Protein language models (PLMs) are often assumed to capture evolutionary information by training on large protein sequence datasets. Yet it remains unclear whether PLMs can reason about evolution—that is, infer evolutionary relationships between sequences. We test this capability by evaluating whether standard PLM usage, frozen or fine-tuned embeddings with distance-based comparison, supports evolutionary reasoning. Existing PLMs consistently fail to recover phylogenetic structure, despite strong performance on sequence-level tasks such as masked-token and contact prediction. We present Phyla, a hybrid state-space and transformer model that jointly processes multiple sequences and is trained using a tree-based objective across 3,000 phylogenies spanning diverse protein families. Phyla outperforms the next-best PLM by 9\% on tree reconstruction and 23\% on taxonomic clustering while remaining alignment- and guide-tree-free. Although classical alignment pipelines achieve higher absolute accuracy, Phyla narrows the gap and achieves markedly lower end-to-end runtime. Applied to real data, Phyla reconstructs biologically accurate clades in the tree of life and resolves genome-scale relationships among Mycobacterium tuberculosis isolates. These findings suggest that, under standard usage, evolutionary reasoning does not reliably emerge from large-scale sequence modeling. Instead, Phyla shows that models trained with phylogenetic supervision can reason about evolution more effectively, offering a biologically grounded path toward evolutionary foundation models.

MOTIVATION: Somatic mosaicism has been implicated in several developmental disorders, cancers, and other diseases. Short tandem repeats (STRs) consist of repeated sequences of 1-6 bp and comprise >1 million loci in the human genome. Somatic mosaicism at STRs is known to play a key role in the pathogenicity of loci implicated in repeat expansion disorders and is highly prevalent in cancers exhibiting microsatellite instability. While a variety of tools have been developed to genotype germline variation at STRs, a method for systematically identifying mosaic STRs is lacking. RESULTS: We introduce prancSTR, a novel method for detecting mosaic STRs from individual high-throughput sequencing datasets. prancSTR is designed to detect loci characterized by a single high-frequency mosaic allele, but can also detect loci with multiple mosaic alleles. Unlike many existing mosaicism detection methods for other variant types, prancSTR does not require a matched control sample as input. We show that prancSTR accurately identifies mosaic STRs in simulated data, demonstrate its feasibility by identifying candidate mosaic STRs in Illumina whole genome sequencing data derived from lymphoblastoid cell lines for individuals sequenced by the 1000 Genomes Project, and evaluate the use of prancSTR on Element and PacBio data. In addition to prancSTR, we present simTR, a novel simulation framework which simulates raw sequencing reads with realistic error profiles at STRs. AVAILABILITY AND IMPLEMENTATION: prancSTR and simTR are freely available at https://github.com/gymrek-lab/trtools. Detailed documentation is available at https://trtools.readthedocs.io/.

Out-of-distribution (OOD) data poses serious challenges in deployed machine learning models, so methods of predicting a model's performance on OOD data without labels are important for machine learning safety. While a number of methods have been proposed by prior work, they often underestimate the actual error, sometimes by a large margin, which greatly impacts their applicability to real tasks. In this work, we identify *pseudo-label shift*, or the difference between the predicted and true OOD label distributions, as a key indicator of this underestimation. Based on this observation, we introduce a novel method for estimating model performance by leveraging optimal transport theory, Confidence Optimal Transport (COT), and show that it provably provides more robust error estimates in the presence of pseudo-label shift. Additionally, we introduce an empirically-motivated variant of COT, Confidence Optimal Transport with Thresholding (COTT), which applies thresholding to the individual transport costs and further improves the accuracy of COT's error estimates. We evaluate COT and COTT on a variety of standard benchmarks that induce various types of distribution shift -- synthetic, novel subpopulation, and natural -- and show that our approaches significantly outperform existing state-of-the-art methods with up to 3x lower prediction errors.

Reinforcement Learning (RL) agents in the real world must satisfy safety constraints in addition to maximizing a reward objective. Model-based RL algorithms hold promise for reducing unsafe real-world actions: they may synthesize policies that obey all constraints using simulated samples from a learned model. However, imperfect models can result in real-world constraint violations even for actions that are predicted to satisfy all constraints. We propose Conservative and Adaptive Penalty (CAP), a model-based safe RL framework that accounts for potential modeling errors by capturing model uncertainty and adaptively exploiting it to balance the reward and the cost objectives. First, CAP inflates predicted costs using an uncertainty-based penalty. Theoretically, we show that policies that satisfy this conservative cost constraint are guaranteed to also be feasible in the true environment. We further show that this guarantees the safety of all intermediate solutions during RL training. Further, CAP adaptively tunes this penalty during training using true cost feedback from the environment. We evaluate this conservative and adaptive penalty-based approach for model-based safe RL extensively on state and image-based environments. Our results demonstrate substantial gains in sample-efficiency while incurring fewer violations than prior safe RL algorithms. Code is available at: https://github.com/Redrew/CAP

We propose State Matching Offline DIstribution Correction Estimation (SMODICE), a novel and versatile regression-based offline imitation learning algorithm derived via state-occupancy matching. We show that the SMODICE objective admits a simple optimization procedure through an application of Fenchel duality and an analytic solution in tabular MDPs. Without requiring access to expert actions, SMODICE can be effectively applied to three offline IL settings: (i) imitation from observations (IfO), (ii) IfO with dynamics or morphologically mismatched expert, and (iii) example-based reinforcement learning, which we show can be formulated as a state-occupancy matching problem. We extensively evaluate SMODICE on both gridworld environments as well as on high-dimensional offline benchmarks. Our results demonstrate that SMODICE is effective for all three problem settings and significantly outperforms prior state-of-art.