AUTHOR=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 

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

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1398935

DOI=10.3389/fimmu.2024.1398935

ISSN=1664-3224

ABSTRACT=<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 <italic>LILR</italic> genes, the genomic region surrounding <italic>LILRB3</italic> and <italic>LILRA6</italic> has yet to be fully characterized due to their significant sequence homology, which makes it difficult to differentiate between them. To examine the <italic>LILRB3</italic> and <italic>LILRA6</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 <italic>LILRB3</italic> and <italic>LILRA6</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 <italic>LILRB3</italic> and <italic>LILRA6</italic> genomic regions in the Japanese population. This deletion spanned three genes, <italic>LILRB3</italic>, <italic>LILRA6</italic>, and <italic>LILRB5</italic>, resulting in <italic>LILRB3</italic> exons 12-13 being located immediately downstream of <italic>LILRB5</italic> exons 1-12 with the loss of <italic>LILRA6</italic>, suggesting the potential expression of a hybrid gene between <italic>LILRB5</italic> and <italic>LILRB3</italic> (<italic>LILRB5-3</italic>). Transcription and subsequent translation of the <italic>LILRB5-3</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 <italic>LILRB5-3</italic> hybrid gene in the CEU population. Our findings provide insight into the genetic and functional diversity of the LILR family.</p>