Lamarck Redux: Transgenerational genetic effects on phenotypes and disease

传统上，遗传学关注基因型和表型之间的直接关联， 个体这种对孟德尔遗传学原理的逻辑关注，导致了我们人类遗传学的一场革命。 了解基本的生物学过程和疾病遗传学。然而，这样的观察 作为全基因组关联研究中的“缺失遗传性”， 变异和疾病风险在重要方面是不完整的。此外，最近有几份报告称， 不同世代的相互作用基因和跨代遗传效应强烈表明， 存在替代的继承模式。这些报告涉及各种各样的胚胎和成年性状 并可能导致功能障碍和疾病，如胚胎死亡、癌症、肥胖和焦虑。 将表型归因于前几代的基因作用是一个基本而深刻的观察 这表明表观遗传（非DNA）和遗传（DNA）机制都指导遗传。我们 这些发现涉及RNA编辑，miRNA生物学，翻译控制以及可能的RNA颗粒。 这些跨代效应。拟议的工作将确定跨代的分子基础 影响和表征跨代表观遗传学的机制。我的成就 比较基因组学，神经管缺陷和睾丸癌的发育生物学， 肥胖和代谢疾病的生理遗传学，以及复杂性状的遗传结构 证明我的能力，以确定困难的问题，并作出重要贡献，在一个异常广泛的 各种生物医学领域。关于跨代遗传效应的拟议工作代表了一种新的 令人兴奋的研究领域，部分原因是它涉及的问题和技术，我渴望 学习，但更重要的是，因为结果可能会彻底改变我们对分子的理解， 遗传机制以及表型变异和疾病风险的评估。

Traditionally genetics has focused on direct associations between genotypes and phenotypes within individuals. This logical focus on principles of Mendelian genetics has led to a revolution in our understanding of fundamental biological processes and disease genetics. However, observations such as 'missing heritability' in genome-wide association studies suggest that our explanations for phenotypic variation and disease risk are incomplete in important ways. In addition, several recent reports of interacting genes in different generations and transgenerational genetic effects strongly suggest that alternative modes of inheritance exist. These reports involve a wide variety of embryonic and adult traits and can lead to dysfunctions and diseases such as embryonic lethality, cancer, obesity and anxiety. Attributing phenotypes to gene action in previous generations is a fundamental and profound observation that suggests that both epigenetic (non-DNA) and genetic (DNA) mechanisms guide inheritance. Our discoveries implicate RNA editing, miRNA biology, translation control as well as perhaps RNA granules in these transgenerational effects. Proposed work will identify the molecular basis for transgenerational effects and characterize the mechanisms for epigenetics across generations. My accomplishments in comparative genomics, the developmental biology of neural tube defects and testicular cancer, the physiological genetics of obesity and metabolic diseases, and the genetic architecture of complex traits demonstrate my ability to identify hard problems and make important contributions in an unusually wide variety of biomedical fields. The proposed work on transgenerational genetic effects represents a new and exciting area of research, partly because it involves questions and technologies that I am eager to learn, but more importantly because the results could revolutionize our understanding of the molecular mechanisms of inheritance as well as assessment of phenotypic variation and disease risk.