Mechanistic understanding of age-dependent genetic architecture

 描述(由申请人提供)： 包括常见疾病在内的大多数生物特征都有很强的遗传基础，但人们对此知之甚少。最近的研究表明，常见和罕见变异的复杂混合塑造了大多数生物特征--它们的确切影响是由广泛的遗传交互作用和生物年龄介导的。这些观察主要是相关的，因为人们对产生上位性和年龄依赖性的机制知之甚少。对这些过程的更好的理解可以确定有助于预测因果因素如何在新的遗传背景和治疗技术中发挥作用的原理，以利用它们的非线性效应来改善疾病。这项研究的广泛目标是识别影响线虫生殖的致病遗传变异，这些变异具有年龄相关的效应大小和上位性交互作用。一旦掌握，我们将在器官和多细胞电路功能的背景下机械地剖析它们的原因。我们将研究生活史是如何改变精子数量的，精子数量是生殖所必需的有限资源，创建与年龄相关的遗传结构。最后，我们将研究负责调节生殖的潜在神经回路是如何塑造上位和衰老的。这些实验将利用线虫的易操纵性来确定与人类疾病研究相关的原则。

 DESCRIPTION (provided by applicant): Most biological traits including common diseases have a strong but poorly understood genetic basis. Recent work suggests that a complex mixture of common and rare variants shape most biological traits - their exact effects mediated by extensive genetic interactions and organismal age. These observations are mainly correlative as little is known about the mechanisms that generate epistasis and age-dependence. Improved understanding of these processes could identify principals useful for predicting how causal factors act in novel genetic backgrounds and therapeutic techniques to take advantage of their non-linear effects to ameliorate disease. The broad objective of the proposed research is the identification of causative genetic variants affecting reproduction in C. elegans with age- dependent effect sizes and epistatic interactions. Once in hand, we will mechanistically dissect their causes in the context of organ and multicellular circuit function. We will study how life history changes in sperm number, a limited resource necessary for reproduction, creates age-dependent genetic architecture. Finally we will study how epistasis and aging are shaped by the function of the underlying neural circuit responsible for regulation of reproduction. These experiments will leverage C. elegans tractability to identify principles relevant to the study of human diseases.