Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function

• Published in: Frontiers in immunology 2024-05, Vol.15, p.1398935
• Main Authors: Hirayasu, Kouyuki, Khor, Seik-Soon, Kawai, Yosuke, Shimada, Mihoko, Omae, Yosuke, Hasegawa, Gen, Hashikawa, Yuko, Tanimoto, Hiromu, Ohashi, Jun, Hosomichi, Kazuyoshi, Tajima, Atsushi, Nakamura, Hiroyuki, Nakamura, Minoru, Tokunaga, Katsushi, Hanayama, Rikinari, Nagasaki, Masao
• Format: Article
• Language: English
• Subjects: Antigens, CD; deletion; DNA Copy Number Variations; Humans; Immunology; LILR; LILRA6; LILRB3; LILRB5; long-read sequencing; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Signal Transduction - genetics; Whole Genome Sequencing
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2024.1398935

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 genes, the genomic region surrounding and has yet to be fully characterized due to their significant sequence homology, which makes it difficult to differentiate between them. To examine the and 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 and was detected in three samples. Using long-read sequencing of these samples, we have discovered a novel large deletion (33,692 bp) in the and genomic regions in the Japanese population. This deletion spanned three genes, , , and , resulting in exons 12-13 being located immediately downstream of exons 1-12 with the loss of , suggesting the potential expression of a hybrid gene between and ( ). Transcription and subsequent translation of the 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 hybrid gene in the CEU population. Our findings provide insight into the genetic and functional diversity of the LILR family.