Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship.
Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship.
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DOI：
10.1101/gr.230938.117
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发表时间：
2018-05
期刊：
影响因子：
7
通讯作者：
Roucou X
中科院分区：
文献类型：
--
作者：
Brunet MA;Levesque SA;Hunting DJ;Cohen AA;Roucou X
技术进步为全外显子组测序和人群蛋白质组学分析带来了前所未有的机会。目前，来自基因组和外显子组测序或蛋白质组学研究的数据针对参考基因组注释进行搜索。这为研究和临床筛选病理的遗传原因提供了基础。然而，目前的基因组注释大大低估了基因内编码的蛋白质组信息。许多研究已经证明了成熟基因转录本中替代（主要是小的，有时重叠）ORF的表达和功能。这对表型和基因型的相关性具有重要影响。由于缺乏证据，大多数替代ORF尚未注释，并且数据库中的这种缺失排除了通过标准蛋白质组学方法（如质谱法）对其进行检测。在这里，我们展示了当前的方法如何倾向于忽视替代ORF，阻碍了新的遗传驱动因素和基础研究的发现。我们讨论了现有的工具和技术，以提高识别蛋白质的替代ORF，并最终提出了一种新的注释系统，允许一个更完整的代表性的转录组和蛋白质组信息包含在一个基因。考虑到区分功能性ORF和随机ORF的关键挑战，建议的管道强调实验数据和保护签名。在数据库中添加替代ORF将使鉴定不那么偶然，并推进研究和基因组知识的步伐。这篇综述强调了医学和研究迫切需要将替代ORF纳入当前的基因组注释中，从而允许将其纳入与表型和基因型相关的假设和模型中。
Technological advances promise unprecedented opportunities for whole exome sequencing and proteomic analyses of populations. Currently, data from genome and exome sequencing or proteomic studies are searched against reference genome annotations. This provides the foundation for research and clinical screening for genetic causes of pathologies. However, current genome annotations substantially underestimate the proteomic information encoded within a gene. Numerous studies have now demonstrated the expression and function of alternative (mainly small, sometimes overlapping) ORFs within mature gene transcripts. This has important consequences for the correlation of phenotypes and genotypes. Most alternative ORFs are not yet annotated because of a lack of evidence, and this absence from databases precludes their detection by standard proteomic methods, such as mass spectrometry. Here, we demonstrate how current approaches tend to overlook alternative ORFs, hindering the discovery of new genetic drivers and fundamental research. We discuss available tools and techniques to improve identification of proteins from alternative ORFs and finally suggest a novel annotation system to permit a more complete representation of the transcriptomic and proteomic information contained within a gene. Given the crucial challenge of distinguishing functional ORFs from random ones, the suggested pipeline emphasizes both experimental data and conservation signatures. The addition of alternative ORFs in databases will render identification less serendipitous and advance the pace of research and genomic knowledge. This review highlights the urgent medical and research need to incorporate alternative ORFs in current genome annotations and thus permit their inclusion in hypotheses and models, which relate phenotypes and genotypes.
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影响因子：
7.7
作者：
Andreev DE;O'Connor PB;Fahey C;Kenny EM;Terenin IM;Dmitriev SE;Cormican P;Morris DW;Shatsky IN;Baranov PV
通讯作者：
Baranov PV
DOI：
10.1038/nrm4069
发表时间：
2015-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Brar GA;Weissman JS
通讯作者：
Weissman JS
影响因子：
4
作者：
Bertrand C;Valet P;Castan-Laurell I
通讯作者：
Castan-Laurell I
影响因子：
3
作者：
Shihab HA;Rogers MF;Ferlaino M;Campbell C;Gaunt TR
通讯作者：
Gaunt TR
DOI：
10.1073/pnas.0308758101
发表时间：
2004-06-01
影响因子：
11.1
作者：
Abramowitz, J;Grenet, D;Birnbaumer, L
通讯作者：
Birnbaumer, L