Discovering a Hidden Proteome in the Human Genome

摘要：将基因组序列信息转化为功能信息是基础和应用生物医学中的重大挑战。许多旨在注释人类基因组的大规模计划的结果导致发现许多新的蛋白质和蛋白质形式存在于蛋白质组中。确定这些蛋白质是如何以及何时产生的，对于理解我们扩展的蛋白质组的大小至关重要。一种可能性是，新的蛋白质是由内部核糖体进入位点（IRES）介导的翻译事件的产物。例如，许多细胞IRES与其产物负责控制细胞生长和死亡的基因相关。IRES介导的翻译是否比以前认为的更普遍是一个观点问题，但有人推测高达10%的RNA转录物在其序列中嵌入了IRES。IRES介导的翻译负责在体液免疫应答中产生MPD6蛋白的发现支持了这一观点。不幸的是，由于我们无法在DNA水平上识别IRES特征，这一领域的科学进展受到了限制。在这里，我们建议开发一个全基因组的方法来寻找的图案，作为IRES和检查他们的优势在人类基因组中的行为。一个综合的实验生物信息学方法将被用来验证这些推定的IRES。这项研究的结果将阐明蛋白质组的范围和性质，这是由一个完善的，非经典的翻译机制编码。由于IRES介导的翻译已知发生在细胞中的压力和改变的条件下，我们的研究结果将是非常宝贵的理解蛋白质表达的疾病状态。通过对人类基因组和这些序列中编码的基因形成更全面的看法，应该有可能认识到基因组中的缺陷如何在特定的疾病形式中表现出来。预计这些知识将导致新的治疗干预措施，可用于改善人类状况。

DESCRIPTION (provided by applicant): Summary: Translating genome sequence information into functional information is a grand challenge in basic and applied biomedicine. Results from many large-scale programs designed to annotate the human genome have led to the discovery that many novel proteins and protein forms exist in the proteome. Determining how and when such proteins are made is essential to understanding the magnitude of our expanded proteome. One possibility is that novel proteins are a product of translation events mediated by internal ribosomal entry sites (IRESs). For example, many cellular IRESs associate with genes whose products are responsible for controlling cell growth and death. Whether IRES-mediated translation is more prevalent than previously thought is a matter of opinion, but some speculate that up to 10% of all RNA transcripts have IRESs imbedded in their sequences. This notion is supported by the discovery that IRES-mediated translation is responsible for making the MPD6 protein in the humoral immune response. Unfortunately, scientific progress in this area has been limited by our inability to identify IRES signatures at the DNA level. Here we propose to develop a genome-wide approach to finding motifs that behave as IRESs and examine their preponderance in the human genome. An integrated experimental-bioinformatics approach will be employed to validate these putative IRESs. Results from this study will illuminate the extent and nature of the proteome that is encoded by a well-established, non-classical translational mechanism. Because IRES-mediated translation is known to occur in cells under stress and in altered conditions, our results will be invaluable to understanding protein expression in disease states. By developing a more global view of the human genome and the genes encoded in these sequences, it should be possible to realize how defects in the genome manifest themselves in specific disease forms. It is expected that such knowledge will lead to new therapeutic interventions that can be used to improve the human condition.