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<p>Integrating single-cell RNA-sequencing (scRNA-seq) data across species is hindered by evolutionary divergence, technical batch effects, and the reliance on one-to-one orthologs. Here, we present Unify, a transfer learning methodology that learns universal cell embeddings by defining functionally coherent, multi-modal macrogenes. This is achieved by combining RNA expression with embeddings from protein language models and general-purpose language models. Unify transcends species boundaries, enabling cross-species comparisons beyond strict gene-level homology. Unify corrects batch effects while preserving conserved biological signals across vast evolutionary distances and enables more accurate prediction of perturbation responses across species, such as from mouse to human. Applied to species separated by over 700 million years, Unify reconstructs more accurate multi-species cell-type evolutionary trees and uncovers convergent gene programs. Together, these results establish Unify as a powerful method for comparative single-cell genomics and evolutionary biology.</p>

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Unify learns cellular evolution with universal multimodal embeddings

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月31日

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  • Huawen Zhong,
  • Wenkai Han,
  • Guoxin Cui,
  • David Gomez-Cabrero,
  • Jesper Tegner,
  • Xin Gao,
  • Manuel Aranda

摘要

Integrating single-cell RNA-sequencing (scRNA-seq) data across species is hindered by evolutionary divergence, technical batch effects, and the reliance on one-to-one orthologs. Here, we present Unify, a transfer learning methodology that learns universal cell embeddings by defining functionally coherent, multi-modal macrogenes. This is achieved by combining RNA expression with embeddings from protein language models and general-purpose language models. Unify transcends species boundaries, enabling cross-species comparisons beyond strict gene-level homology. Unify corrects batch effects while preserving conserved biological signals across vast evolutionary distances and enables more accurate prediction of perturbation responses across species, such as from mouse to human. Applied to species separated by over 700 million years, Unify reconstructs more accurate multi-species cell-type evolutionary trees and uncovers convergent gene programs. Together, these results establish Unify as a powerful method for comparative single-cell genomics and evolutionary biology.