Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2024
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| Online Access: | https://hdl.handle.net/10356/179907 |
| _version_ | 1811677997837582336 |
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| 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 |
| author2 | Singapore Centre for Environmental Life Sciences and Engineering |
| author_facet | Singapore Centre for Environmental Life Sciences and Engineering 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 |
| author_sort | Hirayasu, Kouyuki |
| collection | NTU |
| description | 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 signaling function. Further application of the JoGo-LILR tool to srWGS samples suggested the presence of the LILRB5-3 hybrid gene in the CEU population. Our findings provide insight into the genetic and functional diversity of the LILR family. |
| first_indexed | 2024-10-01T02:46:16Z |
| format | Journal Article |
| id | ntu-10356/179907 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:46:16Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1799072024-09-05T15:30:20Z Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function 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 Singapore Centre for Environmental Life Sciences and Engineering Medicine, Health and Life Sciences Inhibitory receptor Long-read sequencing 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 signaling function. Further application of the JoGo-LILR tool to srWGS samples suggested the presence of the LILRB5-3 hybrid gene in the CEU population. Our findings provide insight into the genetic and functional diversity of the LILR family. Published version The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by JSPS KAKENHI grant number JP23H02714 (KHi), JP21H02681 (MaN); AMED under grant number JP20gm6010021 (KHi), JP23wm0225036 (KHi), JP20ek0109492 (MaN), JP21wm0425009 (MaN), JP20ek0109485 (MaN), JP21ek0109548 (MaN), JP23ek0109675 (MaN), JP23ek0109672 (MaN); JST NBDC Grant Number JPMJND2302 (MaN), and the Naito Foundation (KHi). This work was partially supported by the “Joint Usage/Research Center for Interdisciplinary Large-scale Information Infrastructures” and “High Performance Computing Infrastructure” in Japan (Project ID: jh200047-NWH, jh210018- NWH, jh220014, and jh230016). 2024-09-02T06:25:19Z 2024-09-02T06:25:19Z 2024 Journal Article Hirayasu, K., Khor, S. S., Kawai, Y., Shimada, M., Omae, Y., Hasegawa, G., Hashikawa, Y., Tanimoto, H., Ohashi, J., Hosomichi, K., Tajima, A., Nakamura, H., Nakamura, M., Tokunaga, K., Hanayama, R. & Nagasaki, M. (2024). Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function. Frontiers in Immunology, 15, 1398935-. https://dx.doi.org/10.3389/fimmu.2024.1398935 1664-3224 https://hdl.handle.net/10356/179907 10.3389/fimmu.2024.1398935 38807600 2-s2.0-85194396342 15 1398935 en Frontiers in Immunology © 2024 Hirayasu, Khor, Kawai, Shimada, Omae, Hasegawa, Hashikawa, Tanimoto, Ohashi, Hosomichi, Tajima, Nakamura, Nakamura, Tokunaga, Hanayama and Nagasaki. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Inhibitory receptor Long-read sequencing 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 Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function |
| title | Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function |
| title_full | Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function |
| title_fullStr | Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function |
| title_full_unstemmed | Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function |
| title_short | Identification of the hybrid gene LILRB5-3 by long-read sequencing and implication of its novel signaling function |
| title_sort | identification of the hybrid gene lilrb5 3 by long read sequencing and implication of its novel signaling function |
| topic | Medicine, Health and Life Sciences Inhibitory receptor Long-read sequencing |
| url | https://hdl.handle.net/10356/179907 |
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