SIGLEC16 encodes a DAP12‐associated receptor expressed in macrophages that evolved from its inhibitory counterpart SIGLEC11 and has functional and non‐functional alleles in humans

Sialic acid binding immunoglobulin‐like lectins (Siglec) are important components of immune recognition. The organization of Siglec genes in different species is consistent with rapid selection imposed by pathogens. We studied SIGLEC11 genes in human, rodent, dog, cow and non‐human primates. The lineages of SIGLEC11 genes in these species have undergone dynamic gene duplication and conversion, forming a potential inhibitory (SIGLEC11)/activating (SIGLEC16) receptor pair in chimpanzee and humans. A cDNA encoding human Siglec‐16, currently classed as a pseudogene in the databases (SIGLECP16), is expressed in various cell lines and tissues. A polymorphism screen for the two alleles (wild type and four‐base pair deletion, 4bpΔ) of SIGLEC16 found their frequencies to be 50% amongst the UK population. A search for donor sequences for SIGLEC16 revealed a subfamily of activating Siglec with charged transmembrane domains predicted to associate with ITAM‐encoding adaptor proteins. In support of this, Siglec‐16 was expressed at the cell surface in the presence of DAP12, but not the FcRγ chain. Using antisera specific to the cytoplasmic tail of Siglec‐16, we identified Siglec‐16 expression in CD14+ tissue macrophages and in normal human brain, cancerous oesophagus and lung. This is the first activating human Siglec receptor found to have functional and non‐functional alleles within the population.