Phylogenetic variation and polymorphism at the toll-like receptor 4 locus (TLR4).
BACKGROUND
Differences in responses to bacterial surface lipopolysaccharides (LPSs) are apparent between and within mammalian species. It has been shown in mice that resistance to LPS is caused by defects in the Toll-like receptor 4 gene (Tlr4), the product of which is thought to bind LPS and mediate LPS signal transduction in immune system cells.


RESULTS
We have sequenced the Toll-like receptor 4 gene of humans (TLR4; 19.0 kilobases, kb) and mice (Tlr4; 91.7 kb), as well as the coding region and splice junctions of Tlr4 from 35 mouse (Mus musculus) strains, from the chimpanzee and from the baboon. No other discernible genes or regions of interspecies conservation lies close to Tlr4 and, in both humans and mice, flanking sequences and introns are rich in repeats of retroviral origin. Interstrain analyses reveal that Tlr4 is a polymorphic protein and that the extracellular domain is far more variable than the cytoplasmic domain, both among strains and among species. The cytoplasmic domain of the Tlr4 protein is highly variable at the carboxy-terminal end.


CONCLUSIONS
We suggest that selective evolutionary pressure exerted by microbes expressing structurally distinguishable LPS molecules has produced the high level of variability in the Tlr4 extracellular domain. The highly variable carboxy-terminal region of the cytoplasmic domain is likely to determine the magnitude of the response to LPS within a species.
Smirnova
I
I
The University of Texas Southwestern Medical Center and the Howard Hughes Medical Institute, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9050, USA.
Poltorak
A
A
Chan
E K
EK
McBride
C
C
Beutler
B
B
D000818:Animals; D006224:Cricetinae; D029721:Drosophila Proteins; D014644:Genetic Variation; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D002679:Pan troglodytes; D010215:Papio; D010802:Phylogeny; D011110:Polymorphism, Genetic / Q000235:genetics*; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors