HiTRACE：毛细管电泳的高通量稳健分析
HiTRACE: High-throughput robust analysis for capillary electrophoresis
摘要：
动机：核酸毛细管电泳（CE）是高通量基因组分析和大规模化学作图的基础技术，用于核酸结构推断。尽管基于CE的仪器广泛可用，但在利用其全部能力定量分析RNA和DNA结构、热力学和动力学方面仍然存在挑战。特别是，可用的分析工具的速度慢和自动化差已经阻碍了新一代的研究，每个实验涉及数百个CE特征。结果如下：我们提出了一种计算方法，称为高通量强大的分析毛细管电泳（HiTRACE）自动化的关键任务，在大规模的核酸CE分析，包括配置文件对齐，迄今为止一直是一个限速步骤，在最高通量的实验。我们说明了HiTRACE在13个数据集上的应用，这些数据集代表4种不同的RNA，3种化学修饰策略和多达480种单突变变体;最大的数据集每个包括87，360条带。通过应用一系列强大的动态编程算法，HiTRACE在比对和拟合质量方面优于现有工具，如通过测量包括重复数据集之间的量化条带强度之间的相关性所评估的。此外，虽然这些数据集中最小的需要使用现有方法进行7至10小时的人工干预，但即使是本文中最大的数据集的HiTRACE定量也在3至12分钟内实现。因此，HiTRACE方法解决了在涉及数万个电泳条带的实验中有效和准确分析核酸结构的关键障碍。
英文摘要：
Motivation: Capillary electrophoresis (CE) of nucleic acids is a workhorse technology underlying high-throughput genome analysis and large-scale chemical mapping for nucleic acid structural inference. Despite the wide availability of CE-based instruments, there remain challenges in leveraging their full power for quantitative analysis of RNA and DNA structure, thermodynamics, and kinetics. In particular, the slow rate and poor automation of available analysis tools have bottlenecked a new generation of studies involving hundreds of CE profiles per experiment. Results: We propose a computational method called high-throughput robust analysis for capillary electrophoresis (HiTRACE) to automate the key tasks in large-scale nucleic acid CE analysis, including the profile alignment that has heretofore been a rate-limiting step in the highest throughput experiments. We illustrate the application of HiTRACE on thirteen data sets representing 4 different RNAs, three chemical modification strategies, and up to 480 single mutant variants; the largest data sets each include 87,360 bands. By applying a series of robust dynamic programming algorithms, HiTRACE outperforms prior tools in terms of alignment and fitting quality, as assessed by measures including the correlation between quantified band intensities between replicate data sets. Furthermore, while the smallest of these data sets required 7 to 10 hours of manual intervention using prior approaches, HiTRACE quantitation of even the largest data sets herein was achieved in 3 to 12 minutes. The HiTRACE method therefore resolves a critical barrier to the efficient and accurate analysis of nucleic acid structure in experiments involving tens of thousands of electrophoretic bands.
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