An Interdisciplinary program for systems genomics of complex behaviors

描述(由申请人提供)：在本申请中，我们提出了一个非常雄心勃勃但现实可实现的目标：将北卡罗来纳大学-CH分校的现有专业知识结合成一个卓越的中心，以开发作为一种资源，并展示小鼠合作交叉(CC)的效用，以描绘来自精神病学的复杂表型的遗传和环境决定因素，这是所有生物医学中最棘手的一组问题。我们提出了一个特别具有挑战性的成功定义--我们将识别高概率病因模型(实际上可能很复杂)，然后通过产生新的小鼠品系来证明这些模型的预测能力，这些品系被培育成具有非常低或非常高的表型风险。一旦得到验证，这些高置信度模型就可以在随后的人体研究中进行测试。北卡罗来纳大学中心收集的数据将是更广泛的科学界的宝贵资源，可以用来询问任何数量的生物问题。开发复杂的用户交互数据库以访问收集的大型、复杂的数据集是该项目的一个关键组成部分。要实现这一首要目标，需要拥有丰富多样的科学专业知识--精神病学、人类遗传学、小鼠表型鉴定、小鼠遗传学、统计遗传学、计算生物学和系统生物学。所有这些学科的专家都深度参与了本申请的准备工作，并致力于这里所述的项目。此外，这些不同领域的成功整合并不是微不足道的；然而，我们可以证明，在这一应用程序中的所有科学家在过去五年中都有广泛的互动历史，现在知道如何合作，并对他们同事的专业知识有所了解。北卡罗来纳大学教堂山分校表现出对促进跨学科基因组学研究的强烈承诺，是美国最具合作精神的生物医学研究机构之一，为这里提出的“科学2.0”项目提供了肥沃的背景。公共卫生相关性精神障碍是一个悖论--相关的发病率、死亡率和社会成本是巨大的，然而，尽管进行了一个多世纪的科学研究，但关于核心疾病的病因学几乎没有确凿的事实。尽管GWAS的荟萃分析正在进行中，但早期的结果表明，强有力和可复制的发现是难以捉摸的。我们的建议提供了一种替代模型方法来补充基础精神表型的研究。

DESCRIPTION (provided by applicant): In this application, we propose a highly ambitious yet realistically attainable goal: to align existing expertise at UNC-CH into a center of excellence in order to develop as a resource and demonstrate the utility of the murine Collaborative Cross (CC) to delineate genetic and environmental determinants of complex phenotypes drawn from psychiatry, the most intractable set of problems in all of biomedicine. We propose a particularly challenging definition of success - we will identify high probability etiological models (which can be realistically complex) and then prove the predictive capacity of these models by generating novel strains of mice bred to be at either very low or very high risk of the phenotype. Once validated, these high confidence models can then be tested in subsequent human studies. The data collected at the UNC center would be a valuable resource to the wider scientific community and could be used to interrogate any number of biological problems. The development of sophisticated, user-interactive databases to access the large, complex datasets collected represents a key component of the project. Accomplishing this overarching goal requires an exceptional diversity of scientific expertise - psychiatry, human genetics, mouse phenotyping, mouse genetics, statistical genetics, computational biology, and systems biology. Experts in all of these disciplines were deeply involved in the preparation of this application and are committed to the projects described here. Moreover, successful integration of these diverse fields is non-trivial; however, we can document that all scientists on this application have a history of extensive interactions over the past five years, know now how to work together and have a working knowledge of their colleagues' expertise. UNC-Chapel Hill has a shown an intense commitment to promoting inter-disciplinary genomics research and is one of the most collegial biomedical research institutions in the US which provides a fertile backdrop for "Science 2.0" projects such as that proposed here. PUBLIC HEALTH RELEVANCE Psychiatric disorders are a paradox-the associated morbidity, mortality, and societal costs are enormous and yet, despite over a century of scientific study, there are few hard facts about the etiology of the core diseases. Although GWAS meta-analyses are in progress, early results suggest that strong and replicable findings are elusive. Our proposal provides an alternative model approach to complement the study of fundamental psychiatric phenotypes.