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领域面临的重大挑战。许多旨在注释人类基因组的大型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。一种可能性是新蛋白是由内部核糖体进入位点介导的翻译事件的产物。例如，许多细胞IRESs与基因相关，其产物负责控制细胞生长和死亡。ires介导的翻译是否比之前认为的更普遍还有待观察，但一些人推测，多达10%的RNA转录本在其序列中嵌入了IRESs。这一观点得到了ires介导的翻译在体液免疫反应中产生MPD6蛋白的发现的支持。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，我们建议开发一种全基因组方法来寻找表现为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蛋白质组编码的程度和性质，这是一个完善的，非经典的翻译机制。由于已知ires介导的翻译发生在应激和改变条件下的细胞中，因此我们的结果对于理解疾病状态下的蛋白质表达将是非常宝贵的。通过对人类基因组和这些序列中编码的基因有一个更全面的认识，应该有可能认识到基因组中的缺陷是如何在特定的疾病形式中表现出来的。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.