Integrated human genome annotation: generation of a reference gene set

描述(由申请人提供)：这项建议的具体目标是在人类基因组参考序列上高精度地注释所有基于证据的基因特征。这包括识别所有编码蛋白质的基因座和相关的替代变异体、在公共核苷酸数据库(NCBI/EMBL/DDBJ)中有转录证据的非编码基因座和假基因。为了实现这一目标，我们将整合计算方法，包括最近的比较方法、专家手册注释、能够整合文献信息的方法，以及有针对性的实验方法。基于我们对ENCODE区域的初始GENCODE注释的详尽的实验和计算研究，我们有信心我们可以提供具有高度特异性和敏感性的基因集，这将为其他生物学家和其他ENCODE小组提供关键信息。作为这一过程的一部分，我们将清楚地标记所有明显的基因位点，根据它们可能的当前功能状态对它们进行分类，以便用户被告知哪里出现基因相似的区域最有可能是假基因，或者哪里的转录本证据最有可能是人工事实。在定义人类基因组的蛋白质编码基因领域，有许多积极的小组正在工作。该提案包括大多数此类小组，并与其他关键小组进行协调。关键是，所有小组都带来了丰富的数据集成和评估经验，导致通过多种方法解决注释差异。这给了我们信心，通过这个综合项目，我们将能够消除关于基因及其组成外显子和转录本结构在人类基因组中的准确位置的许多剩余不确定性。 全基因组、高度准确的转录本定义将对无数致力于人类基因组的研究人员具有巨大的价值。由于试剂设计的特异性增加，它将在全球范围内节省大量成本，并提供对人类基因的更完整的查看，特别是那些与疾病相关的基因。在此基础上，可以更准确地描述疾病的遗传原因。

DESCRIPTION (provided by applicant): The specific aim of this proposal is to annotate all the evidence-based gene features at high accuracy on the human genome reference sequence. This includes identifying all the protein-coding loci with associated alternative variants, non-coding loci which have transcript evidence available in the public nucleotide database (NCBI/EMBL/DDBJ) and pseudogenes. To achieve this goal we will integrate computational approaches, including recent comparative methods, expert manual annotation, able to integrate literature information, and targeted experimental approaches. Based on the exhaustive experimental and computation investigation of our initial GENCODE annotation of the ENCODE regions we are confident that we can deliver a gene set with high specificity and sensitivity that will provide critical information to other biologists and other ENCODE groups. As part of this process we will label all apparent gene loci clearly, classifying them according to their likely current functional status, so users are informed where regions that appear gene like are most likely pseudogenes or where transcript evidence is most likely artefactual. There are a number of motivated groups working in the area of defining protein coding genes for the human genome. This proposal includes most such groups and coordinates with other key groups. Critically, all the groups bring extensive experience of data integration and evaluation, leading to the resolution of annotation discrepancies by multiple approaches. This gives us confidence that through this integrated project we will be able to eliminate many of the remaining uncertainties about the precise location of genes and their component exons and transcript structure in the human genome. Genome-wide, highly accurate transcript definition will be of enormous value to the myriad of researchers working on the human genome. It will both have large cost savings worldwide due to increased specificity of reagent design and provide a more complete view of human genes, in particular those associated with disease. From this foundation, more accurate descriptions of the genetic causes of disease can be discovered.