GESTURE: Unsupervised Genotype-specific Behavioral Phenotyping in Rodents via Graph-based Representation Learning

<jats:p>Objective quantification of complex animal behavior is fundamental to neuroscience and pharmacology, yet extracting biologically meaningful insights from high-dimensional pose data remains challenging. This is especially true for subtle phenotypic differences caused by genetic mutations, which frequently evade conventional evaluation metrics. Here, we introduce GESTURE, an unsupervised, graph-based deep generative framework that autonomously discovers and quantifies behavioral structure from raw pose dynamics. Analyzing mice with motor dysfunction alongside wild-type controls, GESTURE identifies a shared vocabulary of behavioral motifs. We show that genotype-specific differences arise from the differential usage of these motifs, yielding distinct "behavioral fingerprints" that reliably separate genotypes without supervision. By modeling behavior as a sequence rather than a static partition, GESTURE measures temporal organization directly: affected animals held motifs longer and transitioned more predictably, revealing a slowing and stereotyping of behavioral sequences rather than a simple reduction in activity. Importantly, GESTURE's graph-based representation enables training across multiple recordings and embedding behaviors into a shared latent space, supporting robust cross-animal comparisons and future cross-experiment alignment. Furthermore, automatically derived metrics of behavioral divergence track the temporal dynamics of expert-annotated disability scores, reaching agreement comparable to independent human raters. Finally, node- and edge-level explainability analyses indicate that the model's latent representations are shaped by a biologically plausible focus on the animal's core motor scaffold. Together, these results position GESTURE as an interpretable and scalable framework for automated behavioral phenotyping, linking genetic perturbation to quantitative behavioral phenotypes.</jats:p>