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arXiv:2604.06106

Nonvariational quantum optimisation approaches to pangenome-guided sequence assembly

Josh Cudby, Sergii Strelchuk

quant-phSubmitted Apr 7, 2026• Announced Apr 8, 2026• 0 citations
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Abstract

Assembling genomes from short-read sequencing data remains difficult in repetitive regions, where reference bias and combinatorial complexity limit existing methods. Pangenome-guided sequence assembly (PGSA) mitigates reference bias by reconstructing an individual genome as a walk through a population-level graph. The associated problem, identifying a walk whose node visits match read-derived copy numbers, is NP-hard and already challenges classical solvers at a moderate scale. We develop near-term quantum optimisation approaches for this computational bottleneck. We consider two problem encodings: an established quadratic unconstrained binary optimisation and a new higher-order binary optimisation (HUBO) formulation. The latter reduces the number of variables from $O(N^2)$ to $O(N\log N)$ and places moderate-sized instances within the qubit budget of current devices. We solve both using the Iterative-QAOA framework, which combines a fixed linear-ramp QAOA schedule with iterative warm-start bias updates, avoiding the overhead of full variational parameter optimisation. A custom circuit compilation strategy reduces hardware gate overhead by up to 67\% compared with standard tools. In noiseless simulations of QUBO problems, Iterative-QAOA reliably identifies optimal assemblies from as few as $10^{-17}\%$ of all candidate solutions, and \textit{IBM} quantum hardware closely reproduces relevant results with sufficient sampling via CVaR-style post-selection. For HUBO, the variable reduction comes at the cost of deeper compiled circuits and greater noise sensitivity: an expected qubit--depth trade-off. Our findings establish pangenome assembly as a concrete, biologically motivated problem class at the scale where quantum optimisation may first provide practical value.

