CIF:Medium:Collaborative Research:An Information-theoretic approach to nanopore sequencing

快速而廉价的DNA测序技术开始通过从个性化医疗到第二代测序仪实现的生态系统理解等应用影响社会。然而，第二代测序技术的广泛适用性受到可以读取的DNA片段长度短的限制。纳米孔测序有可能克服现有技术短读测序的几个缺点。该项目的目标是创建新的基础理论和算法，使纳米孔测序的几个应用成为可能。这项研究将支持纳米孔技术成为领先的下一代测序方法。该项目还包含一个独特的大学间教育和研究计划，其中将包括联合和协作的学生咨询和课程开发。为了实现纳米孔测序的优势，需要开发减少和打击测序错误的方法。在纳米孔测序仪中，DNA通过纳米孔迁移，并且测量通过孔的离子电流变化以推断DNA序列。从DNA序列到观察到的电流迹线的映射具有若干损伤（引起误差），包括影响每次观察的多个核苷酸、纳米孔响应的随机变化、停留时间变化、同步误差和噪声。该项目开发了一个整体的方法，使用信息理论和生物信息学的工具，基于多个相互作用的推力：（1）开发数学模型和（2）纳米孔测序的信息理论，（3）利用纳米孔通道结构的解码算法，以及（4）应用于DNA取证，DNA定相和DNA信息存储的理论和方法。我们将其与现有的实验性纳米孔测序研究计划相结合，指导模型和理论/算法与特定数据以及验证这些想法。

Fast and inexpensive DNA sequencing technology is beginning to impact society through applications ranging from personalized medicine to understanding of ecological systems enabled by second generation sequencers. Wider applicability of second-generation sequencing technology is limited, however, by the short length of the DNA fragments that can be read. Nanopore sequencing has the potential to overcome several shortcomings of state-of-the art short-read sequencing.The goal of this project is to create new foundational theory and algorithms enabling several applications of nanopore sequencing. This research will support nanopore technology to become a leading next-generation sequencing approach. This project also contains a unique inter-university education and research program, which will include joint and collaborative student advising and curricular development.To realize the advantages of nanopore sequencing, methods for reducing and combating sequencing errors need to be developed. In a nanopore sequencer, DNA is transmigrated through a nanopore, and the ion current variations through the pore are measured to infer the DNA sequence. The mapping from the DNA sequence to the observed current trace, has several impairments (causing errors) including multiple nucleotides affecting each observation, random variations in nanopore response, dwelling time variations, synchronization errors, and noise. This project develops a holistic approach using tools from information theory and bio-informatics based on multiple interacting thrusts: (1) developing mathematical models and (2) information theory for nanopore sequencing, (3) decoding algorithms exploiting the structure of the nanopore channel, and (4) the theory and methodology for applications in DNA forensics, DNA phasing and DNA information storage. We couple this with an existing experimental nanopore sequencing research program, guiding models and the theory/algorithms with specific data as well as validating these ideas.