MOTIVATION: Advances in DNA sequencing have outpaced advances in computation, making sequence alignment a major bottleneck in genome data analyses. Classical dynamic programming (DP) algorithms are particularly memory-intensive, especially when computing gap-affine and dual gap-affine alignments. Existing strategies to reduce memory consumption often sacrifice speed or alignment accuracy. RESULTS: We present Singletrack, an efficient algorithm for backtrace gap-affine and dual gap-affine alignments that requires storing a single DP matrix while preserving optimal alignment results. Compared to classical DP algorithms, Singletrack removes the need to store additional matrices (i.e. 2 for gap-affine and 4 for dual gap-affine), significantly reducing memory consumption and, in turn, reducing pressure on the memory hierarchy and improving overall performance. Most importantly, Singletrack is a general backtrace method compatible with state-of-the-art DP-based algorithms and heuristics, such as the Suzuki-Kasahara (SK) and the Wavefront Alignment (WFA) algorithms. We demonstrate that Singletrack reduces memory consumption for both SK and WFA algorithms, lowering SK usage by 2× and 4× and WFA usage by 3× and 5× for gap-affine and dual gap-affine alignments, respectively. Moreover, replacing KSW2's memory-reduction technique with Singletrack accelerates its SK implementation by up to 1.4× at the cost of doubling memory consumption, while Singletrack increases the performance of the WFA implementation in WFA2-lib by 1.2-2.1×. Compared to the efficient linear-memory BiWFA algorithm, the Singletrack-accelerated version of WFA trades a practical increase in memory usage for up to 5.2× higher performance. AVAILABILITY AND IMPLEMENTATION: The Singletrack implementations presented in this work are available on Zenodo (DOI: 10.5281/zenodo.18770585) and GitHub (https://github.com/LorienLV/singletrack).

Multiple HPC applications are often bottlenecked by compute-intensive kernels implementing complex dependency patterns (data-dependency bound). Traditional general-purpose accelerators struggle to effectively exploit fine-grain parallelism due to limitations in implementing convoluted data-dependency patterns (like SIMD) and overheads due to synchronization and data transfers (like GPGPUs). In contrast, custom FPGA and ASIC designs offer improved performance and energy efficiency at a high cost in hardware design and programming complexity and often lack the flexibility to process different workloads. We propose Squire, a general-purpose accelerator designed to exploit fine-grain parallelism effectively on dependency-bound kernels. Each Squire accelerator has a set of general-purpose low-power in-order cores that can rapidly communicate among themselves and directly access data from the L2 cache. Our proposal integrates one Squire accelerator per core in a typical multicore system, allowing the acceleration of dependency-bound kernels within parallel tasks with minimal software changes. As a case study, we evaluate Squire’s effectiveness by accelerating five kernels that implement complex dependency patterns. We use three of these kernels to build an end-to-end read-mapping tool that will be used to evaluate Squire. Squire obtains speedups up to $7.64 \times$ in dynamic programming kernels. Overall, Squire provides an acceleration for an end-to-end application of $3.66 \times$. In addition, Squire reduces energy consumption by up to 56% with a minimal area overhead of $\mathbf{1 0. 5 \%}$ compared to a NeoverseN1 baseline.

Sequence alignment is a fundamental building block for critical applications across multiple fields, such as computational biology and information retrieval.The rapid advancement of genome sequencing technologies and breakthrough generative AI tools, like AlphaFold, has driven an exponential increase in sequencedata production, creating a pressing need for fast and efficient sequence alignment tools to analyze ever-growing biological sequence databases.Notwithstanding the numerous accelerators proposed, from general-purpose architectures (CPUs and GPUs) to domainspecific designs (FPGAs and ASICs), the most efficient solutions suffer from over-specialization and fail to adapt to the wide variety of irregular use cases demanded by practical sequence alignment applications.Thus, it remains a challenge to design an architecture that can balance efficiency and flexibility to meet the demands of real-world alignment applications.This work introduces SMX, a heterogeneous architecture designed for high-performance sequence alignment that supports various configurations for different sequence types (DNA, protein, and ASCII text) and alignment models (including weighted gaps and substitution matrices).SMX integrates an ISA extension (SMX-1D) for irregular and sequential tasks and a specialized coprocessor (SMX-2D) to accelerate regular and parallel tasks, both orchestrated by the general-purpose core to enable seamless integration with state-of-the-art sequence alignment

