Telomere-to-telomere assemblies of human genomes

项目摘要 完成人类基因组的方法将受益于仔细的、有基准的进展，这些进展证明 对二倍体染色体进行完全组装和分相的能力。在我们的高地剩下的未解决的区域- 已知的分辨率基因组图谱包含很长的重复序列。我们研究的长期目标是 开发新的实验方法来完成染色体标尺组装以研究序列 这些新序列的组织、结构多样性和疾病影响。在我们的第一个目标中，我们演示 使用新的方法产生人类基因组的第一个端粒到端粒的阶段性组装 有效利用单倍体完全性葡萄胎(CHM)，并展示其规模化能力 方法提供给一组中药。在第二个目标中，我们将重点放在重复装配的验证方法上以改进 基于我们组装的结构和基准面的精度。在我们的第三个目标中，我们强化单倍型阶段化 方法利用来自二倍体基因组的高覆盖率超长数据指导染色体的阶段性组装。 我们建议优化一种新的、具有成本效益的方法来改进高质量的参考基因组，以达到 完整的端粒到端粒基因组组装。这项研究还有一个额外的好处，那就是它将增加新的 人类基因组序列，以系统地探索经常被忽视的区域的遗传变异 疾病关联和功能研究的一部分。

Project Summary Approaches to complete the human genome will benefit from careful, benchmarked advances that demonstrate the capability to fully assemble and phase diploid chromosomes. The remaining unresolved regions in our high- resolution genomic maps are known to contain long tracts of repeats. The long-term objective of our research is to develop new experimental methods to complete chromosome scale assemblies to study the sequence organization, structural diversity, and disease impact of these novel sequences. In our first aim, we demonstrate the use of new approaches to generate the first telomere-to-telomere phased assembly of a human genome using effectively haploid complete hydatidiform moles (CHMs), and demonstrate the ability to scale these methods to a panel of CHMs. In our second aim we focus on validation methods of repeat assemblies to improve upon the structural and base-level accuracy of our assemblies. In our third aim we harden haplotype phasing method using high coverage ultra long data from diploid genomes to guide phased chromosome assemblies. We propose to optimize a new, cost-effective method of improving high quality reference genomes to reach complete, telomere-to-telomere genome assemblies. This research has the additional benefit that it will add new sequence to the human genome to systematically explore genetic variation of regions frequently overlooked as part of disease association and functional studies.