RESEARCH-PGR: Algorithms and Tools for Improving Genome Assemblies

在过去的15年里，基因组学领域已经产生了数千个植物和动物基因组，每一个基因组都是广泛科学研究的重要资源。在同一时期，DNA测序的速度和成本已经提高了数千倍，这是新基因组大量涌现的主要驱动力。尽管效率很高，但这项新技术也有很大的局限性，其中之一就是一次只能测序一小段DNA，长度为几百个碱基。然后需要将这些“读段”组装在一起以重建基因组，该基因组可能包含分布在数十条染色体上的数十亿个碱基。结果之一是，除了极少数经过深入研究的模式生物外，今天的大多数基因组都以高度碎片化的形式存在，通常由数万个片段组成。绝大多数植物和动物物种自首次出版以来一直保持这种“草案”格式。该项目将创建新的基因组组装软件，使科学家能够使用新的测序技术来修复这些基因组草案，不仅纠正错误，而且还将许多小片段拼接在一起，为广泛的物种创造更好的组装。这些改进的基因组将反过来为更准确的基因目录、更好的基因组结构和进化分析以及更深入地理解基因组生物学提供基础。基因组组装长期以来一直是一项极具挑战性的计算任务，这是由于许多基因组的复杂重复性以及测序工作中产生的大规模数据。下一代测序（NGS）极大地扩大了组装问题的规模，原始数据集从2000年代中期的数百万个读数增加到近年来的数十亿个读数。最近引入的具有高错误率的超长读段技术使得组装更具挑战性，但这些序列的大长度提供了更多连续组装的可能性。该项目旨在开发基因组组装的新技术，并改善科学家在许多研究领域使用的广泛植物物种的基因组。调查人员将通过两个相关的目标来实现这些改进。首先，他们将开发新的和改进的组装算法，将联合收割机Illumina序列与来自Oxford Nanopore，Pacific Biosciences等的第三代测序技术相结合。新的算法将允许研究人员将联合收割机低成本的短读段与高成本、高错误的长读段结合起来，以产生更好的基因组组装。其次，他们将开发一种新的算法，利用密切相关物种的现有基因组构建组装体，而无需生成新数据。研究人员将通过从公开的数据中重新组装多个植物基因组来展示他们的方法。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Over the past fifteen years, the field of genomics has generated thousands of plant and animal genomes, each of which is an important resource for a broad range of scientific studies. During the same time period, DNA sequencing has become thousands of times faster and cheaper, which has been the main driver of this flood of new genomes. Despite its efficiency, the new technology has significant limitations, one of which is that only a short stretch of DNA, a few hundred bases in length, can be sequenced at a time. These "reads" then need to be assembled together to reconstruct a genome, which might contain billions of bases spread across dozens of chromosomes. One consequence is that most genomes today, except for a very tiny number of intensively-studied model organisms, exist in highly fragmented form, often comprising tens of thousands of fragments. The vast majority of plant and animal species have remained in this "draft" format ever since their initial publication. This project will create new genome assembly software that will make it possible for scientists to use new sequencing technology to fix these draft genomes, not only correcting errors but also stitching together many of the small fragments to create much better assemblies for a very broad range of species. These improved genomes will, in turn, provide the foundation for more accurate gene catalogs, better analyses of genome structure and evolution, and a deeper understanding of the biology of genomes.Genome assembly has long been an extremely challenging computational task, due to the complex repetitive nature of many genomes and to the large scale of the data generated in a sequencing effort. Next-generation sequencing (NGS) has dramatically expanded the scale of the assembly problem, with raw data sets increasing from millions of reads in the mid-2000s to billions of reads in recent years. The recent introduction of very-long-read technologies with high error rates has made assembly even more challenging, but the great length of these sequences offers the possibility of much more contiguous assemblies. This project aims to develop new technology for genome assembly and to improve the genomes of a broad range of plant species that are used by scientists across many fields of research. The investigators will pursue these improvements through two related aims. First, they will develop new and improved assembly algorithms that combine Illumina sequences with third-generation sequencing technologies from Oxford Nanopore, Pacific Biosciences, and others. The new algorithms will allow investigators to combine low-cost short reads with higher-cost, high-error long reads to produce dramatically better genome assemblies. Second, they will develop a new algorithm to construct an assembly using the existing genome of a closely related species, without the need to generate new data. The investigators will demonstrate their methods by re-assembling multiple plant genomes from publicly available data. All assemblies will be released rapidly to the community, and all software will be free and open source.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.