MOTIVATION: Pairwise sequence alignment is a core component of multiple sequencing-data analysis tools. Recent advancements in sequencing technologies have enabled the generation of longer sequences at a much lower price. Thus, long-read sequencing technologies have become increasingly popular in sequencing-based studies. However, classical sequence analysis algorithms face significant scalability challenges when aligning long sequences. As a result, several heuristic methods have been developed to improve performance at the expense of accuracy, as they often fail to produce the optimal alignment. RESULTS: This paper introduces QuickEd, a sequence alignment algorithm based on a bound-and-align strategy. First, QuickEd effectively bounds the maximum alignment-score using efficient heuristic strategies. Then, QuickEd utilizes this bound to reduce the computations required to produce the optimal alignment. Compared to O(n2) complexity of traditional dynamic programming algorithms, QuickEd's bound-and-align strategy achieves O(ns^) complexity, where n is the sequence length and s^ is an estimated upper bound of the alignment-score between the sequences. As a result, QuickEd is consistently faster than other state-of-the-art implementations, such as Edlib and BiWFA, achieving performance speedups of 4.2-5.9× and 3.8-4.4×, respectively, aligning long and noisy datasets. In addition, QuickEd maintains a stable memory footprint below 35 MB while aligning sequences up to 1 Mbp. AVAILABILITY AND IMPLEMENTATION: QuickEd code and documentation are publicly available at https://github.com/maxdoblas/QuickEd.

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.

MOTIVATION: Recent advances in sequencing technologies have stressed the critical role of sequence analysis algorithms and tools in genomics and healthcare research. In particular, sequence alignment is a fundamental building block in many sequence analysis pipelines and is frequently a performance bottleneck both in terms of execution time and memory usage. Classical sequence alignment algorithms are based on dynamic programming and often require quadratic time and memory with respect to the sequence length. As a result, classical sequence alignment algorithms fail to scale with increasing sequence lengths and quickly become memory-bound due to data-movement penalties. RESULTS: Processing-In-Memory (PIM) is an emerging architectural paradigm that seeks to accelerate memory-bound algorithms by bringing computation closer to the data to mitigate data-movement penalties. This work presents BIMSA (Bidirectional In-Memory Sequence Alignment), a PIM design and implementation for the state-of-the-art sequence alignment algorithm BiWFA (Bidirectional Wavefront Alignment), incorporating new hardware-aware optimizations for a production-ready PIM architecture (UPMEM). BIMSA supports aligning sequences up to 100K bases, exceeding the limitations of state-of-the-art PIM implementations. First, BIMSA achieves speedups up to 22.24× (11.95× on average) compared to state-of-the-art PIM-enabled implementations of sequence alignment algorithms. Second, achieves speedups up to 5.84× (2.83× on average) compared to the highest-performance multicore CPU implementation of BiWFA. Third, BIMSA exhibits linear scalability with the number of compute units in memory, enabling further performance improvements with upcoming PIM architectures equipped with more compute units and achieving speedups up to 9.56× (4.7× on average). AVAILABILITY AND IMPLEMENTATION: Code and documentation are publicly available at https://github.com/AlejandroAMarin/BIMSA.

