TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans.
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.
Ferwerda
Bart
B
Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
McCall
Matthew B B
MB
Alonso
Santos
S
Giamarellos-Bourboulis
Evangelos J
EJ
Mouktaroudi
Maria
M
Izagirre
Neskuts
N
Syafruddin
Din
D
Kibiki
Gibson
G
Cristea
Tudor
T
Hijmans
Anneke
A
Hamann
Lutz
L
Israel
Shoshana
S
ElGhazali
Gehad
G
Troye-Blomberg
Marita
M
Kumpf
Oliver
O
Maiga
Boubacar
B
Dolo
Amagana
A
Doumbo
Ogobara
O
Hermsen
Cornelus C
CC
Stalenhoef
Anton F H
AF
van Crevel
Reinout
R
Brunner
Han G
HG
Oh
Djin-Ye
DY
Schumann
Ralf R
RR
de la Rúa
Concepcion
C
Sauerwein
Robert
R
Kullberg
Bart-Jan
BJ
van der Ven
André J A M
AJ
van der Meer
Jos W M
JW
Netea
Mihai G
MG
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*
C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4