title: Haplotype structure and positive selection at TLR1.
abstract: Toll-like receptor 1, when dimerized with Toll-like receptor 2, is a cell surface receptor that, upon recognition of bacterial lipoproteins, activates the innate immune system. Variants in TLR1 associate with the risk of a variety of medical conditions and diseases, including sepsis, leprosy, tuberculosis, and others. The foremost of these is rs5743618 c.2079T>G(p.(Ile602Ser)), the derived allele of which is associated with reduced risk of sepsis, leprosy, and other diseases. Interestingly, 602Ser, which shows signatures of selection, inhibits TLR1 surface trafficking and subsequent activation of NFκB upon recognition of a ligand. This suggests that reduced TLR1 activity may be beneficial for human health. To better understand TLR1 variation and its link to human health, we have typed all 7 high-frequency missense variants (>5% in at least one population) along with 17 other variants in and around TLR1 in 2548 individuals from 56 populations from around the globe. We have also found additional signatures of selection on missense variants not associated with rs5743618, suggesting that there may be multiple functional alleles under positive selection in this gene.
authors.affiliation: 1] Department of Genetics, Yale University, New Haven, CT, USA [2] Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Heffelfinger
authors.affiliation: Department of Genetics, Yale University, New Haven, CT, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pakstis
authors.affiliation: Department of Genetics, Yale University, New Haven, CT, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Speed
authors.affiliation: Department of Genetics, Yale University, New Haven, CT, USA.
authors.forename: Allison P
authors.initials: AP
authors.lastname: Clark
authors.affiliation: Department of Genetics, Yale University, New Haven, CT, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Haigh
authors.affiliation: Life Technologies, Foster City, CA, USA.
authors.forename: Rixun
authors.initials: R
authors.lastname: Fang
authors.affiliation: 1] Life Technologies, Foster City, CA, USA [2] President & Founder, Biology for Global Good, Sam Ramon, CA, USA.
authors.forename: Mahohar R
authors.identifier: 0000000250000856
authors.initials: MR
authors.lastname: Furtado
authors.affiliation: Department of Genetics, Yale University, New Haven, CT, USA.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Kidd
authors.affiliation: Department of Genetics, Stanford University, Palo Alto, CA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Snyder
mesh_terms: D000483:Alleles; D056426:Genetic Loci; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface; D012641:Selection, Genetic; D051194:Toll-Like Receptor 1 / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D011956:Receptors, Cell Surface; D051194:Toll-Like Receptor 1