Lamarck Redux: Transgenerational genetic effects on phenotypes and disease

描述 摘要： 传统遗传学关注个体内基因型和表型之间的直接关联。这种对孟德尔遗传学原理的逻辑关注导致了我们对基本生物学过程和疾病遗传学的理解的革命。然而，全基因组关联研究中的“缺失遗传性”等观察结果表明，我们对表型变异和疾病风险的解释在重要方面是不完整的。此外，最近几份关于不同世代的基因相互作用和跨代遗传效应的报告强烈表明存在替代的遗传模式。这些报告涉及各种各样的胚胎和成人特征，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，表明表观遗传（非DNA）和遗传（DNA）机制都指导遗传。我们的发现涉及RNA编辑，miRNA生物学，翻译控制以及可能的RNA颗粒在这些跨代效应。拟议的工作将确定跨代效应的分子基础，并表征跨代表观遗传学的机制。我在比较基因组学，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方面的成就表明我有能力识别困难的问题，并在各种各样的生物医学领域做出重要贡献。关于跨代遗传效应的拟议工作代表了一个新的令人兴奋的研究领域，部分原因是它涉及我渴望学习的问题和技术，但更重要的是，因为这些结果可能会彻底改变我们对遗传的分子机制以及表型评估的理解。

DESCRIPTION Abstract: 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 phenotyp