Yale Center for Mendelian Genomics

 描述(申请人提供)：这是耶鲁大学孟德尔基因组学中心的续签申请。将孟德尔突变与特征联系起来的生物学改变了我们对每个器官系统的理解，确定了治疗目标，并使临床前诊断和降低疾病风险成为可能。我们知道少于3,000个基因突变的后果。大约有19,000个蛋白质编码基因，其中绝大多数在系统发育过程中是保守的，即使考虑到30%的致命性，无疑还有数千个孟德尔基因座等待发现。如果不能更好地了解每个基因突变的后果，临床测序的充分利用就不会实现。强大的外显子组和基因组测序的出现为发现新的孟德尔性状基因座提供了前所未有的机会。在当前的周期中，通过对来自世界各地的研究人员的7000多个外显子进行测序，我们已经高度自信地确定了180个新的孟德尔性状基因座，35个表型扩展，以及数百个可能是一系列性状和遗传机制的新性状基因座，包括从头突变、不完全外显和复杂的罕见隐性性状。几个新的基因座具有直接的治疗意义。这些结果表明，许多新的性状基因座仍有待描述和解决，这促使人们努力完成人类的“Knock Out”图谱。我们现在建议，在现有研究的基础上，通过将高质量外显子组成本降低到330美元，通过对20,000多个样本进行测序，至少再识别500个性状基因座，以促进对基因组、健康和疾病的理解。

 DESCRIPTION (provided by applicant): This is a renewal application for the Yale Center for Mendelian Genomics. The biology linking Mendelian mutations to traits has transformed our understanding of every organ system, identifying therapeutic targets, and allowing preclinical diagnosis and mitigation of disease risk. We know the consequence of mutation of fewer than 3,000 genes. With ~19,000 protein-coding genes, the vast majority of which are conserved across phylogeny, even allowing for 30% lethality, there are doubtless thousands of Mendelian loci awaiting discovery. The full utility of clinical sequencing will not be realized without bette understanding of the consequence of mutation of every gene. The advent of robust exome and genome sequencing allows unprecedented opportunity for discovery of new Mendelian trait loci. In the current cycle, by sequencing more than 7000 exomes from investigators world-wide we have identified 180 new Mendelian trait loci with high confidence, 35 phenotypic expansions, and hundreds more that are likely new trait loci across a range of traits and genetic mechanisms, including de novo mutations, incomplete penetrance, and complex rare recessive traits. Several new loci have immediate therapeutic implications. These results underscore that many new trait loci remain to be described and solved, motivating efforts to complete the human `knock out' map. We now propose, by building upon the current studies and through reduction in high quality exome cost to $330, to identify at least another 500 trait loci via the sequencing of more than 20,000 samples, advancing the understanding of genomes, health and disease.