{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:58:43Z","timestamp":1790607523594,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T00:00:00Z","timestamp":1715644800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Leukocyte immunoglobulin (Ig)-like receptors (LILRs) on human chromosome 19q13.4 encode 11 immunoglobulin superfamily receptors, exhibiting genetic diversity within and between human populations. Among the <jats:italic>LILR<\/jats:italic> genes, the genomic region surrounding <jats:italic>LILRB3<\/jats:italic> and <jats:italic>LILRA6<\/jats:italic> has yet to be fully characterized due to their significant sequence homology, which makes it difficult to differentiate between them. To examine the <jats:italic>LILRB3<\/jats:italic> and <jats:italic>LILRA6<\/jats:italic> genomic region, a tool named JoGo-LILR CN Caller, which can call copy number from short-read whole genome sequencing (srWGS) data, was applied to an extensive international srWGS dataset comprising 2,504 samples. During this process, a previously unreported loss of both <jats:italic>LILRB3<\/jats:italic> and <jats:italic>LILRA6<\/jats:italic> was detected in three samples. Using long-read sequencing of these samples, we have discovered a novel large deletion (33,692 bp) in the <jats:italic>LILRB3<\/jats:italic> and <jats:italic>LILRA6<\/jats:italic> genomic regions in the Japanese population. This deletion spanned three genes, <jats:italic>LILRB3<\/jats:italic>, <jats:italic>LILRA6<\/jats:italic>, and <jats:italic>LILRB5<\/jats:italic>, resulting in <jats:italic>LILRB3<\/jats:italic> exons 12-13 being located immediately downstream of <jats:italic>LILRB5<\/jats:italic> exons 1-12 with the loss of <jats:italic>LILRA6<\/jats:italic>, suggesting the potential expression of a hybrid gene between <jats:italic>LILRB5<\/jats:italic> and <jats:italic>LILRB3<\/jats:italic> (<jats:italic>LILRB5-3<\/jats:italic>). Transcription and subsequent translation of the <jats:italic>LILRB5-3<\/jats:italic> hybrid gene were also verified. The hybrid junction was located within the intracellular domain, resulting in an LILRB5 extracellular domain fused to a partial LILRB3 intracellular domain with three immunoreceptor tyrosine-based inhibitory motifs (ITIMs), suggesting that LILRB5-3 acquired a novel signaling function. Further application of the JoGo-LILR tool to srWGS samples suggested the presence of the <jats:italic>LILRB5-3<\/jats:italic> hybrid gene in the CEU population. Our findings provide insight into the genetic and functional diversity of the LILR family.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1398935","type":"journal-article","created":{"date-parts":[[2024,5,14]],"date-time":"2024-05-14T04:51:28Z","timestamp":1715662288000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling 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