CRSPR II Supplement: Consortium for the production and cryopreservation of knockout mice

参考人类基因组的注释已经确定了大约20,000个蛋白质编码基因 以及3000个非编码RNA。这些基因共同协调着生物体的发育， 支持细胞、组织、器官系统以及生理和行为的所有方面的功能。这个 10000基因组计划揭示了人类基因组中超乎寻常的多样性水平，但对大多数基因来说 既不知道正常版本的功能，也不知道功能丧失变体的疾病后果。 老鼠提供了一条了解基因及其变种功能的途径。虚拟共享 在发育、生理、解剖和代谢方面与人类相似，这在健康人群中很明显 以及患病的州。这反映了这两个物种的基因相似之处。产生突变的小鼠 使用ES细胞技术是一种灵敏的生物检测系统，从中可以深刻了解 它们的功能可以收集，也为进一步研究提供了持久的生物资源。 这项建议的目标是从ES细胞资源中产生有条件的突变小鼠 根据之前的NIH(KOMP)和EU(EUCOMM)资助的计划产生的靶向LacZ标记的等位基因。 我们和其他人将利用这些小鼠来发现基因的功能。我们建议进行这项工作(^ 并形成了一个由三个研究所组成的联合体(贝勒医学院、桑格研究所 和MRC Harwell)作为平等的合作伙伴共同努力实现这一目标。我们将产生老鼠 对应于桑格研究所分布的1500个来自ES细胞的突变基因。我们将描述 每个靶基因的成体和胚胎表达模式以及通过繁殖决定了 每个人对胚胎发育和生育的需求(如果有的话)。所有的等位基因都将被冷冻保存 并放置在存储库中，所有数据都将存储在中央数据协调中心，以 支持进一步的学习。 相关性(请参阅说明)： 一个普通人身上的20,000个基因中的大多数都是正常的，但我们也有数百个基因断裂。 虽然一些断裂的基因会导致严重的疾病，如囊性纤维化或癌症，但另一些基因几乎没有或 没有后果，或者只有在压力下才能发挥作用。目前我们对它的功能有了一定的了解 只有三分之一的人类基因。如果我们要充分了解人类的健康和疾病，我们必须扩大 对我们所有基因的基因功能的了解。

Annotation of the reference human genome has identified approximately 20,000 protein coding genes as well as 3,000 non-coding RNAs. Together these genes orchestrate the development of the organism, supporting all aspects of the function of cells, tissues, organ systems as well physiology and behavior. The lOOOgenome project has revealed extraordinary levels of diversity in human genomes, yet for most genes neither the function of normal version nor the disease consequence of loss-of-function variants is known. The mouse provides a route to understand the function of genes and their variants. IVIice share developmental, physiological, anatomical and metabolic parallels with humans, which are evident in healthy as well as diseased states. These reflect similarities of the genes in both species. Mutant mice generated using ES cell technology are a sensitive biological assay system from which a deep understanding of function can be gleaned and they also provide a long lasting biological resource for further study. The objective of this proposal is to generate mutant mice from a resource of ES cells with conditionally targeted, lacZ-tagged alleles generated under previous NIH (KOMP) and EU (EUCOMM) funded programs. We and others will use these mice to discover the function of genes. We are proposing to carry out this wor(^ at scale and have formed a consortium of three Institutes (Baylor College of Medicine, the Sanger Institute and MRC Harwell) to work together as equal partners to achieve this objective. We will generate mice corresponding to 1500 mutant genes from ES cells distributed by the Sanger Institute. We will characterize the adult and embryonic expression pattern of the each targeted gene and by breeding determine the requirement of each for embryonic development and fertility, if any. All of the alleles will be cryo-preserved and placed in a repository and all of the data will be deposited in a centralized data coordination center to support further studies. RELEVANCE (See instructions): Most of the 20,000 genes in a typical person are normal but we also have several hundred broken ones. While some broken genes can cause severe disease such as cystic fibrosis or cancer, others have little or no consequence, or function only under stress. Currently we have some understanding of the function of just one third of human genes. If we are to fully understand human health and disease we must expand knowledge of gene function to all of our genes.