MOTIVATION: Raw nanopore signal analysis is a common approach in genomics to provide fast and resource-efficient analysis without translating the signals to bases (i.e. without basecalling). However, existing solutions cannot interpret raw signals directly if a reference genome is unknown due to a lack of accurate mechanisms to handle increased noise in pairwise raw signal comparison. Our goal is to enable the direct analysis of raw signals without a reference genome. To this end, we propose Rawsamble, the first mechanism that can identify regions of similarity between all raw signal pairs, known as all-vs-all overlapping, using a hash-based search mechanism. RESULTS: We use these overlaps to construct de novo assembly graphs with an existing assembler, miniasm, off-the-shelf. To our knowledge, these are the first de novo assemblies ever constructed directly from raw signals without basecalling. Our extensive evaluations across multiple genomes of varying sizes show that Rawsamble provides a significant speedup (on average by 5.01× and up to 23.10×) and reduces peak memory usage (on average by 5.74× and up to by 22.00×) compared to a conventional genome assembly pipeline using the state-of-the-art tools for basecalling (Dorado's fastest mode) and overlapping (minimap2) on a CPU. We find that around one-third of Rawsamble's overlapping pairs are also found by minimap2. We find that when we use overlapping reads from Rawsamble, we can construct unitigs that are (i) as accurate as those built from minimap2's overlaps and (ii) up to half a chromosome in length (e.g. 2.3 million bases for E. coli). AVAILABILITY AND IMPLEMENTATION: Rawsamble is available at https://github.com/CMU-SAFARI/RawHash. We also provide the scripts to fully reproduce our results on our GitHub page.

Metagenomics, the study of the genome sequences of diverse organisms in a common environment, has led to significant advances in many fields. Since the species present in a metagenomic sample are not known in advance, metagenomic analysis commonly involves the key tasks of determining the species present in a sample and their relative abundances. These tasks require searching large metagenomic databases containing information on different species’ genomes. Metagenomic analysis suffers from significant data movement overhead due to moving large amounts of low-reuse data from the storage system to the rest of the system. In-storage processing can be a fundamental solution for reducing this overhead. However, designing an in-storage processing system for metagenomics is challenging because existing approaches to metagenomic analysis cannot be directly implemented in storage effectively due to the hardware limitations of modern SSDs.We propose MegIS, the first in-storage processing system designed to significantly reduce the data movement overhead of the end-to-end metagenomic analysis pipeline. MegIS is enabled by our lightweight design that effectively leverages and orchestrates processing inside and outside the storage system. Through our detailed analysis of the end-to-end metagenomic analysis pipeline and careful hardware/software co-design, we address in-storage processing challenges for metagenomics via specialized and efficient 1) task partitioning, 2) data/computation flow coordination, 3) storage technology-aware algorithmic optimizations, 4) data mapping, and 5) lightweight in-storage accelerators. MegIS’s design is flexible, capable of supporting different types of metagenomic input datasets, and can be integrated into various metagenomic analysis pipelines. Our evaluation shows that MegIS outperforms the state-of-the-art performance- and accuracy-optimized software metagenomic tools by 2.7× – 37.2× and 6.9×–100.2×, respectively, while matching the accuracy of the accuracy-optimized tool. MegIS achieves 1.5×–5.1× speedup compared to the state-of-the-art metagenomic hardware-accelerated (using processing-in-memory) tool, while achieving significantly higher accuracy.

Genome sequence analysis is fundamental to medical breakthroughs such as developing vaccines, enabling genome editing, and facilitating personalized medicine. The exponentially expanding sequencing datasets and complexity of sequencing algorithms necessitate performance enhancements. While the performance of software solutions is constrained by their underlying hardware platforms, the utility of fixed-function accelerators is restricted to only certain sequencing algorithms.This paper presents QUETZAL, the first general-purpose vector acceleration framework designed for high efficiency and broad applicability across a diverse set of genomics algorithms. While a commercial CPU’s vector datapath is a promising candidate to exploit the data-level parallelism in genomics algorithms, our analysis finds that its performance is often limited due to long-latency scatter/gather memory instructions. QUETZAL introduces a hardware-software co-design comprising an accelerator microarchitecture closely integrated with the CPU’s vector datapath, alongside novel vector instructions to fully capitalize on the proposed hardware. QUETZAL integrates a set of scratchpad-style buffers meticulously designed to minimize latency associated with scatter/gather instructions during the retrieval of input genome sequences data. QUETZAL supports both short and long reads, and different types of sequencing data formats. A combination of hardware and software techniques enables QUETZAL to reduce the latency of memory instructions, perform complex computation using a single instruction, and transform data representations at runtime, resulting in overall efficiency gain. QUETZAL significantly accelerates a vectorized CPU baseline on modern genome sequence analysis algorithms by 5.7×, while incurring a small area overhead of 1.4% post place-and-route at the 7nm technology node compared to an HPC ARM CPU.

