The rationales for the development of technology that will enable extremely cheap, high speed sequencing are well established. Chief among these is the enablement of personalized medicine. There are currently in development several technologies that promise to markedly decrease the cost of sequencing a human genome. It is unclear, however, that any of these will be able to do so drastically enough to allow whole genome sequencing to become a routine clinical tool. Additionally, those technologies which are most promising on this cost parameter look as if they will face difficulties with respect to performance characteristics such as read length. One technology that promises to be cheap and fast and to provide long read lengths is nanopore-based sequencing. To date, however, nanopore sequencing has faced a number of technical challenges. The method of Hybridization-Assisted Nanopore Sequencing (HANS) overcomes these hurdles. HANS utilizes libraries of probes to detect subsequences in the target DNA as in sequencing by hybridization (SBH). HANS differs from SBH, however, in that positional information is also extracted thus completely circumventing, the limitations of SBH and making genome length sequencing feasible. The HANS platform will be capable of sequencing a human genome for substantially less than $1000. Additionally, it promises to do so quickly and accurately. Our specific aims are as follows: 1) Synthesize and test oligonucleotide tags for their ability to enhance the nanopore's capacity to detect the presence and determine the positions of the oligonucleotides on the target DNA. 2) Determine the optimal algorithmic approach for sequence reconstruction and estimate values for the performance characteristics of the sequencing platform.
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