新加坡国立大学Boxiang Liu研究团队发现，外周血单细胞RNA测序将细胞类型特异性的剪接调控，与自身免疫和炎症性疾病联系起来。相关论文于2024年12月3日在线发表在《自然—遗传学》杂志上。

据悉，可变剪接对复杂性状有贡献，但在不同遗传谱系的与性状相关的细胞类型中，是否存在差异仍不清楚。

研究人员描述了来自亚洲免疫多样性图谱的474名健康供体的，约100万个外周血单核细胞中的细胞类型特异性、性别偏向和谱系偏向的可变剪接。研究人员发现了广泛的性别偏向和谱系偏向的差异剪接，其中大部分是细胞类型特异性的。

研究人员识别了11577个独立的顺式剪接数量性状位点（sQTL）、607个反式s基因和107个动态sQTL。顺式eQTL与反式sQTL的共定位揭示了，HNRNPLL和PTPRC之间的细胞类型特异性调控关系。研究人员观察到，cis-sQTL效应在自身免疫和炎症性疾病的遗传易感性中富集。

具体来说，研究人员功能性验证了一个亚洲特异性的sQTL，该sQTL破坏了TCHP外显子4的5'剪接位点，推测其在东亚人群中调节格雷夫斯病的风险。该研究突显了祖先多样性对剪接的影响，并提供了一条单细胞分辨率下，剖析其在复杂疾病中作用的路线图。

附：英文原文

Title: Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases

Author: Tian, Chi, Zhang, Yuntian, Tong, Yihan, Kock, Kian Hong, Sim, Donald Yuhui, Liu, Fei, Dong, Jiaqi, Jing, Zhixuan, Wang, Wenjing, Gao, Junbin, Tan, Le Min, Han, Kyung Yeon, Tomofuji, Yoshihiko, Nakano, Masahiro, Buyamin, Eliora Violain, Sonthalia, Radhika, Ando, Yoshinari, Hatano, Hiroaki, Sonehara, Kyuto, Jin, Xin, Loh, Marie, Chambers, John, Hon, Chung-Chau, Choi, Murim, Park, Jong-Eun, Ishigaki, Kazuyoshi, Okamura, Tomohisa, Fujio, Keishi, Okada, Yukinori, Park, Woong-Yang, Shin, Jay W., Roca, Xavier, Prabhakar, Shyam, Liu, Boxiang

Issue&Volume: 2024-12-03

Abstract: Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5′ splice site of TCHP exon 4 that putatively modulates the risk of Graves’ disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution.

DOI: 10.1038/s41588-024-02019-8

Source: https://www.nature.com/articles/s41588-024-02019-8