SUMMARY: Raw nanopore signals can be analyzed while they are being generated, a process known as real-time analysis. Real-time analysis of raw signals is essential to utilize the unique features that nanopore sequencing provides, enabling the early stopping of the sequencing of a read or the entire sequencing run based on the analysis. The state-of-the-art mechanism, RawHash, offers the first hash-based efficient and accurate similarity identification between raw signals and a reference genome by quickly matching their hash values. In this work, we introduce RawHash2, which provides major improvements over RawHash, including more sensitive quantization and chaining algorithms, weighted mapping decisions, frequency filters to reduce ambiguous seed hits, minimizers for hash-based sketching, and support for the R10.4 flow cell version and POD5 and SLOW5 file formats. Compared to RawHash, RawHash2 provides better F1 accuracy (on average by 10.57% and up to 20.25%) and better throughput (on average by 4.0× and up to 9.9×) than RawHash. AVAILABILITY AND IMPLEMENTATION: RawHash2 is available at https://github.com/CMU-SAFARI/RawHash. We also provide the scripts to fully reproduce our results on our GitHub page.

Profile hidden Markov models (pHMMs) are widely employed in various bioinformatics applications to identify similarities between biological sequences, such as DNA or protein sequences. In pHMMs, sequences are represented as graph structures, where states and edges capture modifications (i.e., insertions, deletions, and substitutions) by assigning probabilities to them. These probabilities are subsequently used to compute the similarity score between a sequence and a pHMM graph. The Baum-Welch algorithm, a prevalent and highly accurate method, utilizes these probabilities to optimize and compute similarity scores. Accurate computation of these probabilities is essential for the correct identification of sequence similarities. However, the Baum-Welch algorithm is computationally intensive, and existing solutions offer either software-only or hardware-only approaches with fixed pHMM designs. When we analyze state-of-the-art works, we identify an urgent need for a flexible, high-performance, and energy-efficient hardware-software co-design to address the major inefficiencies in the Baum-Welch algorithm for pHMMs. We introduce ApHMM , the first flexible acceleration framework designed to significantly reduce both computational and energy overheads associated with the Baum-Welch algorithm for pHMMs. ApHMM employs hardware-software co-design to tackle the major inefficiencies in the Baum-Welch algorithm by (1) designing flexible hardware to accommodate various pHMM designs, (2) exploiting predictable data dependency patterns through on-chip memory with memoization techniques, (3) rapidly filtering out unnecessary computations using a hardware-based filter, and (4) minimizing redundant computations. ApHMM achieves substantial speedups of 15.55×–260.03×, 1.83×–5.34×, and 27.97× when compared to CPU, GPU, and FPGA implementations of the Baum-Welch algorithm, respectively. ApHMM outperforms state-of-the-art CPU implementations in three key bioinformatics applications: (1) error correction, (2) protein family search, and (3) multiple sequence alignment, by 1.29×–59.94×, 1.03×–1.75×, and 1.03×–1.95×, respectively, while improving their energy efficiency by 64.24×–115.46×, 1.75×, and 1.96×.

Memory isolation is critical for system reliability, security, and safety. Unfortunately, read disturbance can break memory isolation in modern DRAM chips. For example, RowHammer is awell-studied read-disturb phenomenon where repeatedly opening and closing (i.e., hammering) a DRAM row many times causes bitflips in physically nearby rows.

Basecalling, an essential step in many genome analysis studies, relies on large Deep Neural Network s (DNN s) to achieve high accuracy. Unfortunately, these DNN s are computationally slow and inefficient, leading to considerable delays and resource constraints in the sequence analysis process. A Computation-In-Memory (CIM) architecture using memristors can significantly accelerate the performance of DNN s. However, inherent device non-idealities and architectural limitations of such designs can greatly degrade the basecalling accuracy, which is critical for accurate genome analysis. To facilitate the adoption of memristor-based CIM designs for basecalling, it is important to (1) conduct a comprehensive analysis of potential CIM architectures and (2) develop effective strategies for mitigating the possible adverse effects of inherent device non-idealities and architectural limitations.

