The 200 mammals project: sequencing genomes by a novel cost-effective method, yielding a high resolution annotation of the human genome

项目摘要 200种哺乳动物项目是一个由NHGRI资助的项目， 疾病研究的无与伦比的力量，大大加快了研究重点是确定因果变异 对于许多人类疾病。自2016年推出以来，我们已经制作和分享了超过200个基因组组件。 130个新的，非常多样化的哺乳动物物种，并完成了有史以来最大的多基因组 对齐。这个有240个物种的联盟，甚至比我们最初的雄心勃勃的目标要大得多。 提议因此，我们第一次有能力在细胞中识别特定的单核苷酸。 人类基因组在一亿年的哺乳动物进化中异常保守。 在此，我们请求对200个哺乳动物项目再提供一年的支助， 在项目的前三年。仅通过对布罗德研究所团队的工资支持，我们将 能够完成关键资源和工具的开发和传播。这项工作对于确保 对该项目的资助为疾病研究人员带来了非凡的价值。 (1)生成并验证整个人类基因组以及 关键模式物种的基因组。（1）在UCSC浏览器中的基因组轨迹， 四个基因组的约束和加速：人类（hg 38），黑猩猩（panTro 6），小鼠（mm 10）和狗 （canFam 3）;（2）一个软件工具，使研究人员能够为240个物种中的任何一个生成这种轨迹 在排列中。 (2)为在人类疾病研究中使用200种哺乳动物保护评分提供资源和工具。 （1）人类SNPs作为新的功能基因的进化保守性和加速性的测量 （2）将SNP注释整合到S-LDSC（复杂疾病的遗传结构）中， PolyFun（复杂疾病位点的精细绘图）;（3）200种哺乳动物的重新定义改进值 对于不同的疾病和疾病结构，相对于先前的功能注释的保守性得分。 (3)注释蛋白质编码基因，转座因子，并在我们的每一个新的基因组重复 组件.表：对于每个组装，我们将提供（1）确定的基因位置目录 使用我们的比对比较分析;（2）典型重复序列和转座因子的目录。 (4)确定特殊哺乳动物特征的基因组基础。基因座目录 与人类所未见的特殊特征有关，包括冬眠，对极端环境的耐受性， 温度和血糖变异性的耐受性。

PROJECT SUMMARY The 200 Mammals Project is an NHGRI-funded project building a comparative genomics resource of unparalleled power for disease research, to greatly accelerate research focused on identifying causal variants for many human diseases. Since our launch in 2016, we have made and shared genome assemblies for over 130 new, extraordinarily diverse, mammalian species, and completed the largest ever multiple genome alignment. This alignment, with 240 species, is far bigger than even the ambitious goals of our original proposal. As a result, for the first time, we have the power to identify specific single nucleotides in the human genome as unusually conserved over the 100 million years of mammalian evolution. Here, we request one additional year of support for the 200 Mammals Project, scaled back from the annual commitment in the project's first three years. With salary support for the Broad Institute team alone, we will be able to complete development of, and disseminate, key resources and tools. This work is crucial to ensuring the funding committed to this project yields exceptional value for disease researchers. (1) Generate and validate sequence conservation scores across the human genome, as well as in the genomes of key model species. Deliverables: (1) Genome tracks in the UCSC browser annotating both constraint and acceleration for four genomes: human (hg38), chimpanzee (panTro6), mouse (mm10) and dog (canFam3); (2) A software tool that will enable researchers to generate such tracks for any of the 240 species in the alignment. (2) Provide resources and tools for using 200 Mammals conservation scores in human disease studies. Deliverables: (1) Measures of evolutionary conservation and acceleration at human SNPs as a new functional annotation; (2) Integration of SNP annotation into S-LDSC (genetic architecture of complex disease) and PolyFun (finemapping of complex disease loci); (3) Metrics defining improved value of the 200 Mammals conservation scores over prior functional annotations for different diseases and disease architectures. (3) Annotate protein-coding genes, transposable elements, and repeats in each of our new genome assemblies. Deliverables: For each assembly, we will provide (1) a catalog of gene locations determined using comparative analysis of our alignment; (2) a catalog of canonical repeats and transposable elements. (4) Identify the genomic basis of exceptional mammalian traits. Deliverables: A catalog of genomic loci associated with exceptional traits not seen in humans, including hibernation, tolerance of extreme temperatures, and tolerance of blood glucose variability.