Arm usage has substantially grown in the High-Performance Computing (HPC) community. Japanese supercomputer Fugaku, powered by Arm-based A64FX processors, held the top position on the Top500 list between June 2020 and June 2022, currently sitting in the fourth position. The recently released 7th generation of Amazon EC2 instances for compute-intensive workloads (C7 g) is also powered by Arm Graviton3 processors. Projects like European Mont-Blanc and U.S. DOE/NNSA Astra are further examples of Arm irruption in HPC. In parallel, over the last decade, the rapid improvement of genomic sequencing technologies and the exponential growth of sequencing data has placed a significant bottleneck on the computational side. While most genomics applications have been thoroughly tested and optimized for x86 systems, just a few are prepared to perform efficiently on Arm machines. Moreover, these applications do not exploit the newly introduced Scalable Vector Extensions (SVE). This paper presents GenArchBench, the first genome analysis benchmark suite targeting Arm architectures. We have selected computationally demanding kernels from the most widely used tools in genome data analysis and ported them to Arm-based A64FX and Graviton3 processors. Overall, the GenArch benchmark suite comprises 13 multi-core kernels from critical stages of widely-used genome analysis pipelines, including base-calling, read mapping, variant calling, and genome assembly. Our benchmark suite includes different input data sets per kernel (small and large), each with a corresponding regression test to verify the correctness of each execution automatically. Moreover, the porting features the usage of the novel Arm SVE instructions, algorithmic and code optimizations, and the exploitation of Arm-optimized libraries. We present the optimizations implemented in each kernel and a detailed performance evaluation and comparison of their performance on four different HPC machines (i.e., A64FX, Graviton3, Intel Xeon Skylake Platinum, and AMD EPYC Rome). Overall, the experimental evaluation shows that Graviton3 outperforms other machines on average. Moreover, we observed that the performance of the A64FX is significantly constrained by its small memory hierarchy and latencies. Additionally, as proof of concept, we study the performance of a production-ready tool that exploits two of the ported and optimized genomic kernels.

The ever-increasing yields in genome sequence data production pose a computational challenge to current genome sequence analysis tools, jeopardizing the future of personalized medicine. Leveraging hardware accelerators (GPUs, FPGAs, and ASICs) to accelerate computationally-intensive algorithms like sequence alignment has become paramount. Recently, the wavefront alignment algorithm was introduced, significantly reducing the execution time to perform sequence alignment. This paper presents the first-ever ASIC accelerator of the WFA integrated into a RISC-V system-on-chip. Our designed chip greatly accelerates sequence alignment, delivering up to 1076 × better performance over the CPU implementation of the WFA running on the RISC-V core of the chip.

Sequence alignment remains a fundamental problem in computer science with practical applications ranging from pattern matching to computational biology. The ever-increasing volumes of genomic data produced by modern DNA sequencers motivate improved software and hardware sequence alignment accelerators that scale with longer sequence lengths and high error rates without losing accuracy. Furthermore, the wide variety of use cases requiring sequence alignment demands flexible and efficient solutions that can match or even outperform expensive application-specific accelerators.

MOTIVATION: Advances in genomics and sequencing technologies demand faster and more scalable analysis methods that can process longer sequences with higher accuracy. However, classical pairwise alignment methods, based on dynamic programming (DP), impose impractical computational requirements to align long and noisy sequences like those produced by PacBio and Nanopore technologies. The recently proposed wavefront alignment (WFA) algorithm paves the way for more efficient alignment tools, improving time and memory complexity over previous methods. However, high-performance computing (HPC) platforms require efficient parallel algorithms and tools to exploit the computing resources available on modern accelerator-based architectures. RESULTS: This paper presents WFA-GPU, a GPU (graphics processing unit)-accelerated tool to compute exact gap-affine alignments based on the WFA algorithm. We present the algorithmic adaptations and performance optimizations that allow exploiting the massively parallel capabilities of modern GPU devices to accelerate the alignment computations. In particular, we propose a CPU-GPU co-design capable of performing inter-sequence and intra-sequence parallel sequence alignment, combining a succinct WFA-data representation with an efficient GPU implementation. As a result, we demonstrate that our implementation outperforms the original multi-threaded WFA implementation by up to 4.3× and up to 18.2× when using heuristic methods on long and noisy sequences. Compared to other state-of-the-art tools and libraries, the WFA-GPU is up to 29× faster than other GPU implementations and up to four orders of magnitude faster than other CPU implementations. Furthermore, WFA-GPU is the only GPU solution capable of correctly aligning long reads using a commodity GPU. AVAILABILITY AND IMPLEMENTATION: WFA-GPU code and documentation are publicly available at https://github.com/quim0/WFA-GPU.