Nanopore sequencers generate electrical raw signals in real-time while sequencing long genomic strands. These raw signals can be analyzed as they are generated, providing an opportunity for real-time genome analysis. An important feature of nanopore sequencing, Read Until, can eject strands from sequencers without fully sequencing them, which provides opportunities to computationally reduce the sequencing time and cost. However, existing works utilizing Read Until either (i) require powerful computational resources that may not be available for portable sequencers or (ii) lack scalability for large genomes, rendering them inaccurate or ineffective. We propose RawHash, the first mechanism that can accurately and efficiently perform real-time analysis of nanopore raw signals for large genomes using a hash-based similarity search. To enable this, RawHash ensures the signals corresponding to the same DNA content lead to the same hash value, regardless of the slight variations in these signals. RawHash achieves an accurate hash-based similarity search via an effective quantization of the raw signals such that signals corresponding to the same DNA content have the same quantized value and, subsequently, the same hash value. We evaluate RawHash on three applications: (i) read mapping, (ii) relative abundance estimation, and (iii) contamination analysis. Our evaluations show that RawHash is the only tool that can provide high accuracy and high throughput for analyzing large genomes in real-time. When compared to the state-of-the-art techniques, UNCALLED and Sigmap, RawHash provides (i) 25.8× and 3.4× better average throughput and (ii) significantly better accuracy for large genomes, respectively. Source code is available at https://github.com/CMU-SAFARI/RawHash.

MOTIVATION: Pairwise sequence alignment is a very time-consuming step in common bioinformatics pipelines. Speeding up this step requires heuristics, efficient implementations, and/or hardware acceleration. A promising candidate for all of the above is the recently proposed GenASM algorithm. We identify and address three inefficiencies in the GenASM algorithm: it has a high amount of data movement, a large memory footprint, and does some unnecessary work. RESULTS: We propose Scrooge, a fast and memory-frugal genomic sequence aligner. Scrooge includes three novel algorithmic improvements which reduce the data movement, memory footprint, and the number of operations in the GenASM algorithm. We provide efficient open-source implementations of the Scrooge algorithm for CPUs and GPUs, which demonstrate the significant benefits of our algorithmic improvements. For long reads, the CPU version of Scrooge achieves a 20.1×, 1.7×, and 2.1× speedup over KSW2, Edlib, and a CPU implementation of GenASM, respectively. The GPU version of Scrooge achieves a 4.0×, 80.4×, 6.8×, 12.6×, and 5.9× speedup over the CPU version of Scrooge, KSW2, Edlib, Darwin-GPU, and a GPU implementation of GenASM, respectively. We estimate an ASIC implementation of Scrooge to use 3.6× less chip area and 2.1× less power than a GenASM ASIC while maintaining the same throughput. Further, we systematically analyze the throughput and accuracy behavior of GenASM and Scrooge under various configurations. As the best configuration of Scrooge depends on the computing platform, we make several observations that can help guide future implementations of Scrooge. AVAILABILITY AND IMPLEMENTATION: https://github.com/CMU-SAFARI/Scrooge.

A critical step of genome sequence analysis is the mapping of sequenced DNA fragments (i.e., reads) collected from an individual to a known linear reference genome sequence (i.e., sequence-to-sequence mapping). Recent works replace the linear reference sequence with a graph-based representation of the reference genome, which captures the genetic variations and diversity across many individuals in a population. Mapping reads to the graph-based reference genome (i.e., sequence-to-graph mapping) results in notable quality improvements in genome analysis. Unfortunately, while sequence-to-sequence mapping is well studied with many available tools and accelerators, sequence-to-graph mapping is a more difficult computational problem, with a much smaller number of practical software tools currently available.

Graphics Processing Units (GPUs) are widely-used accelerators for data-parallel applications. In many GPU applications, GPU memory bandwidth bottlenecks performance, causing underutilization of GPU cores. Hence, disabling many cores does not affect the performance of memory-bound workloads. While simply power-gating unused GPU cores would save energy, prior works attempt to better utilize GPU cores for other applications (ideally compute-bound), which increases the GPU’s total throughput. In this paper, we introduce Morpheus, a new hardware/software co-designed technique to boost the performance of memory-bound applications. The key idea of Morpheus is to exploit unused core resources to extend the GPU last level cache (LLC) capacity. In Morpheus, each GPU core has two execution modes: compute mode and cache mode. Cores in compute mode operate conventionally and run application threads. However, for the cores in cache mode, Morpheus invokes a software helper kernel that uses the cores’ on-chip memories (i.e., register file, shared memory, and L1) in a way that extends the LLC capacity for a running memory-bound workload. Morpheus adds a controller to the GPU hardware to forward LLC requests to either the conventional LLC (managed by hardware) or the extended LLC (managed by the helper kernel). Our experimental results show that Morpheus improves the performance and energy efficiency of a baseline GPU architecture by an average of 39% and 58%, respectively, across several memory-bound workloads. Morpheus’ performance is within 3% of a GPU design that has a quadruple-sized conventional LLC. Morpheus can thus contribute to reducing the hardware dedicated to a conventional LLC by exploiting idle cores’ on-chip memory resources as additional cache capacity.