A human binary interactome reference map by 2020

一个参考人类基因组序列和随后长达十年的~ 20，000（20 K）蛋白质注释- 编码基因的发现使得与疾病相关的基因组变异发现激增。我们现在可以 预计几乎完全描述了人类群体中所有与疾病相关的基因组变异。基因组 然而，如果单独进行测序，将留下关于基因型-表型的基本问题 关系未解决。对于鉴定出的绝大多数基因组变异， 它们干扰相应基因或基因产物的功能。为了“连接基因组的点”， 革命，功能和背景必须分配大量的基因型变化。目前我们 我对人类细胞中发生的分子、生物化学和功能相互作用知之甚少 并且是生物功能所必需的。过去关于蛋白质相互作用的发现，如蛋白质-蛋白质 相互作用（PPI）一直高度偏向于对“流行”蛋白质，代表了一小部分， 20 Kx 20 K基因的200，000，000对的完整空间。系统的、高质量的、全基因组的努力， 创建分子相互作用的社区资源构成了解决这一问题的最佳方案。正如 参考基因组序列提供了一个基本的社区资源， 遗传学，全基因组或全蛋白质组相互作用网络的参考图谱，或“相互作用组网络”， 将是充分理解基因型-表型关系的关键。 该申请是自1998年以来NHGRI资助的第五次竞争性更新，以解决 通过蛋白质组规模的二元相互作用组网络的实验映射，上述挑战。 在对模式生物中相互作用基因组作图策略的发展进行了两个周期的研究之后， 第三次更新专门针对人类PPI。我们现在正处于一个激动人心的阶段， 路线图，以提供“2018年人类二元相互作用组参考图”作为广泛有用的资源， 科学界，出版前发布12个互补的高质量全基因组20 Kx 20 K 沿着的PPI数据集。最终，我们估计，最终的参考地图很可能是一个命令， 其规模大于科学界使用小规模放射性同位素检测PPI的集体努力。 实验，将是一个宝贵的工具，连接点的基因组学，并将作为一个支架，启动 无偏见和详尽的功能表征大量的基因组变异相关的 人类疾病

A reference human genome sequence and the subsequent decade-long annotation of ~20,000 (20K) protein- coding genes has enabled an explosion of disease-associated genomic variant discovery. We can now anticipate a nearly full description of all disease-related genomic variations in the human population. Genomic sequencing, however, if performed in isolation, will leave fundamental questions about genotype-phenotype relationships unresolved. For the vast majority of genomic variations identified, it remains unclear if and how they perturb the function of the corresponding genes or gene products. To “connect the dots” of the genomic revolution, functions and context must be assigned for large numbers of genotypic changes. Currently, we know relatively few of the molecular, biochemical, and functional interactions that take place in human cells and that are necessary for biological functions. Past discoveries about interactions such as protein-protein interactions (PPIs) have been highly biased towards pairs of `popular' proteins, representing a tiny fraction of the full space of 200,000,000 pairings of 20Kx20K genes. Systematic, high-quality, genome-wide efforts to create community resources of molecular interactions constitute the best solution to this problem. Just as reference genome sequences provided a fundamental community resource that revolutionized human genetics, reference maps of genome-wide or proteome-wide interaction networks, or “interactome networks”, will be critical to fully understand genotype-phenotype relationships. This application is the fifth competitive renewal of a grant funded by NHGRI since 1998 to address the challenge described above through experimental mapping of binary interactome networks at proteome-scale. After devoting two cycles to the development of interactome mapping strategies in model organisms, this is the third renewal specifically addressing human PPIs. We are now at the exciting stage of presenting a three-year roadmap to deliver “A human binary interactome reference map by 2018” as a broadly useful resource for the scientific community, with pre-publication release of 12 complementary high-quality genome-wide 20Kx20K PPI datasets along the way. Ultimately, the resulting reference map, which we estimate may well be an order of magnitude larger than the collective efforts of the scientific community to detect PPIs using small-scale experiments, will be an invaluable tool to connect the dots of genomics and will serve as a scaffold to initiate unbiased and exhaustive functional characterizations of large numbers of genomic variations associated with human disease.