A new view of transcriptome complexity and regulation through the lens of local splicing variations.
A new view of transcriptome complexity and regulation through the lens of local splicing variations.
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DOI：
10.7554/elife.11752
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发表时间：
2016-02-01
期刊：
影响因子：
7.7
通讯作者：
Barash Y
中科院分区：
文献类型：
--
作者：
Vaquero-Garcia J;Barrera A;Gazzara MR;González-Vallinas J;Lahens NF;Hogenesch JB;Lynch KW;Barash Y
选择性剪接（AS）可以严重影响基因功能和疾病，但映射剪接变异仍然是一个挑战。在这里，我们提出了一种新的方法来定义和量化mRNA剪接的局部剪接变异（LSV）的单位。LSV捕获先前定义的可变剪接类型以及更复杂的转录变异。构建了第一个来自12个小鼠组织的LSV全基因组图谱，我们发现复杂的LSV构成了超过30%的组织依赖性转录变异，并影响特定的蛋白质家族。我们发现复杂LSV的流行在人类中是保守的，并确定了数百个LSV是特定于大脑亚区或改变阿尔茨海默氏症患者。其中包括Camk 2家族中的新型同种型和Ptbp 1中的新型毒物外显子，Ptbp 1是神经发生中的关键剪接因子。我们预计，这里提出的方法将提高与组织特异性剪接变异的遗传变异，表型和疾病的能力。DOI：http://dx.doi.org/10.7554/eLife.11752.001基因包含编码指令来构建其他分子，这些分子统称为基因产物。构建这些产物需要基因的指令在称为转录的过程中被复制到RNA分子中。超过90%的人类基因经历一个过程，通过该过程，转录的RNA分子的不同片段被去除或保留。这个过程被称为选择性剪接，导致单个基因编码不同的基因产物，这些基因产物可以以不同的方式发挥作用。选择性剪接也意味着基因产物在不同的细胞、组织和个体之间存在差异。其中一些变异可能是有害的，并导致疾病。然而，目前的方法很难准确地识别由于选择性剪接引起的基因产物的变异，并观察这些产物在人群（如患者和健康对照组）之间的差异。Vaquero-Garcia、Barrera、Gazzara等人现在已经开发了新的方法来定义、测量和可视化RNA基因产物中的变异。首先，从蜥蜴到人类的一系列物种的剪接变异被编目，这表明一些相当复杂的变异比以前认识到的要普遍得多。这些复杂的变异以前没有被研究过，但新方法表明，它们构成了从人类基因复制的RNA产物变异的三分之一。Vaquero-Garcia，Barrera，Gazzara等人随后表明，新方法比以前的方法更准确，更灵敏，可用于发现以前未知的剪接变异。例如，将新方法应用于其他研究中收集的数据，揭示了对大脑发育和活动至关重要的基因变异。进一步的分析表明，这些变化在阿尔茨海默病患者的大脑样本中也发生了变化。Vaquero-Garcia，Barrera，Gazzara等人开发的新方法现在可以为基因产物变异提供新的线索，特别是以前没有研究过的更复杂的变异。下一个挑战是使用这些工具来更好地了解剪接变体的调控和目的，以及它们如何导致人类疾病。DOI：http://dx.doi.org/10.7554/eLife.11752.002网站
Alternative splicing (AS) can critically affect gene function and disease, yet mapping splicing variations remains a challenge. Here, we propose a new approach to define and quantify mRNA splicing in units of local splicing variations (LSVs). LSVs capture previously defined types of alternative splicing as well as more complex transcript variations. Building the first genome wide map of LSVs from twelve mouse tissues, we find complex LSVs constitute over 30% of tissue dependent transcript variations and affect specific protein families. We show the prevalence of complex LSVs is conserved in humans and identify hundreds of LSVs that are specific to brain subregions or altered in Alzheimer's patients. Amongst those are novel isoforms in the Camk2 family and a novel poison exon in Ptbp1, a key splice factor in neurogenesis. We anticipate the approach presented here will advance the ability to relate tissue-specific splice variation to genetic variation, phenotype, and disease. DOI: http://dx.doi.org/10.7554/eLife.11752.001 Genes contain coded instructions to build other molecules that are collectively referred to as gene products. Building these products requires the gene’s instructions to be copied into a molecule of RNA in a process called transcription. Over 90% of human genes undergo a process by which different segments of the transcribed RNA molecule are either removed or retained. This process, termed alternative splicing, results in a single gene encoding different gene products that can perform in different ways. Alternative splicing can also mean that gene products vary between different cells, tissues and individuals. Some of these variations can be harmful and lead to disease. However, it is difficult with current methods to accurately identify variations in gene products that are due to alternative splicing and see how these products differ between groups of people, such as patients and healthy controls. Vaquero-Garcia, Barrera, Gazzara et al. have now developed new methods to define, measure and visualize the variations in RNA gene products. First, splicing variations were catalogued across a range of species from lizards to humans, which revealed that some fairly complicated variations were much more common than previously appreciated. These complex variations had not been studied much before, but the new methods showed that they make up a third of the variations in the RNA products copied from human genes. Vaquero-Garcia, Barrera, Gazzara et al. then showed that the new methods are more accurate and sensitive than previous methods, and can be used to discover splicing variations that were previously unknown. For example, applying the new methods to data collected in other studies revealed variations in genes that are important for brain development and activity. Further analysis then showed that these variations were also altered in brain samples from patients with Alzheimer disease. The new methods developed by Vaquero-Garcia, Barrera, Gazzara et al. can now shed new light on gene product variations, especially the more complex ones that have not been studied before. The next challenge is to use these tools to better understand the regulation and purpose of splicing variants and how they can contribute to diseases in humans. DOI: http://dx.doi.org/10.7554/eLife.11752.002