The Duke FUNCTION Center: Pioneering the comprehensive identification of combinatorial noncoding causes of disease

摘要：改变基因调控元件活性的非编码遗传变异对 健康、疾病和进化。因为测量调节元件活性长期以来一直是一个主要挑战， 数以千计的基因与疾病之间的联系，其内在机制仍不清楚。最新进展 在高通量技术中，已经颠覆性地提高了测量个体活动的能力， 调控元件，以及这些方法的第一次人口和基因组规模的使用正在进行中。 然而，监管因素并不是单独行动的。它们与启动子、其他调控元件和启动子相互作用。 围绕着染色质，所有的方式都是复杂的，难以预测的。虽然现在有很多 技术，以衡量个别监管要素的活动，概括的影响， 调控元件的组合是非常不足的，严重阻碍了建立基因的努力。 对性状和疾病的调节作用。杜克功能卓越中心的目标是 基因组科学是使调控元件的组合活性的研究成为常规。目的 1是开发一套新的技术来测量调控元件的组合效应， 内源性基因组背景。这些技术将利用最近发现的CRISPR酶 除了Cas9，它极大地扩展了操纵人类基因组的能力。目标2是开发匹配的 计算，统计和进化模型需要解释和预测的测量效果， 调节变体的组合对人类性状和疾病的影响。目标3是展示广泛的适用性 通过对流行率从常见疾病到常见疾病的人类疾病的个案研究开发的技术 变成了超级稀有案例研究的例子将包括精神分裂症，罕见的隐性疾病， 未确诊的遗传疾病我们还将在全国范围内征求申请，以确定试点项目 这将扩大应用到其他疾病领域。目标4是建立一个电子平台， 从非编码基因组的功能研究的结果，以广泛的研究社区。该平台将 将我们的结果与其他实验室和联盟（如ENCODE）的研究结果相结合，并将使 具有不同专业知识的研究人员从中心受益。最后，我们的教育和推广目标是 扩大地方和国家的基因组学能力，并特别强调增加使用我们的新的 转化研究的技术。该项目的预期结果将是人类的范式转变 遗传学和基因组学，最终有可能了解完整的监管复杂性， 控制人类基因的表达。我们预计，这种能力将特别强大的翻译 基因关联到疾病机制，从而创造了关于哪些基因 对疾病的贡献最大，以及如何操纵这些基因以获得治疗益处。从长远来看，我们认为 这项工作对于实现全基因组测序检测疾病原因的全部潜力至关重要。

ABSTRACT: Noncoding genetic variation that alters gene regulatory element activity has major impacts on health, disease, and evolution. Because measuring regulatory element activity has long been a major challenge, the mechanisms underlying thousands of genetic associations with disease remain unknown. Recent advances in high-throughput technologies have disruptively advanced the ability to measure the activity of individual regulatory elements, and the first population- and genome-scale uses of those methods are now underway. However, regulatory elements do not act alone. They interact with promoters, other regulatory elements, and the surrounding chromatin, all in ways that are complex and difficult to predict. Though there are now a plethora of technologies to measure the activity of individual regulatory elements, the ability to recapitulate the effects of combinations of regulatory elements is woefully inadequate and severely hinders efforts to establish the gene regulatory contributions to traits and diseases. The goal of the Duke FUNCTION Center of Excellence in Genomic Science is to make the study of the combinatorial activity of regulatory elements routine. Aim 1 is to develop a suite of new technologies to measure the combinatorial effects of regulatory elements in their endogenous genomic contexts. Those technologies will leverage very recent discoveries of CRISPR enzymes other than Cas9 that greatly expand the ability to manipulate the human genome. Aim 2 is to develop the matched computational, statistical, and evolutionary models needed to interpret and predict the measured effects of combinations of regulatory variants on human traits and diseases. Aim 3 is to demonstrate the broad applicability of the technologies developed through case studies of human diseases with prevalence ranging from common to ultra rare. Example case studies will include studies of schizophrenia, rare recessive disorders, and undiagnosed genetic disorders. We will also use a nationwide request for applications to identify Pilot Projects that will expand applications to other disease areas. Aim 4 is to create an electronic platform for distributing results from functional studies of the noncoding genome to the broad research community. The platform will integrate our results with those from studies in other labs and consortia, such as ENCODE; and will enable researchers with diverse expertise to benefit from the Center. Finally, our Education and Outreach Aim is to expand genomics capacity locally and nationally, and with a particular emphasis on increasing use of our new technologies for translational research. The expected outcome of this project will be a paradigm shift in human genetic and genomics in which it will become possible to finally understand the full regulatory complexity that controls the expression of human genes. We anticipate that ability will be particularly powerful for translating genetic associations into disease mechanisms, thus creating a windfall of new knowledge about which genes contribute most to disease, and how to manipulate those genes for therapeutic benefit. Long term, we envision this work being critical to realizing the full potential of whole genome sequencing to detect causes of disease.