Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain
Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain
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DOI：
10.1038/s41380-019-0583-1
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发表时间：
2020-01-01
影响因子：
11
通讯作者：
Tunbridge, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Clark, Michael B.;Wrzesinski, Tomasz;Tunbridge, Elizabeth M.
RNA剪接是将遗传变异与精神疾病联系起来的关键机制。剪接谱在大脑中特别多样化，难以准确识别和量化。我们开发了一种新的方法来应对这一挑战，将远程PCR和纳米孔测序与新型生物信息学管道相结合。我们鉴定了CACNA1C在人脑中的全长编码转录本。CACNA1C是一种精神病风险基因，编码电压门控钙通道Ca（v）1.2。我们发现，CACNA1C的转录谱是大大超过赞赏，确定38个新的外显子和241个新的成绩单复杂。重要的是，许多新的变体是丰富的，并预测编码功能改变的通道。剪接模式在脑区域之间变化，特别是在小脑中。我们证明，人类转录本的多样性（从而蛋白质异构体的多样性）仍然不足的特点，并提供了一个可行的和具有成本效益的方法来解决这个问题。详细了解异构体的多样性将是必不可少的精神基因组研究结果转化为病理生理学的见解和新的精神药理学目标。
RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel Ca(v)1.2. We show that CACNA1C's transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.