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.

中文翻译：

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分析印度尼西亚群岛的遗传驱动的选择性剪接


影响基因功能能力的调节机制之一是选择性剪接 （AS）。先前探索人体组织剪接景观的研究表明，AS 对人类生物学做出了贡献，尤其是在疾病进展和免疫反应方面。尽管如此，这种现象在人类人群中的特征仍然很差，并且尚不清楚遗传和环境变异如何导致 AS。在这里，我们检查了一组来自三个传统岛屿种群的 115 个印度尼西亚样本，这些样本跨越了东南亚岛屿的特征遗传祖先线。我们在岛屿之间进行全球 AS 分析，以确定功能上重要的 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 1,500 个显著的差异 AS 事件。此外，我们鉴定了 6,000 多个与剪接变化相关的遗传变异（剪接数量性状基因座 [sQTL]），其中一些由类似巴布亚的遗传祖先驱动，仅显示出与来自其他群体的其他公开可用的 sQTL 数据集的部分重叠。RNA 结合活性的计算预测表明，这些 sQTL 中的一小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地区之一的基因调控中的作用。