MOTIVATION: Pairwise sequence alignment remains a fundamental problem in computational biology and bioinformatics. Recent advances in genomics and sequencing technologies demand faster and scalable algorithms that can cope with the ever-increasing sequence lengths. Classical pairwise alignment algorithms based on dynamic programming are strongly limited by quadratic requirements in time and memory. The recently proposed wavefront alignment algorithm (WFA) introduced an efficient algorithm to perform exact gap-affine alignment in O(ns) time, where s is the optimal score and n is the sequence length. Notwithstanding these bounds, WFA's O(s2) memory requirements become computationally impractical for genome-scale alignments, leading to a need for further improvement. RESULTS: In this article, we present the bidirectional WFA algorithm, the first gap-affine algorithm capable of computing optimal alignments in O(s) memory while retaining WFA's time complexity of O(ns). As a result, this work improves the lowest known memory bound O(n) to compute gap-affine alignments. In practice, our implementation never requires more than a few hundred MBs aligning noisy Oxford Nanopore Technologies reads up to 1 Mbp long while maintaining competitive execution times. AVAILABILITY AND IMPLEMENTATION: All code is publicly available at https://github.com/smarco/BiWFA-paper. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The RISC-V open Instruction Set Architecture (ISA) has proven to be a solid alternative to licensed ISAs. In the past 5 years, a plethora of industrial and academic cores and accelerators have been developed implementing this open ISA. In this paper, we present Sargantana, a 64-bit processor based on RISC-V that implements the RV64G ISA, a subset of the vector instructions extension (RVV 0.7.1), and custom application-specific instructions. Sargantana features a highly optimized 7-stage pipeline implementing out-of-order write-back, register renaming, and a non-blocking memory pipeline. Moreover, Sar-gantana features a Single Instruction Multiple Data (SIMD) unit that accelerates domain-specific applications. Sargantana achieves a 1.26 GHz frequency in the typical corner, and up to 1.69 GHz in the fast corner using 22nm FD-SOI commercial technology. As a result, Sargantana delivers a 1.77× higher Instructions Per Cycle (IPC) than our previous 5-stage in-order DVINO core, reaching 2.44 CoreMark/MHz. Our core design delivers comparable or even higher performance than other state-of-the-art academic cores performance under Autobench EEMBC benchmark suite. This way, Sargantana lays the foundations for future RISC-V based core designs able to meet industrial-class performance requirements for scientific, real-time, and high-performance computing applications.

An FPGA accelerator for the computation of the semi-global Levenshtein distance between a pattern and a reference text is presented. The accelerator provides an important benefit to reduce the execution time of read-mappers used in short-read genomic sequencing. Previous attempts to solve the same problem in FPGA use the Myers algorithm following a column approach to compute the dynamic programming table. We use an approach based on diagonals that allows for some resource savings while maintaining a very high throughput of 1 alignment per clock cycle. The design is implemented in OpenCL and tested on two FPGA accelerators. The maximum performance obtained is 91.5 MPairs/s for 100 × 120 sequences and 47 MPairs/s for 300 × 360 sequences, the highest ever reported for this problem.

In the last years, advances in next-generation sequencing technologies have enabled the proliferation of genomic applications that guide personalized medicine. These applications have an enormous computational cost due to the large amount of genomic data they process. The first step in many of these applications consists in aligning reads against a reference genome. Very recently, the wavefront alignment algorithm has been introduced, significantly reducing the execution time of the read alignment process. This paper presents the first FPGA-based hardware/software co-designed accelerator of such relevant algorithm. Compared to the reference WFA CPU-only implementation, the proposed FPGA accelerator achieves performance speedups of up to 13.5 × while consuming up to 14.6 × less energy.

MOTIVATION: Pairwise alignment of sequences is a fundamental method in modern molecular biology, implemented within multiple bioinformatics tools and libraries. Current advances in sequencing technologies press for the development of faster pairwise alignment algorithms that can scale with increasing read lengths and production yields. RESULTS: In this article, we present the wavefront alignment algorithm (WFA), an exact gap-affine algorithm that takes advantage of homologous regions between the sequences to accelerate the alignment process. As opposed to traditional dynamic programming algorithms that run in quadratic time, the WFA runs in time O(ns), proportional to the read length n and the alignment score s, using O(s2) memory. Furthermore, our algorithm exhibits simple data dependencies that can be easily vectorized, even by the automatic features of modern compilers, for different architectures, without the need to adapt the code. We evaluate the performance of our algorithm, together with other state-of-the-art implementations. As a result, we demonstrate that the WFA runs 20-300× faster than other methods aligning short Illumina-like sequences, and 10-100× faster using long noisy reads like those produced by Oxford Nanopore Technologies. AVAILABILITY AND IMPLEMENTATION: The WFA algorithm is implemented within the wavefront-aligner library, and it is publicly available at https://github.com/smarco/WFA.

