纳米孔测序仪序列重建的基本边界和方法
Fundamental Bounds and Approaches to Sequence Reconstruction from Nanopore Sequencers
摘要：
纳米孔测序仪正在成为高通量测序的有前途的新平台。与其他技术一样，测序仪错误对其有效使用构成了重大挑战。在本文中，我们提出了一种新的信息理论分析的影响插入-缺失（插入缺失）错误的纳米孔测序仪。特别地，我们考虑以下问题：（i）对于给定的插入缺失错误特性和速率，作为序列长度的函数的准确重建的概率是多少;（ii）在由插入缺失错误引起的失真范围内的“典型”序列的数量是多少;（iii）使用复制挤压（DNA链通过纳米孔的过程），减少失真界限所需的副本数量是多少，以便在失真界限内仅存在一个典型序列。我们的研究结果提供了一些重要的见解：（i）在插入缺失和替换错误的存在下，可以准确重建的序列的最大长度相对较小;（ii）在失真范围内的典型序列的数量很大;（iii）复制挤出是一种有效的独特重建技术。特别是，我们证明了复制品的数量是序列长度的缓慢函数（对数）-这意味着通过复制挤出，我们可以使用纳米孔测序仪对大读数进行测序。我们的模型分别考虑了插入缺失和替代错误。在这个意义上，当在单个模型中考虑两个误差模式时，可以将其视为提供关于重建长度和重复的（紧密）界限以用于精确重建。
英文摘要：
Nanopore sequencers are emerging as promising new platforms for high-throughput sequencing. As with other technologies, sequencer errors pose a major challenge for their effective use. In this paper, we present a novel information theoretic analysis of the impact of insertion-deletion (indel) errors in nanopore sequencers. In particular, we consider the following problems: (i) for given indel error characteristics and rate, what is the probability of accurate reconstruction as a function of sequence length; (ii) what is the number of `typical' sequences within the distortion bound induced by indel errors; (iii) using replicated extrusion (the process of passing a DNA strand through the nanopore), what is the number of replicas needed to reduce the distortion bound so that only one typical sequence exists within the distortion bound. Our results provide a number of important insights: (i) the maximum length of a sequence that can be accurately reconstructed in the presence of indel and substitution errors is relatively small; (ii) the number of typical sequences within the distortion bound is large; and (iii) replicated extrusion is an effective technique for unique reconstruction. In particular, we show that the number of replicas is a slow function (logarithmic) of sequence length -- implying that through replicated extrusion, we can sequence large reads using nanopore sequencers. Our model considers indel and substitution errors separately. In this sense, it can be viewed as providing (tight) bounds on reconstruction lengths and repetitions for accurate reconstruction when the two error modes are considered in a single model.
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