Abstract
Variational autoencoders (VAEs) trained on multiple sequence alignments (MSAs) have emerged as powerful generative models for biological sequences, with applications ranging from disease variant prediction to functional RNA design. However, standard biological VAE training treats all sequences as exchangeable, ignoring the rich evolutionary structure that organizes homologous sequences from evolutionarily close to highly divergent. We propose Evolutionary Curriculum Learning (ECL), a training strategy that exploits this structure by progressively exposing the model to sequences of increasing evolutionary distance from sampled anchors, following a power-law expansion schedule. Applied to two architecturally distinct VAE models and two biological domains--protein variant effect prediction with EVE and RNA family sequence generation with RfamGen--ECL improves downstream task performance across five random seeds per configuration. Mean ClinVar classification AUROC rises from 0.981 to 0.989 for p53; for PTEN, ECL attains 1.000 in every seed whereas the baseline is unstable (mean 0.905, falling as low as 0.54). For RNA, ECL raises mean covariance-model bit scores on all three families tested and exceeds its seed-matched baseline in 12 of 15 training runs, though with only three families the effect cannot be established as significant at the family level. Ablation experiments show that progressively expanding the sampled sequences by evolutionary distance outperforms fixed-size neighborhood sampling in addition to uniform random sampling. Evolutionary distance is therefore a useful inductive bias for ordering the training curriculum in biological sequence modeling.
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May 7, 2026cs.LG
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Zhongmou Chao, Poompol Buathong, Ekaterina Selivanovitch +2
Apr 30, 2026cs.LG
Proteins are shaped by gradual evolution under biophysical and functional constraints. Protein language models learn rich evolutionary constraints from large-scale sequences, and discrete diffusion-based protein language models~(\eg, DPLMs) are promising for both understanding and generation. However, existing DPLMs typically rely on masked diffusion that contradicts a simple biological intuition: proteins evolve through accumulated edits, not by emerging from masks. Consequently, these frameworks lack explicit pretraining objectives for substitution and insertion/deletion (indel) operations, limiting both optimization-style post-editing and flexible guided generation. To address these limitations, we present DPLM-Evo, an evolutionary discrete diffusion framework that explicitly predicts substitution, insertion, and deletion operations during denoising. DPLM-Evo decouples an upsampled-length latent alignment space from the variable-length observed sequence space, which makes indel-aware generation tractable. To better align substitutions with real evolution, we further introduce a contextualized evolutionary noising kernel that produces biologically informed, context-dependent mutation patterns. Across tasks, DPLM-Evo improves sequence understanding and achieves state-of-the-art mutation effect prediction performance on ProteinGym in the single-sequence setting. It also enables variable-length simulated evolution, and post-editing/optimization of existing proteins via explicit edit trajectories.
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Jun 3, 2026cs.NE
Neuroevolution is a representative neural architecture search paradigm that evolves both network topology and weights through evolutionary algorithms. In this paper, we propose Seq103, a unified NEAT-style neuroevolution framework for compact sequence architecture discovery. Seq103 consists of a shared evolutionary backbone and an optional recurrent extension. The shared backbone includes an elementary node-and-connection representation, per-class RMSE-based evaluation, mutation-based evolution with class-wise recombination, and elitism. The optional hidden-state mechanism extends the search space with hidden-state nodes and hidden connections, enabling temporal memory when step-wise recurrent inference is required. With this design, Seq103 applies the same core search pipeline to both step-wise recurrent and sample-wise feedforward sequence classification. In recurrent tasks, the hidden-state extension is enabled to provide temporal memory; in feedforward tasks, it is disabled while the shared evolutionary backbone remains unchanged. We evaluate Seq103 on 8 text classification datasets and the full UCRArchive2018 benchmark with 128 univariate time-series datasets. On step-wise tasks, Seq103 retains 86.96% of the best-baseline accuracy on average while using 34.6x to 3218.0x fewer parameters. On sample-wise tasks over the full UCRArchive2018 benchmark, Seq103 retains 81.95% of the best-baseline accuracy on average while using 11.8x to 160,601.0x fewer parameters.
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