[论文解读] Fundamental Bounds and Approaches to Sequence Reconstruction from Nanopore Sequencers

Jarek Duda, Wojciech Szpankowski+1 more|arXiv (Cornell University)|Jan 11, 2016

Nanopore and Nanochannel Transport Studies参考文献 9被引用 4

一句话总结

本文对纳米孔测序仪的序列重建进行了信息论分析，将插入缺失和替换错误建模为黏性插入-删除信道。推导了可重建序列长度的根本界限，并表明通过复制的外推可实现唯一重建，且复制次数仅需对数级别，从而在高错误率下使长读长测序成为可能。

ABSTRACT

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.

研究动机与目标

• 分析在现实错误模型下，纳米孔测序仪序列重建的根本极限。
• 确定在给定插入缺失和替换错误率下，可准确重建的最大序列长度。
• 量化为实现畸变界内的唯一重建所需复制的外推次数。
• 建立对广泛错误模型具有鲁棒性的理论界限，为抗错测序提供基础。

提出的方法

• 将纳米孔测序仪建模为黏性插入-删除信道，以分别捕捉插入缺失和替换错误。
• 利用信息论推导准确重建概率作为序列长度和错误率的函数的界限。
• 应用Kullback-Leibler散度量化参考序列与错误读长之间的可区分性。
• 分析由错误引起的畸变界内典型序列的数量，以评估重建的模糊性。
• 推导为将畸变界缩小至单一典型序列以实现唯一重建所需复制次数。
• 使用真实纳米孔数据（例如Jain等人提供的数据）中的经验错误分布来参数化模型，并验证分析界限。

实验结果

研究问题

• RQ1 在已知纳米孔测序仪中插入缺失和替换错误率的前提下，可准确重建的最大序列长度是多少？
• RQ2 由插入缺失和替换错误引起的畸变界内存在多少典型序列？
• RQ3 需要多少复制的外推才能确保畸变界内仅存在一个典型序列，从而实现唯一重建？
• RQ4 在给定错误模型下，所需复制次数如何随序列长度变化？
• RQ5 所推导的界限与现有纳米孔测序研究的实证结果相比如何？

主要发现

• 由于高错误率，存在插入缺失和替换错误时，可准确重建的最大序列长度相对较小。
• 由错误引起的畸变界内典型序列数量庞大，表明在无复制的情况下重建存在显著模糊性。
• 复制外推是一种实现唯一重建的有效技术，因为它可将畸变界缩小至单一典型序列。
• 为实现唯一重建所需的复制次数随序列长度呈对数增长，从而使长读长测序成为可能。
• 在仅替换错误的情况下，唯一重建所需的读长数量大致按 ln(n)/2.89 的比例增长。
• 该模型对组合错误模型提供了紧密的下界，因其分别处理插入缺失和替换错误，提供了保守但分析严谨的性能范围。