Recognition of unknown conserved alternatively spliced exons.
Recognition of unknown conserved alternatively spliced exons.
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DOI：
10.1371/journal.pcbi.0010015
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发表时间：
2005-07
影响因子：
4.3
通讯作者：
Burge CB
中科院分区：
文献类型：
--
作者：
Ohler U;Shomron N;Burge CB
大多数哺乳动物蛋白质编码基因的分裂结构使得通过可变剪接（AS）过程从单个基因位点产生多种不同的mRNA和蛋白质异构体成为可能。我们提出一种基于成对隐马尔可夫模型的计算方法，称为UNCOVER，用于发现迄今为止尚未被检测到的受AS影响的保守编码外显子序列。将UNCOVER应用于已知人类和小鼠基因的直系同源内含子，可预测在两个物种中都存在的跳跃外显子或保留内含子，同时将它们与保守的非编码序列区分开来。该模型的准确性通过一组经过整理的具有已知保守AS事件的基因进行评估。对由ENCODE区域所代表的约1%的人类基因组中跳跃外显子的预测产生了50多个新的外显子候选者。通过对15个具有强烈UNCOVER预测且缺乏EST证据的内含子进行RT - PCR和测序分析，验证了5个新预测的AS外显子。这些结果意味着在已知基因的当前注释中仍然完全缺失大量保守的外显子序列和相关异构体。UNCOVER还识别出少量保守内含子保留的候选者。
可变剪接是一种一个基因可产生不止一种蛋白质变体的过程：在加工成成熟转录本的过程中，mRNA前体的特定部分被包含或排除。它在哺乳动物基因组中非常普遍，并且变体通常对特定的细胞类型、发育状态或环境变化具有特异性。直到最近，此类变体的鉴定仅仅依赖于表达序列标签（ESTs）的测序和比较，但可用的ESTs数量不足以涵盖所有条件下的所有变体。
奥勒等人现在设计了一种基于成对隐马尔可夫模型的比较基因组学算法，该算法可识别基因中那些经过可变剪接且在ESTs中未被观察到的部分。从人类和小鼠中保守的已知注释基因出发，他们扫描这些基因的相应内含子对，以识别与模型匹配的保守序列。对一些新预测的实验验证表明，该方法能够成功地揭示尚未知晓且不属于大型EST文库的剪接变体。与最近提出的互补计算方法一起，这种方法有助于我们完善对可变剪接所产生的转录本多样性的认识。
The split structure of most mammalian protein-coding genes allows for the potential to produce multiple different mRNA and protein isoforms from a single gene locus through the process of alternative splicing (AS). We propose a computational approach called UNCOVER based on a pair hidden Markov model to discover conserved coding exonic sequences subject to AS that have so far gone undetected. Applying UNCOVER to orthologous introns of known human and mouse genes predicts skipped exons or retained introns present in both species, while discriminating them from conserved noncoding sequences. The accuracy of the model is evaluated on a curated set of genes with known conserved AS events. The prediction of skipped exons in the ~1% of the human genome represented by the ENCODE regions leads to more than 50 new exon candidates. Five novel predicted AS exons were validated by RT-PCR and sequencing analysis of 15 introns with strong UNCOVER predictions and lacking EST evidence. These results imply that a considerable number of conserved exonic sequences and associated isoforms are still completely missing from the current annotation of known genes. UNCOVER also identifies a small number of candidates for conserved intron retention. Alternative splicing is a process in which more than one protein variant can be produced from one gene: Specific parts of the mRNA precursor are included or excluded during the processing into the mature transcript. It is very prevalent in mammalian genomes, and variants are often specific for particular cell types, developmental states, or environmental changes. The identification of such variants has until recently relied solely on the sequencing and comparison of expressed sequence tags (ESTs), but the number of available ESTs is not large enough to cover all variants under all conditions. Ohler et al. have now devised a comparative genomics algorithm based on a pair hidden Markov model, which identifies parts of genes that are alternatively spliced and have not been observed in ESTs. Starting from known annotated genes conserved in human and mouse, they scan corresponding intron pairs of these genes to identify conserved sequences that match the model. Experimental validation of a number of new predictions show that the approach can successfully uncover splice variants that are as yet unknown and not part of the large libraries of ESTs. Together with recently proposed complementary computational methods, this approach helps us to complete our knowledge about the transcript diversity created by alternative splicing.
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