Given the overwhelming impact of machine learning on the last decade, several libraries and frameworks have been developed in recent years to simplify the design and training of neural networks, providing array-based programming, automatic differentiation and user-friendly access to hardware accelerators. None of those tools, however, was designed with native and transparent support for Cloud Computing or heterogeneous High-Performance Computing (HPC). The DeepHealth Toolkit is an open source Deep Learning toolkit aimed at boosting productivity of data scientists operating in the medical field by providing a unified framework for the distributed training of neural networks, which is able to leverage hybrid HPC and cloud environments in a transparent way for the user. The toolkit is composed of a Computer Vision library, a Deep Learning library, and a front-end for non-expert users; all of the components are focused on the medical domain, but they are general purpose and can be applied to any other field. In this paper, the principles driving the design of the DeepHealth libraries are described, along with details about the implementation and the interaction between the different elements composing the toolkit. Finally, experiments on common benchmarks prove the efficiency of each separate component and of the DeepHealth Toolkit overall.

MOTIVATION: DNA methylation is essential for normal embryogenesis and development in mammals and can be captured at single base pair resolution by whole genome bisulfite sequencing (WGBS). Current available analysis tools are becoming rapidly outdated as they lack sensible functionality and efficiency to handle large amounts of data now commonly created. RESULTS: We developed gemBS, a fast high-throughput bioinformatics pipeline specifically designed for large scale BS-Seq analysis that combines a high performance BS-mapper (GEM3) and a variant caller specifically for BS-Seq data (BScall). gemBS provides genotype information and methylation estimates for all genomic cytosines in different contexts (CpG and non-CpG) and a set of quality reports for comprehensive and reproducible analysis. gemBS is highly modular and can be easily automated, while producing robust and accurate results. AVAILABILITY AND IMPLEMENTATION: gemBS is released under the GNU GPLv3+ license. Source code and documentation are freely available from www.statgen.cat/gemBS. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The recent advent of high-throughput sequencing machines producing big amounts of short reads has boosted the interest in efficient string searching techniques. As of today, many mainstream sequence alignment software tools rely on a special data structure, called the FM-index, which allows for fast exact searches in large genomic references. However, such searches translate into a pseudo-random memory access pattern, thus making memory access the limiting factor of all computation-efficient implementations, both on CPUs and GPUs. Here, we show that several strategies can be put in place to remove the memory bottleneck on the GPU: more compact indexes can be implemented by having more threads work cooperatively on larger memory blocks, and a k-step FM-index can be used to further reduce the number of memory accesses. The combination of those and other optimisations yields an implementation that is able to process about two Gbases of queries per second on our test platform, being about 8 × faster than a comparable multi-core CPU version, and about 3 × to 5 × faster than the FM-index implementation on the GPU provided by the recently announced Nvidia NVBIO bioinformatics library.

Approximate string matching is a very important problem in computational biology; it requires the fast computation of string distance as one of its essential components. Myers' bit-parallel algorithm improves the classical dynamic programming approach to Levenshtein distance computation, and offers competitive performance on CPUs. The main challenge when designing an efficient GPU implementation is to expose enough SIMD parallelism while at the same time keeping a relatively small working set for each thread.

The FM-index is a data structure which is seeing more and more pervasive use, in particular in the field of high-throughput bioinformatics. Algorithms based on it show a pseudo-random memory access pattern. As a consequence, they are usually bound by memory bandwidth rather than CPU usage. Naive GPU implementations are no exception. Here we show that the combination of a compact design of the FM-index and a thread-cooperative approach can be used to restore a proper balance. The resulting solution is less memory-bandwidth intensive, and allows full exploitation of the computational resources of the GPU across several GPU architectures.