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1. HQAlign: aligning nanopore reads for SV detection using current-level modeling

   https://doi.org/10.1093/bioinformatics/btad580  

   Joshi, Dhaivat; Diggavi, Suhas; Chaisson, Mark J; Kannan, Sreeram (October 2023, Bioinformatics)

   Alkan, Can (Ed.)

   Abstract MotivationDetection of structural variants (SVs) from the alignment of sample DNA reads to the reference genome is an important problem in understanding human diseases. Long reads that can span repeat regions, along with an accurate alignment of these long reads play an important role in identifying novel SVs. Long-read sequencers, such as nanopore sequencing, can address this problem by providing very long reads but with high error rates, making accurate alignment challenging. Many errors induced by nanopore sequencing have a bias because of the physics of the sequencing process and proper utilization of these error characteristics can play an important role in designing a robust aligner for SV detection problems. In this article, we design and evaluate HQAlign, an aligner for SV detection using nanopore sequenced reads. The key ideas of HQAlign include (i) using base-called nanopore reads along with the nanopore physics to improve alignments for SVs, (ii) incorporating SV-specific changes to the alignment pipeline, and (iii) adapting these into existing state-of-the-art long-read aligner pipeline, minimap2 (v2.24), for efficient alignments. ResultsWe show that HQAlign captures about 4%–6% complementary SVs across different datasets, which are missed by minimap2 alignments while having a standalone performance at par with minimap2 for real nanopore reads data. For the common SV calls between HQAlign and minimap2, HQAlign improves the start and the end breakpoint accuracy by about 10%–50% for SVs across different datasets. Moreover, HQAlign improves the alignment rate to 89.35% from minimap2 85.64% for nanopore reads alignment to recent telomere-to-telomere CHM13 assembly, and it improves to 86.65% from 83.48% for nanopore reads alignment to GRCh37 human genome. Availability and implementationhttps://github.com/joshidhaivat/HQAlign.git. 

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2. FrameD: framework for DNA-based data storage design, verification, and validation

   https://doi.org/10.1093/bioinformatics/btad572  

   Volkel, Kevin D.; Lin, Kevin N.; Hook, Paul W.; Timp, Winston; Keung, Albert J.; Tuck, James M.; Kelso, ed., Janet (September 2023, Bioinformatics)

   Abstract MotivationDNA-based data storage is a quickly growing field that hopes to harness the massive theoretical information density of DNA molecules to produce a competitive next-generation storage medium suitable for archival data. In recent years, many DNA-based storage system designs have been proposed. Given that no common infrastructure exists for simulating these storage systems, comparing many different designs along with many different error models is increasingly difficult. To address this challenge, we introduce FrameD, a simulation infrastructure for DNA storage systems that leverages the underlying modularity of DNA storage system designs to provide a framework to express different designs while being able to reuse common components. ResultsWe demonstrate the utility of FrameD and the need for a common simulation platform using a case study. Our case study compares designs that utilize strand copies differently, some that align strand copies using multiple sequence alignment algorithms and others that do not. We found that the choice to include multiple sequence alignment in the pipeline is dependent on the error rate and the type of errors being injected and is not always beneficial. In addition to supporting a wide range of designs, FrameD provides the user with transparent parallelism to deal with a large number of reads from sequencing and the need for many fault injection iterations. We believe that FrameD fills a void in the tools publicly available to the DNA storage community by providing a modular and extensible framework with support for massive parallelism. As a result, it will help accelerate the design process of future DNA-based storage systems. Availability and implementationThe source code for FrameD along with the data generated during the demonstration of FrameD is available in a public Github repository at https://github.com/dna-storage/framed, (https://dx.doi.org/10.5281/zenodo.7757762). 

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3. QAlign: aligning nanopore reads accurately using current-level modeling

   Dhaivat Joshi, Shunfu Mao (March 2021, Bioinformatics)

   null (Ed.)

