Variants affecting exon skipping contribute to complex traits.
Variants affecting exon skipping contribute to complex traits.
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DOI：
10.1371/journal.pgen.1002998
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Lussier YA
中科院分区：
文献类型：
--
作者：
Lee Y;Gamazon ER;Rebman E;Lee Y;Lee S;Dolan ME;Cox NJ;Lussier YA
影响选择性剪接和不同基因转录物的相对数量的DNA变体已被证明是某些孟德尔疾病的风险等位基因。然而，对于任何单一贡献变体的低优势比特征的复杂性状，很少有研究调查剪接变体的贡献。本研究的总体目标是发现和表征影响选择性剪接的变异体在复杂性状的遗传病因学中可能发挥的作用，其中包括大量的常见人类疾病。具体而言，我们假设，剪接调控元件中的单核苷酸多态性（SNP）可以通过计算机模拟来表征，以识别影响剪接的变体，并且这些变体可能有助于复杂疾病的病因学以及个体间可变性转录物的比率。我们利用高通量表达谱来1）实验验证我们对跳过外显子的计算机预测，2）在复杂的人类性状和疾病背景下，表征内含子遗传变异在选择性剪接事件中的分子作用。我们认为内含子SNPs在剪接调控元件中起着遗传调控的作用，并表明其相关的外显子跳跃事件可以影响蛋白质结构域和结构。我们发现，我们将预测影响外显子跳跃的SNPs富集在一组SNPs中，这些SNPs被报道与复杂的人类特征相关。选择性剪接是一种常见的真核细胞机制，允许从一个基因产生多个蛋白质，并且在所有人类基因的40%-90%中发生。选择性剪接已被证明对许多关键的生物过程，包括发育，进化，甚至心理行为都很重要。此外，选择性剪接与15%-50%的人类遗传疾病（包括乳腺癌）有关;然而，遗传变异调节这一过程的确切机制仍有待充分阐明。在这项研究中，我们开发了一种综合的方法，利用基于序列的分析和全基因组表达谱，以确定可能影响选择性剪接的遗传变异。我们还评估了它们在已建立的疾病相关变异中的富集。我们的研究提供了对这些变异功能的深入了解，并强调了它们对复杂的人类特征和疾病的重要性。
DNA variants that affect alternative splicing and the relative quantities of different gene transcripts have been shown to be risk alleles for some Mendelian diseases. However, for complex traits characterized by a low odds ratio for any single contributing variant, very few studies have investigated the contribution of splicing variants. The overarching goal of this study is to discover and characterize the role that variants affecting alternative splicing may play in the genetic etiology of complex traits, which include a significant number of the common human diseases. Specifically, we hypothesize that single nucleotide polymorphisms (SNPs) in splicing regulatory elements can be characterized in silico to identify variants affecting splicing, and that these variants may contribute to the etiology of complex diseases as well as the inter-individual variability in the ratios of alternative transcripts. We leverage high-throughput expression profiling to 1) experimentally validate our in silico predictions of skipped exons and 2) characterize the molecular role of intronic genetic variations in alternative splicing events in the context of complex human traits and diseases. We propose that intronic SNPs play a role as genetic regulators within splicing regulatory elements and show that their associated exon skipping events can affect protein domains and structure. We find that SNPs we would predict to affect exon skipping are enriched among the set of SNPs reported to be associated with complex human traits. Alternative splicing is a common eukaryotic cellular mechanism that allows for the production of multiple proteins from one gene and occurs in 40%–90% of all human genes. Alternative splicing has been shown to be important for many critical biological processes, including development, evolution, and even psychological behavior. Additionally, alternative splicing has been associated with 15%–50% of human genetic diseases, including breast cancer; however, the precise mechanism by which genetic variations regulate this process remains to be fully elucidated. In this study, we develop an integrative approach that utilizes sequence-based analysis and genome-wide expression profiling to identify genetic variations that may affect alternative splicing. We also evaluate their enrichment among established disease-associated variations. Our study provides insights into the functionality of these variations and emphasizes their importance for complex human traits and diseases.
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影响因子：
12.3
作者：
Cirulli ET;Singh A;Shianna KV;Ge D;Smith JP;Maia JM;Heinzen EL;Goedert JJ;Goldstein DB;Center for HIV/AIDS Vaccine Immunology (CHAVI)
通讯作者：
Center for HIV/AIDS Vaccine Immunology (CHAVI)
剪接的组织特异性遗传控制：对复杂性状的研究的影响。
影响因子：
9.8
作者：
Heinzen EL;Ge D;Cronin KD;Maia JM;Shianna KV;Gabriel WN;Welsh-Bohmer KA;Hulette CM;Denny TN;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
12.3
作者：
通讯作者：
--
影响因子：
10.5
作者：
HUH, GS;HYNES, RO
通讯作者：
HYNES, RO
影响因子：
14.9
作者：
Hubbard, T;Barker, D;Clamp, M
通讯作者：
Clamp, M