School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia; Melbourne Integrative Genomics, University of Melbourne, Parkville, VIC 3010, Australia; Bioinformatics and Cellular Genomics, St Vincents Institute of Medical Research, Fitzroy, VIC 3065, Australia; Human Genomics and Evolution, St Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
Genome Diversity and Disease Laboratory, Mochtar Riady Institute of Nanotechnology, Tangerang 15811, Indonesia.
Am J Hum Genet. 2024 Nov 7;111(11):2458-2477. doi: 10.1016/j.ajhg.2024.09.004. Epub 2024 Oct 8.
One of the regulatory mechanisms influencing the functional capacity of genes is alternative splicing (AS). Previous studies exploring the splicing landscape of human tissues have shown that AS has contributed to human biology, especially in disease progression and the immune response. Nonetheless, this phenomenon remains poorly characterized across human populations, and it is unclear how genetic and environmental variation contribute to AS. Here, we examine a set of 115 Indonesian samples from three traditional island populations spanning the genetic ancestry cline that characterizes Island Southeast Asia. We conduct a global AS analysis between islands to ascertain the degree of functionally significant AS events and their consequences. Using an event-based statistical model, we detected over 1,500 significant differential AS events across all comparisons. Additionally, we identify over 6,000 genetic variants associated with changes in splicing (splicing quantitative trait loci [sQTLs]), some of which are driven by Papuan-like genetic ancestry, and only show partial overlap with other publicly available sQTL datasets derived from other populations. Computational predictions of RNA binding activity reveal that a fraction of these sQTLs directly modulate the binding propensity of proteins involved in the splicing regulation of immune genes. Overall, these results contribute toward elucidating the role of genetic variation in shaping gene regulation in one of the most diverse regions in the world.
影响基因功能能力的调控机制之一是可变剪接（AS）。之前探索人类组织剪接图谱的研究表明，AS 有助于人类生物学，特别是在疾病进展和免疫反应中。尽管如此，这种现象在人类群体中仍未得到充分描述，也不清楚遗传和环境变异如何导致 AS。在这里，我们研究了来自三个跨越特征为东南亚岛屿的遗传祖先梯度的传统岛屿人群的 115 个印度尼西亚样本。我们在岛屿之间进行了全面的 AS 分析，以确定具有功能意义的 AS 事件的程度及其后果。使用基于事件的统计模型，我们在所有比较中检测到超过 1500 个显著差异的 AS 事件。此外，我们还鉴定出超过 6000 个与剪接变化相关的遗传变异（剪接数量性状基因座 [sQTL]），其中一些是由巴布亚样遗传祖先驱动的，并且仅与其他源自其他人群的公开可用 sQTL 数据集部分重叠。对 RNA 结合活性的计算预测表明，这些 sQTL 中的一部分直接调节参与免疫基因剪接调节的蛋白质的结合倾向。总体而言，这些结果有助于阐明遗传变异在塑造世界上最多样化的地区之一的基因调控中的作用。