   Efficient and accurate alignment of DNA/RNA sequence reads to each other or to a reference genome/transcriptome is an important problem in genomic analysis. Nanopore sequencing has emerged as a major sequencing technology and many long-read aligners have been designed for aligning nanopore reads. However, the high error rate makes accurate and efficient alignment difficult. Utilizing the noise and error characteristics inherent in the sequencing process properly can play a vital role in constructing a robust aligner. In this article, we design QAlign, a pre-processor that can be used with any long-read aligner for aligning long reads to a genome/transcriptome or to other long reads. The key idea in QAlign is to convert the nucleotide reads into discretized current levels that capture the error modes of the nanopore sequencer before running it through a sequence aligner.We show that QAlign is able to improve alignment rates from around 80\% up to 90\% with nanopore reads when aligning to the genome. We also show that QAlign improves the average overlap quality by 9.2, 2.5 and 10.8\% in three real datasets for read-to-read alignment. Read-to-transcriptome alignment rates are improved from 51.6\% to 75.4\% and 82.6\% to 90\% in two real datasets.https://github.com/joshidhaivat/QAlign.git.Supplementary data are available at Bioinformatics online. 

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4. Towards quantum belief propagation for LDPC decoding in wireless networks

   https://doi.org/10.1145/3372224.3419207  

   Kasi, Srikar; Jamieson, Kyle (September 2020, Proceedings of the 26th Annual International Conference on Mobile Computing and Networking (ACM MobiCom))

   We present Quantum Belief Propagation (QBP), a Quantum Annealing (QA) based decoder design for Low Density Parity Check (LDPC) error control codes, which have found many useful applications in Wi-Fi, satellite communications, mobile cellular systems, and data storage systems. QBP reduces the LDPC decoding to a discrete optimization problem, then embeds that reduced design onto quantum annealing hardware. QBP's embedding design can support LDPC codes of block length up to 420 bits on real state-of-the-art QA hardware with 2,048 qubits. We evaluate performance on real quantum annealer hardware, performing sensitivity analyses on a variety of parameter settings. Our design achieves a bit error rate of 10--8 in 20 μs and a 1,500 byte frame error rate of 10--6 in 50 μs at SNR 9 dB over a Gaussian noise wireless channel. Further experiments measure performance over real-world wireless channels, requiring 30 μs to achieve a 1,500 byte 99.99% frame delivery rate at SNR 15-20 dB. QBP achieves a performance improvement over an FPGA based soft belief propagation LDPC decoder, by reaching a bit error rate of 10--8 and a frame error rate of 10--6 at an SNR 2.5--3.5 dB lower. In terms of limitations, QBP currently cannot realize practical protocol-sized (e.g., Wi-Fi, WiMax) LDPC codes on current QA processors. Our further studies in this work present future cost, throughput, and QA hardware trend considerations. 

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5. Sequencing Illumina libraries at high accuracy on the ONT MinION using R2C2

   https://doi.org/10.1101/gr.277031.122  

   Zee, Alexander; Deng, Dori Z.Q.; Adams, Matthew; Schimke, Kayla D.; Corbett-Detig, Russell; Russell, Shelbi L.; Zhang, Xuan; Schmitz, Robert J.; Vollmers, Christopher (November 2022, Genome Research)

   High-throughput short-read sequencing has taken on a central role in research and diagnostics. Hundreds of different assays take advantage of Illumina short-read sequencers, the predominant short-read sequencing technology available today. Although other short-read sequencing technologies exist, the ubiquity of Illumina sequencers in sequencing core facilities and the high capital costs of these technologies have limited their adoption. Among a new generation of sequencing technologies, Oxford Nanopore Technologies (ONT) holds a unique position because the ONT MinION, an error-prone long-read sequencer, is associated with little to no capital cost. Here we show that we can make short-read Illumina libraries compatible with the ONT MinION by using the rolling circle to concatemeric consensus (R2C2) method to circularize and amplify the short library molecules. This results in longer DNA molecules containing tandem repeats of the original short library molecules. This longer DNA is ideally suited for the ONT MinION, and after sequencing, the tandem repeats in the resulting raw reads can be converted into high-accuracy consensus reads with similar error rates to that of the Illumina MiSeq. We highlight this capability by producing and benchmarking RNA-seq, ChIP-seq, and regular and target-enriched Tn5 libraries. We also explore the use of this approach for rapid evaluation of sequencing library metrics by implementing a real-time analysis workflow. 

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