TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans.

Proc Natl Acad Sci U S A 2007 Oct 9;104(42):16645-50. Epub 2007 Oct 9.

Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0704828104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2034238PMC
October 2007
43 Reads
9.809 Impact Factor

Publication Analysis

Top Keywords

immune system
12
modern humans
12
migration modern
12
innate immune
8
evolutionary pressure
8
polymorphisms tlr4
8
infectious diseases
8
infectious pressures
4
genetic functional
4
europe genetic
4
asia europe
4
susceptibility severe
4
functional studies
4
shaped genetic
4
system infectious
4
increased susceptibility
4
infections contrast
4
pressures environments
4
distributions populations
4
allele cosegregation
4

References

(Supplied by CrossRef)

Allison et al.
BMJ 1954

Flint et al.
Nature; Physical Science (London) 1986

Agarwal et al.
Blood 2000

Dean et al.
Science 1996

Akira et al.
Nature reviews. Immunology 2004

Lemaitre et al.
Cell 1996

Poltorak et al.
Science 1998

Means et al.
The Journal of Immunology 1999

PNAS 2006

Journal of Infectious Diseases 2002

Rallabhandi et al.
The Journal of Immunology 2006

Similar Publications