Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms

Jun Inamo, Akari Suzuki, Mahoko Takahashi Ueda, Kensuke Yamaguchi, Hiroshi Nishida, Katsuya Suzuki, Yuko Kaneko, Tsutomu Takeuchi, Hiroaki Hatano, Kazuyoshi Ishigaki, Yasushi Ishihama, Kazuhiko Yamamoto and Yuta Kochi ()
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Jun Inamo: Tokyo Medical and Dental University (TMDU)
Akari Suzuki: RIKEN Center for Integrative Medical Sciences
Mahoko Takahashi Ueda: Tokyo Medical and Dental University (TMDU)
Kensuke Yamaguchi: Tokyo Medical and Dental University (TMDU)
Hiroshi Nishida: Kyoto University
Katsuya Suzuki: Keio University School of Medicine
Yuko Kaneko: Keio University School of Medicine
Tsutomu Takeuchi: Keio University School of Medicine
Hiroaki Hatano: RIKEN Center for Integrative Medical Sciences
Kazuyoshi Ishigaki: RIKEN Center for Integrative Medical Sciences
Yasushi Ishihama: Kyoto University
Kazuhiko Yamamoto: RIKEN Center for Integrative Medical Sciences
Yuta Kochi: Tokyo Medical and Dental University (TMDU)

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Alternative splicing events are a major causal mechanism for complex traits, but they have been understudied due to the limitation of short-read sequencing. Here, we generate a full-length isoform annotation of human immune cells from an individual by long-read sequencing for 29 cell subsets. This contains a number of unannotated transcripts and isoforms such as a read-through transcript of TOMM40-APOE in the Alzheimer’s disease locus. We profile characteristics of isoforms and show that repetitive elements significantly explain the diversity of unannotated isoforms, providing insight into the human genome evolution. In addition, some of the isoforms are expressed in a cell-type specific manner, whose alternative 3’-UTRs usage contributes to their specificity. Further, we identify disease-associated isoforms by isoform switch analysis and by integration of several quantitative trait loci analyses with genome-wide association study data. Our findings will promote the elucidation of the mechanism of complex diseases via alternative splicing.

Date: 2024
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DOI: 10.1038/s41467-024-48615-4

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