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Assembling genomes from short-read sequencing data remains difficult in repetitive regions, where reference bias and combinatorial complexity limit existing methods. Pangenome-guided sequence assembly (PGSA) mitigates reference bias by reconstructing an individual genome as a walk through a population-level graph. The associated problem, identifying a walk whose node visits match read-derived copy numbers, is NP-hard and already challenges classical solvers at a moderate scale. We develop near-term quantum optimisation approaches for this computational bottleneck. We consider two problem encodings: an established quadratic unconstrained binary optimisation and a new higher-order binary optimisation (HUBO) formulation. The latter reduces the number of variables from O(N2)O(N^2)O(N2) to O(Nlog⁡N)O(N\log N)O(NlogN) and places moderate-sized instances within the qubit budget of current devices. We solve both using the Iterative-QAOA framework, which combines a fixed linear-ramp QAOA schedule with iterative warm-start bias updates, avoiding the overhead of full variational parameter optimisation. A custom circuit compilation strategy reduces hardware gate overhead by up to 67% compared with standard tools. In noiseless simulations of QUBO problems, Iterative-QAOA reliably identifies optimal assemblies from as few as 10−17%10^{-17}\%10−17% of all candidate solutions, and \textit{IBM} quantum hardware closely reproduces relevant results with sufficient sampling via CVaR-style post-selection. For HUBO, the variable reduction comes at the cost of deeper compiled circuits and greater noise sensitivity: an expected qubit--depth trade-off. Our findings establish pangenome assembly as a concrete, biologically motivated problem class at the scale where quantum optimisation may first provide practical value.
The Quantum Approximate Optimisation Algorithm (QAOA) has emerged as a leading candidate for near-term quantum advantage in combinatorial optimisation, but most evaluations remain confined to synthetic benchmarks such as random MaxCut instances. Translating QAOA to real-world problem instances -- with irregular graph structures, heterogeneous constraint types, and practical scale requirements -- introduces additional challenges including QUBO formulation overhead, hardware embedding costs, and the performance gap between QAOA on structured real instances vs. random benchmarks. This paper presents the Real-World QAOA (RW-QAOA) framework, a systematic methodology for applying QAOA to four real-world application domains: supply chain network optimisation, financial portfolio rebalancing, telecommunications frequency assignment, and traffic signal timing optimisation. RW-QAOA introduces three methodological contributions: a domain-adaptive QUBO formulator (DAQF) encoding real-world constraints as penalised QUBO terms with penalty coefficient auto-tuning; a warm-start initialisation strategy (WSIS) using classical heuristic solutions to seed QAOA parameter search; and a layered noise adaptation protocol (LNAP) adjusting circuit depth based on real-time device calibration data. RW-QAOA is evaluated on real problem instances from industry partners across all four domains on IBM Quantum Eagle (127-qubit). RW-QAOA achieves solution quality within 4.2% of classical exact solvers across all four domains, outperforming classical greedy heuristics by 12.4% (SD = 3.8%) on average. WSIS reduces QAOA parameter convergence iterations by 48.4%. LNAP improves approximation ratio by 8.4pp vs. fixed-depth QAOA under device noise variation.
Abstract Genome assembly is important in infectious disease surveillance, antimicrobial resistance monitoring, and cancer genomics. The task of reconstructing full genomic sequences from fragmented reads, can be framed as a large scale combinatorial optimisation problem. Recent advances in quantum computing have introduced new optimisation algorithms with potential advantages for navigating complex combinatorial search spaces. However, practical deployment is limited by noisy intermediate-scale quantum (NISQ) hardware, including restricted qubit counts, limited connectivity, and high error rates. In this research, we employ the Hamiltonian Auto Decomposition Optimisation Framework (HADOF), an algorithm agnostic framework that enables scalable quantum optimisation through federated solving across small subproblems. HADOF enabled the quantum-assisted genome assembly of a 7.1 Million base pairs Pseudomonas aeruginosa genome, to our knowledge, representing the largest genome assembly graph studied on real quantum hardware to date. The results achieved a 99.348% genome fraction and 1.0 duplication ratio, demonstrating that biologically plausible genome reconstructions can be obtained despite current hardware limitations.
Accurate prediction of mRNA secondary structure is critical for understanding gene expression, translation efficiency, and advancing mRNA-based therapeutics. However, the combinatorial complexity of possible foldings, especially in long sequences, poses significant computational challenges for classical algorithms. In this work, we propose a scalable, quantum-centric optimization framework that integrates quantum sampling with classical post-processing to tackle this problem. Building on a Quadratic Unconstrained Binary Optimization (QUBO) formulation of the mRNA folding task, we develop two complementary workflows: a Conditional Value at Risk (CVaR)-based variational quantum algorithm enhanced with gauge transformations and local search, and an Instantaneous Quantum Polynomial (IQP) circuit-based scheme where training is done classically and sampling is delegated to quantum hardware. We demonstrate the effectiveness of these approaches using IBM quantum processors, solving problem instances with up to 156 qubits and circuits containing up to 950 nonlocal gates, corresponding to mRNA sequences of up to 60 nucleotides. Additionally, we validate scalability of the CVaR algorithm on a tensor network simulator, reaching up to 354 qubits in noiseless settings. These results demonstrate the growing practical capabilities of hybrid quantum-classical methods for tackling large-scale biological optimization problems.
Metagenomic analysis of the 'microbial dark matter'-the vast majority of microorganisms lacking reference genomes-depends critically on de novo assembly methods. These approaches enable genome reconstruction directly from sequencing data without prior genomic knowledge, revealing previously unknown microbial diversity. Here, we introduce a graph transformation algorithm that converts bidirected compressed De Bruijn genomic graphs into directed graphs, then formulate the de novo assembly challenge as a Quadratic Unconstrained Binary Optimization (QUBO) problem addressable through the Quantum Approximate Optimization Algorithm (QAOA). Computational exploration was conducted on the Eviden Qaptiva 800 emulator using real-world viral data. Our analysis reveals that while QAOA successfully identifies valid assembly paths in small-scale instances, qubit requirements scale linearly with graph edge counts, presenting a bottleneck for larger bacterial genomes. To address this scalability issue, we propose a graph decomposition strategy to break down large assembly graphs into manageable subgraphs. This study establishes a proof-of-concept for quantum-enhanced de novo assembly, exploring the capabilities of QAOA against classical solvers and highlighting a path toward quantum-driven de novo assembly.
The increasing complexity of industrial scheduling and transport routing problems motivates the study of alternative optimization formulations and computational paradigms. In this work, we study how higher-order unconstrained binary optimization (HUBO) formulations of such problems map onto quantum optimization workflows in both noisy and fault-tolerant regimes. We consider three representative logistics and manufacturing use cases and formulate each as a HUBO problem. This captures process intricacies, such as highly correlated assembly-line scheduling rules, which are difficult to express faithfully with the standard quadratic (QUBO) form, while at the same time reducing the number of binary variables required in the quantum mapping, thus lowering qubit demand. We compare the HUBO formulations with corresponding QUBO encodings, highlighting a key trade-off: while HUBO reduces qubit requirements through compact binary encoding, it introduces higher-order interaction terms that increase circuit depth, limiting feasibility on current quantum hardware. The proposed formulations are validated using classical solvers across several problem instances and benchmark small routing problem instances using bias-field digitized counterdiabatic quantum optimization in classical simulation. We complement these results with a resource and scalability analysis, focusing on the capacitated vehicle routing problem as a representative large-scale industrial use case. Our analysis indicates that while HUBO formulations offer advantages in qubit scaling compared to QUBO encodings, their practical implementation is constrained by gate fidelity, coherence, and circuit depth, making hybrid quantum-classical workflows and early fault-tolerant quantum hardware the most plausible settings for their practical use.
Abstract The difficult computational task of de novo genome assembly is to piece together the original DNA sequence from a collection of overlapping pieces. The issue can be expressed as an NP-hard quadratic unconstrained binary optimization (QUBO) problem. To solve QUBO problems more effectively than conventional techniques, quantum computing presents a viable alternative. This is because quantum annealers and gate-based quantum algorithms may take advantage of quantum effects like superposition and entanglement. But there are drawbacks to quantum computing as well, such scalability, noise, and decoherence. In this work, we present a hybrid quantum-classical optimization algorithm that solves the QUBO problem of de novo genome assembly by utilizing the advantages of both paradigms. To find near-optimal solutions in the presence of defects and noise, our technique combines a classical local search heuristic with a quantum approximate optimization algorithm (QAOA). We assess our algorithm's performance against current quantum and conventional approaches using both artificial and actual data sets. We demonstrate that our algorithm can outperform the state-of-the-art methods in terms of accuracy and computing cost, and it has the potential to solve intricate and large-scale genome assembly challenges.