Profiling genetically driven alternative splicing across the Indonesian archipelago.

IF 8.1 1区 生物学 Q1 GENETICS & HEREDITY American journal of human genetics Pub Date : 2024-11-07 Epub Date: 2024-10-08 DOI:10.1016/j.ajhg.2024.09.004
Neke Ibeh, Pradiptajati Kusuma, Chelzie Crenna Darusallam, Safarina G Malik, Herawati Sudoyo, Davis J McCarthy, Irene Gallego Romero
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Abstract

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.

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剖析印度尼西亚群岛的基因驱动替代剪接。
替代剪接(AS)是影响基因功能的调控机制之一。以前对人体组织剪接情况的研究表明,AS 对人类生物学,尤其是疾病进展和免疫反应有很大的影响。然而,这一现象在人类群体中的特征仍然不明显,遗传和环境变异是如何导致AS的还不清楚。在这里,我们研究了一组来自三个传统岛屿人群的 115 个印度尼西亚样本,这些样本跨越了东南亚岛屿的遗传祖先系。我们对岛屿之间的AS进行了全面分析,以确定功能上重要的AS事件的程度及其后果。利用基于事件的统计模型,我们在所有比较中发现了超过 1,500 个显著差异的 AS 事件。此外,我们还发现了 6000 多个与剪接变化相关的遗传变异(剪接定量性状位点 [sQTLs]),其中一些是由类似巴布亚人的遗传祖先驱动的,并且只与其他公开的来自其他人群的 sQTL 数据集有部分重叠。对 RNA 结合活性的计算预测显示,这些 sQTLs 中的一部分直接调节了参与免疫基因剪接调控的蛋白质的结合倾向。总之,这些结果有助于阐明遗传变异在世界上最多样化地区之一的基因调控中的作用。
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来源期刊
CiteScore
14.70
自引率
4.10%
发文量
185
审稿时长
1 months
期刊介绍: The American Journal of Human Genetics (AJHG) is a monthly journal published by Cell Press, chosen by The American Society of Human Genetics (ASHG) as its premier publication starting from January 2008. AJHG represents Cell Press's first society-owned journal, and both ASHG and Cell Press anticipate significant synergies between AJHG content and that of other Cell Press titles.
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