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谨慎的、基准化的进展，这些进展表明， 完全组装和定相二倍体染色体的能力。在我们的高- 已知分辨率基因组图谱包含长的重复序列。我们研究的长期目标是 开发新的实验方法来完成染色体规模的组装， 组织，结构多样性和疾病的影响，这些新的序列。在我们的第一个目标中，我们展示了 使用新方法产生人类基因组的第一个端粒到端粒的分阶段组装 使用有效的单倍体完全性葡萄胎（CHM），并证明有能力扩大这些 方法到一组CHM。在我们的第二个目标中，我们专注于重复组装的验证方法，以提高 我们的组件的结构和基础精度。在我们的第三个目标中， 方法使用来自二倍体基因组的高覆盖超长数据来指导定相染色体组装。 我们建议优化一种新的，具有成本效益的方法，以提高高质量的参考基因组， 完整的端粒到端粒的基因组组装。这项研究还有一个额外的好处， 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.