Mechanistic understanding of age-dependent genetic architecture

 描述（由申请人提供）： 大多数生物特征，包括常见疾病，都有很强的遗传基础，但人们对遗传基础知之甚少。最近的研究表明，常见和罕见变异的复杂混合物塑造了大多数生物特征-它们的确切影响由广泛的遗传相互作用和生物体年龄介导。这些观察结果主要是相关的，因为对产生上位性和年龄依赖性的机制知之甚少。对这些过程的进一步理解可以确定用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，以利用其非线性效应来改善疾病。拟议研究的广泛目标是鉴定影响C.具有年龄依赖效应大小和上位性相互作用。一旦掌握，我们将在器官和多细胞回路功能的背景下机械地剖析其原因。我们将研究生活史如何改变精子数量，这是繁殖所必需的有限资源，创造了年龄依赖的遗传结构。最后，我们将研究上位性和衰老是如何由负责生殖调节的潜在神经回路的功能塑造的。这些实验将利用C。elegans的易处理性，以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.