The heterogeneous allelic repertoire of human toll-like receptor (TLR) genes.
Toll-Like Receptors (TLR) are critical elements of the innate arm of the vertebrate immune system. They constitute a multigenic family of receptors which collectively bind a diverse array of--exogeneous as well as endogeneous--ligands. An exponential burst of knowledge has defined their biological role in fight against infections and generation/modulation of auto-immune disorders. Hence, they could at least be conceptually recognized--despite being structurally unrelated - as innate counterparts to Major Histocompatibility Complex (MHC) molecules--equally recognizing antigenic ligands (albeit structurally more homogeneous i.e., peptides), again derived from self and/or non-self sources--preeminent this time in adaptive immunity. Our great disparities in face of infections and/or susceptibility to auto-immune diseases have provoked an intense search for genetic explanations, in part satisfied by the extraordinary MHC allelic repertoire. An equally in-depth and systematic analysis of TLR diversity is lacking despite numerous independent reports of a growing number of SNPs within these loci. The work described here aims at providing a preliminary picture of the allelic repertoire--and not purely SNPs--of all 10 human TLR coding sequences (with exception of TLR3) within a single cohort of up to 100 individuals. It appears from our work that TLR are unequally polymorphic: TLR2 (DNA alleles: 7/protein alleles: 3), 4 (4/3), 7 (6/3), 8 (9/2) and 9 (8/3) being comparatively least diverse whereas TLR1 (11/10), 5 (14/12), 6 (10/8) and 10 (15/10) show a substantial number of alleles. In addition to allelic assignment of a large number of SNPs, 10 new polymorphic positions were hereby identified. Hence this work depicts a first overview of the diversity of almost all human TLR genes, a prelude for large-scale population genetics as well as genetic association studies.
Georgel
Philippe
P
Laboratoire d'Immunogénétique Moléculaire Humaine, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
Macquin
Cécile
C
Bahram
Seiamak
S
D000483:Alleles; D003001:Cloning, Molecular; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D019281:Dimerization; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D008024:Ligands; D008957:Models, Genetic; D009841:Oligonucleotides / Q000235:genetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D051193:Toll-Like Receptors / Q000235:genetics* / Q000378:metabolism
D008024:Ligands; D009841:Oligonucleotides; D051193:Toll-Like Receptors; D004247:DNA