Single-cell foundation modeling with species-nativeprotein tokens links regenerative competence across frog and mouse

Abstract

Appendage regenerative capacity varies dramatically across species, developmental stages, and anatomical sites, yet comparing functional transitions across organisms remains difficult because gene vocabularies diverge. Cross-species single-cell analysis conventionally collapses divergent genomes to one-to-one orthologs--a reduction that is not neutral. Here, we construct a species-native input representation for allotetraploid Xenopus laevis that preserves duplicated L and S homeologs (96.39% feature coverage versus 53.14% under symbol collapse) within a frozen universal cell embedding (UCE). A causally validated tail-organizer contrast defines a portable vector competence ruler. While baseline representations (direct expression, SVD, Harmony) recover organizer identity, only species-native UCE preserves the stage-52-versus-stage-58 limb competence transition, which ortholog collapse reverses. Applied without refitting, the ruler distinguishes regenerative from fibrotic digit repair in adult mice and resolves an aligned component in state-balanced macrophages, an ordering reproduced by simpler representations. Preserving species-native gene vocabularies carries functional contrasts across evolutionary and genomic boundaries.