Kouyuki Hirayasu ^1,2,3,4* Seik-Soon Khor ^5,6 Yosuke Kawai ⁵ Mihoko Shimada ⁵ Yosuke Omae ⁵ Gen Hasegawa ³ Yuko Hashikawa ⁷ Hiromu Tanimoto ⁴ Jun Ohashi ⁸ Kazuyoshi Hosomichi ⁹ Atsushi Tajima ¹⁰ Hiroyuki Nakamura ¹¹ Minoru Nakamura ^12,13,14,15 Katsushi Tokunaga ⁵ Rikinari Hanayama ^1,3,4,7 Masao Nagasaki ^15,16

• ¹ Advanced Preventive Medical Sciences Research Center, Kanazawa University, Kanazawa, Japan
• ² Department of Evolutionary Immunology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
• ³ Department of Immunology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
• ⁴ Department of Immunology, School of Medical and Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
• ⁵ Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
• ⁶ Singapore Centre for Environmental Life Science Engineering, Nanyang Technological University, Singapore, Singapore
• ⁷ Nano Life Science Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
• ⁸ Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
• ⁹ Laboratory of Computational Genomics, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
• ¹⁰ Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
• ¹¹ Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
• ¹² Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Japan
• ¹³ Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
• ¹⁴ Headquarters of Primary Biliary Cholangitis (PBC) Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
• ¹⁵ Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
• ¹⁶ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

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 LILR genes, the genomic region surrounding LILRB3 and LILRA6 has yet to be fully characterized due to their significant sequence homology, which makes it difficult to differentiate between them. To examine the LILRB3 and LILRA6 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 LILRB3 and LILRA6 was detected in three samples. Using long-read sequencing of these samples, we have discovered a novel large deletion (33,692 bp) in the LILRB3 and LILRA6 genomic regions in the Japanese population. This deletion spanned three genes, LILRB3, LILRA6, and LILRB5, resulting in LILRB3 exons 12-13 being located immediately downstream of LILRB5 exons 1-12 with the loss of LILRA6, suggesting the potential expression of a hybrid gene between LILRB5 and LILRB3 (LILRB5-3). Transcription and subsequent translation of the LILRB5-3 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 signalling function. Further application of the JoGo-LILR tool to srWGS samples suggested the presence of the LILRB5-3 hybrid gene in the CEU populations. Our findings provide insight into the genetic and functional diversity of the LILR family.