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arXiv:2609.16640

Graph construction in QUBO-based recursive phylogenetic tree reconstruction

Yoshiki Kanazawa, Takahiko Koyama

q-bio.PEquant-phSubmitted Sep 15, 2026• Announced Sep 16, 2026• Revised Sep 23, 2026 (v2)
v1 · Sep 15, 2026v2 · Sep 23, 2026
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Abstract

Molecular sequence data are used to reconstruct evolutionary relationships among taxa, but reconstruction accuracy depends not only on the tree-building method but also on how pairwise sequence relationships are represented. We evaluated sequence-to-affinity representations in a recursive normalized-cut (Ncut) framework whose graph-partitioning subproblems were formulated as quadratic unconstrained binary optimization (QUBO) models and solved using Simulated Bifurcation. Using simulated amino-acid and nucleotide datasets spanning multiple tree-generation settings and evolutionary divergence, we compared normalized bit-score affinities with representations derived from transformed sequence similarities and evolutionary distances, examined post-swap refinement, and used neighbor joining (NJ) as a distance-based comparator. Affinity representation substantially affected internal split recovery, particularly for nucleotide data. JC69-based local affinities maintained comparatively high accuracy as divergence increased, whereas normalized bit-score and BLAST-derived kernel representations declined more markedly. Post-swap refinement generally improved recovery, but not consistently across individual reconstructions. NJ achieved higher mean split recovery than corresponding recursive Ncut reconstructions for WAG and JC69 distances across all evaluated conditions, whereas recursive Ncut outperformed NJ for BLAST-derived logarithmic distances under some conditions. These results show that graph construction is an important determinant of recursive Ncut-based phylogenetic reconstruction. A representation that performs well within Ncut does not necessarily provide the most accurate use of the underlying pairwise distances. Pairwise representation, affinity transformation, optimization, and recursive tree construction should therefore be evaluated jointly.

Comments
23 pages, 6 figures, plus a graphical abstract; revised manuscript; author list updated

