Lamarck Redux: Transgenerational genetic effects on phenotypes and disease

Lamarck Redux：跨代遗传对表型和疾病的影响

基本信息

批准号：
8722583
负责人：
JOSEPH H. NADEAU
金额：
$ 87.23万
依托单位：
PACIFIC NORTHWEST RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8722583
关键词：
Adult Affect Anxiety Apoptosis Architecture Area Attenuated Behavior Biological Process Biology Cell Proliferation Cellular biology Characteristics Collaborations Complex Cytoplasmic Granules DNA Daughter Dependency Development Developmental Biology Developmental Process Diet Disease ES Cell Line Embryo Embryonic Development Epigenetic Process Functional disorder Gene Expression Generations Genes Genetic Genotype Germ Cells Hereditary Disease Heritability Histones In Vitro Individual Lead Learning Location Long-Term Effects Malignant Neoplasms Malignant neoplasm of testis Mediating Messenger RNA Metabolic Diseases Methylation MicroRNAs Modeling Molecular Mus Neural Tube Defects Obesity Outcome Parents Phenotype Physiological Predisposition Principal Investigator Process Proteomics RNA RNA Editing Redux Reporting Research Risk Role Signal Transduction Source Stem Cell Factor Suggestion System Technology Testing Time Tissues Translations Universities Utah Variant Washington Work base comparative genomics disease phenotype disorder risk egg embryonic stem cell essays gene discovery gene function genome wide association study genome-wide in vivo offspring paralogous gene programs receptor research study response sperm cell trait

项目摘要

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.

传统上，遗传学关注的是基因型和表型之间的直接关联。个人。这种对孟德尔遗传学原理的逻辑关注导致了我们的革命。了解基本的生物过程和疾病遗传学。然而，诸如此类的观察因为全基因组关联研究中的“遗传性缺失”表明我们对表型的解释变异和疾病风险在重要方面是不完整的。此外，最近的几份报告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。这些报告涉及多种胚胎和成人特征并可能导致胚胎死亡、癌症、肥胖和焦虑等功能障碍和疾病。将表型归因于前几代的基因作用是一项基本而深刻的观察这表明表观遗传（非 DNA）和遗传（DNA）机制都指导着遗传。我们的这些发现涉及 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并表征跨代表观遗传学的机制。我的成就在比较基因组学、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展示我识别难题并在异常广泛的领域做出重要贡献的能力各种生物医学领域。拟议的跨代遗传效应工作代表了一种新的方法和令人兴奋的研究领域，部分原因是它涉及我渴望了解的问题和技术学习，但更重要的是因为结果可能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。