A system approach to the analysis of Heterotaxy Candiate Genes

描述(申请人提供)：先天畸形是美国和欧洲婴儿死亡的主要原因。然而，我们对先天性畸形的遗传原因了解很少。为了发现这些遗传原因，我们和其他人在患者身上进行了人类基因组学分析。我们特别关注的是异质性，这是一种左右格局的紊乱。正常情况下，我们的内部器官沿左右轴不对称分布，如果做不到这一点，可能会导致严重的疾病，包括先天性心脏病、肠道旋转不良和免疫缺陷。人类对这些患者的遗传分析已经确定了许多候选基因，但这些基因的功能相关性尚不清楚，因为对大多数患者来说，没有强有力的遗传学证据(第二无关等位基因)。此外，这些基因是多样的，并不属于明确的途径-事实上，巨大的 这些候选基因中的大多数都是从左到右模式的新基因。为此，我们提出了一种系统的方法来分析这些异质性候选基因。我们将首先根据现有的遗传证据对这些基因进行优先排序，然后使用无偏见的方法，包括基因表达、功能获得和功能丧失分析，以使用我们的高通量模型Xenopus来确定这些基因中哪些在左右模式中发挥作用。我们的初步结果表明，许多但不是所有这些候选基因对左右图案的形成都是重要的。然后，我们将采取一种公正的系统方法，将这些异质性候选基因置于左右信号基因调控网络中。我们的初步结果表明，这种系统方法识别了不同途径之间意想不到的和有趣的桥梁，识别了已知基因未预期的功能，并识别了未知功能基因的特定功能。通过这种方式，我们希望提高我们对异位融合的理解，并开发出一种通用的模型来处理许多先天性畸形。

DESCRIPTION (provided by applicant): Congenital malformations are the major cause of infant mortality in the US and Europe. However, we have a poor understanding of the genetic causes of congenital malformations. In order to discover these genetic causes, we and others have employed human genomics analyses on patients. In particular we have focused on Heterotaxy, a disorder of left-right patterning. Normally, our internal organs are asymmetrically distributed along the left-right axis and failure to do so can lead to severe disease including congenital heart disease, gut malrotation, and immune deficiencies. Human genetic analysis of these patients has identified many candidate genes, but the functional relevance of these genes is unclear since strong genetic evidence (second unrelated alleles) is not available for most of them. In addition, these genes are diverse and do not fall into clear pathways~ in fact, the vast majority of these candidate genes are novel to left-right patterning. For this reason, we propose a systems approach to the analysis of these heterotaxy candidate genes. We will first prioritize these genes based on available genetic evidence and then use an unbiased approach, which will include gene expression, gain of function, and loss of function analysis to determine which of these genes play a role in left- right patterning using our high-throughput model, Xenopus. Our preliminary results indicate that many but not all of these candidate genes are important for left-right patterning. Then we will take an unbiased systems approach to placing these heterotaxy candidate genes into the left-right signaling gene regulatory network. Our preliminary results demonstrate that this systems approach identifies unexpected and interesting bridges between different pathways and identifies functions not otherwise expected of known gene and identifies specific functions of genes with no known function. In this way, we hope to improve our understanding of heterotaxy and develop a general model to approach many congenital malformations.