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Molecular sequence data are used to reconstruct evolutionary relationships among taxa, but reconstruction accuracy depends not only on the tree-building method but also on how pairwise sequence relationships are represented. We evaluated sequence-to-affinity representations in a recursive normalized-cut (Ncut) framework whose graph-partitioning subproblems were formulated as quadratic unconstrained binary optimization (QUBO) models and solved using Simulated Bifurcation. Using simulated amino-acid and nucleotide datasets spanning multiple tree-generation settings and evolutionary divergence, we compared normalized bit-score affinities with representations derived from transformed sequence similarities and evolutionary distances, examined post-swap refinement, and used neighbor joining (NJ) as a distance-based comparator.
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These results show that graph construction is an important determinant of recursive Ncut-based phylogenetic reconstruction. A representation that performs well within Ncut does not necessarily provide the most accurate use of the underlying pairwise distances. Pairwise representation, affinity transformation, optimization, and recursive tree construction should therefore be evaluated jointly.
Abstract Quantum computing applies principles of quantum mechanics, such as superposition and entanglement, to process information with exponential parallelism. This paradigm offers significant computational advantages over classical methods, particularly for NP-hard problems like phylogenetic tree reconstruction in evolutionary biology. Phylogenetic trees model the evolutionary relationships among species or genes, and their reconstruction is computationally challenging as the number of possible topologies grows exponentially with the number of taxa. To address this, biologists often rely on heuristic methods; however, recent work has shown that recursive graph-cut techniques can achieve high accuracy in phylogenetic inference, though at high computational cost. In this study, we present a quantum algorithm based on the normalized cut ( NcutN_{\text {cut}}Ncut​ N cut ) criterion, enabling efficient recursive graph partitioning. Implemented using Quantum Annealing (QA) and the Quantum Approximate Optimization Algorithm (QAOA), demonstrating promising results on real quantum hardware for complex bioinformatics tasks.
This paper sets out a computational workflow that reconstructs the phylogeny of human Y-chromosome populations from a Variant Call Format (VCF) file of biallelic Single Nucleotide Polymorphisms (SNP). The two classical phylogenetic decisions - topology selection and root placement - are cast as Quadratic Unconstrained Binary Optimisation (QUBO) problems. The workflow combines two QUBO formulations with an Alternating Direction Method of Multipliers (ADMM) decomposition strategy and a plug-in Digitized Counter-Diabatic Quantum Optimization (DCQO) solver, enabling large phylogenetic optimization problems to be executed across multiple classical or quantum computing resources. The DCQO gate-based optimizer drives each ADMM-block QUBO with short-depth counter-diabatic circuits in the impulse regime, without the necessity for an outer variational loop. The combination of ADMM decomposition and the DCQO block solver facilitates problem sizes that surpass the qubit budget of any individual digital quantum processing unit call, while maintaining the integrity of the original objective. The workflow extracts genotype information from VCF files, reconstructs topology and rooting through two QUBO formulations, and annotates the resulting tree using PhyloTree. The resultant data set comprises a Nexus-annotated rooted tree, in addition to diagnostic figures. The workflow demonstrates the potential of modest-scale QUBO formulations combined with ADMM decomposition to serve as a scalable alternative to greedy heuristics in the domain of population genomics.
Maximum compatibility provides a criterion for phylogenetic reconstruction in which the objective is to retain a maximum set of mutually compatible characters. For binary characters, pairwise compatibility can be represented by a weighted graph whose vertices correspond to characters and whose edges connect compatible pairs. A leading algorithm by Cherry [BMC Bioinformatics, 18(1):127, 2017] uses this representation to identify maximum compatible character sets as maximum weight cliques. We formulate the problem as maximum weight independent set enumeration on the complement graph and use deterministic postprocessing to map sampled bit strings to maximal feasible solutions. To explore the prospects of quantum computational advantage, we further construct bespoke correction-in-the-loop Quantum Approximate Optimisation Algorithm instances and find that traditional Lagrange multiplier choices may not be optimal for the enumeration problem on noisy devices. We also introduce lossless graph reductions with reconstruction rules that preserve the complete set of optimal solutions. Our results indicate that graph reduction and sampling can be effectively combined to address the enumeration bottleneck in maximum compatibility phylogeny, while retaining exact reconstruction when the residual optimum set is completely resolved. We enhance Cherry's approach to maximum compatibility by introducing graph reduction techniques and quantum sampling. Our classical benchmarks show a clear difference between finding one optimum and recovering the optimum set in practice. We demonstrate the utility of our methods on graphs constructed from SARS-CoV-2 sequences.
Bioinformatics has, among others, the issue of solving complex computational problems with vast amounts of sequencing data. Recently, a new computing architecture, the annealing machine, has emerged that applies to actual problems and is available for practical use. This novel architecture can solve discrete optimisation problems by replacing algorithms designed under the von Neumann architecture. To perform computations on the annealing machine, quadratic unconstrained binary optimisation (QUBO) formulations should be constructed and optimised according to the application. In this study, we developed an algorithm under the annealing machine architecture to solve sequence alignment problems, a known fundamental process widely used in genetic analysis, such as mutation detection and genome assembly. We constructed a QUBO formulation based on dynamic programming to solve a pairwise sequence alignment and derived its general form. We compared with conventional methods to solve 40 bp of pairwise alignment problem. Our implementation, named qualign, solved sequence alignment problems with accuracy comparable to that of conventional methods. Although a small pairwise alignment was solved owing to the limited memory size of this method, this is the first step of the application of annealing machines. We showed that our QUBO formulation solved the sequencing alignment problem. In the future, increasing the memory size of annealing machine will allow annealing machines to impact a wide range of bioinformatics applications positively.Availability: the source code of qualign is available at https://github.com/ymatsumoto/qualign
Combinatorial optimization problems are typically formulated using Quadratic Unconstrained Binary Optimization (QUBO), where constraints are enforced through penalty terms that introduce auxiliary variables and rapidly increase Hamiltonian complexity, limiting scalability on near term quantum devices. In this work, we systematically study Quadratic Unconstrained D-ary Optimization (QUDO) as an alternative formulation in which decision variables are encoded directly in higher dimensional Hilbert spaces. We demonstrate that QUDO naturally captures structural constraints across a range of problem classes, including the Traveling Salesman Problem, two variants of the Vehicle Routing Problem, graph coloring, job scheduling, and Max-K-Cut, without the need for extensive penalty constructions. Using a qudit-level implementation of the Quantum Approximate Optimization Algorithm (qudit QAOA), we benchmark these formulations against their binary QUBO counterparts and exact classical solutions. Our study show consistently improved approximation ratios and substantially reduced computational overhead at comparable circuit depths, highlighting QUDO as a scalable and expressive representation for quantum combinatorial optimization.
We investigate a link between Graph Neural Networks (GNNs) and Quadratic Unconstrained Binary Optimization (QUBO) problems, laying the groundwork for GNNs to approximate solutions for these computationally challenging tasks. By analyzing the sensitivity of QUBO formulations, we frame the solution of QUBO problems as a heterophilic node classification task. We then propose QUBO-GNN, an architecture that integrates graph representation learning techniques with QUBO-aware features to approximate solutions efficiently. Additionally, we introduce a self-supervised data generation mechanism to enable efficient and scalable training data acquisition even for large-scale QUBO instances. Experimental evaluations of QUBO-GNN across diverse QUBO problem sizes demonstrate its superior performance compared to exhaustive search and heuristic methods. Finally, we discuss open challenges in the emerging intersection between QUBO optimization and GNN-based learning.