authors.lastname: Dolo
authors.forename: Ogobara
authors.initials: O
authors.lastname: Doumbo
authors.forename: Cornelus C
authors.initials: CC
authors.lastname: Hermsen
authors.forename: Anton F H
authors.initials: AF
authors.lastname: Stalenhoef
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Djin-Ye
authors.initials: DY
authors.lastname: Oh
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.forename: Concepcion
authors.initials: C
authors.lastname: de la Rúa
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: André J A M
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D004641:Emigration and Immigration; D019143:Evolution, Molecular; D005260:Female; D006239:Haplotypes; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007239:Infections / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011153:Population / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4