Excess of rare amino acid polymorphisms in the toll-like receptor 4 in humans

The Toll-like receptor 4 protein acts as the transducing subunit of the lip opolysaccharide receptor complex and assists in (fie detection of Gram-nega tive pathogens within the mammalian host. Several lines of evidence support the view that variation at the TLR4 locus may alter host susceptibility to Gram-negative infection or the outcome of infection. Here, we surveyed TLR 4 sequence variation in the complete-coding region (2.4 kb) in 348 individu als from several population samples; in addition, a subset of the individua ls was surveyed at 1.1 kb of intronic sequence. More than 90% of the chromo somes examined encoded the same structural isoform of TLR4, while the rest harbored 12 rare amino acid variants. Conversely, the variants at silent si tes (intronic and synonymous positions) occur at both low and high frequenc ies and are consistent with a neutral model of mutation and random drift. T he spectrum of allele frequencies for amino acid variants shows a significa nt skew toward lower frequencies relative to both the neutral model and the pattern observed at linked silent sites. This is consistent with the hypot hesis weak purifying selection acted oil TLR4 and that most mutations affec ting TLR4 protein structure have at least mildly deleterious phenotypic eff ects. These results may imply that genetic variants contributing to disease susceptibility occur at low frequencies in the population and suggest stra tegies for optimizing the design of disease-mapping studies.