Discovering a Hidden Proteome in the Human Genome

描述(申请人提供)：摘要：将基因组序列信息转换为功能信息在基础和应用生物医学中是一个巨大的挑战。对人类基因组进行注释的许多大规模程序的结果导致发现蛋白质组中存在许多新的蛋白质和蛋白质形式。确定这些蛋白质是如何以及何时制造的，对于理解我们扩大的蛋白质组的规模是至关重要的。一种可能性是，新的蛋白质是由内部核糖体进入位点(IRESS)介导的翻译事件的产物。例如，许多细胞内的IRESS与其产物负责控制细胞生长和死亡的基因有关。IRES介导的翻译是否比之前认为的更普遍还是一个意见问题，但一些人推测，高达10%的RNA转录本的序列中嵌入了IRES。IRES介导的翻译负责在体液免疫反应中产生MPD6蛋白，这一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签名，这一领域的科学进步受到了限制。在这里，我们建议开发一种全基因组的方法来寻找表现为IRESS的基序，并检查它们在人类基因组中的优势。将采用综合实验-生物信息学方法来验证这些假定的IRESS。这项研究的结果将阐明由一种成熟的、非经典的翻译机制编码的蛋白质组的范围和性质。由于已知IRES介导的翻译发生在压力和条件改变的细胞中，我们的结果将对理解疾病状态下的蛋白质表达非常有价值。通过发展对人类基因组和这些序列中编码的基因的更全面的看法，应该可以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.