Systematic evaluation of single-cell multimodal data integration for comprehensive human reference atlas.

Acera-Mateos, M.; Adiconis, X.; Li, J.-K.; Marchese, D.; Caratu, G.; Hon, C.-C.; Tiwari, P.; Kojima, M.; Vieth, B.; Murphy, M. A.; Simmons, S. K.; Lefevre, T.; Claes, I.; O'Connor, C. L.; Menon, R.; Otto, E. A.; Ando, Y.; Vandereyken, K.; Kretzler, M.; Bitzer, M.; Fraenkel, E.; Voet, T.; Enard, W.; Carnici, P.; Heyn, H.; Levin, J. Z.; Mereu, E.

doi:10.1101/2025.03.06.637075

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bioRxiv · 10.1101/2025.03.06.637075

Systematic evaluation of single-cell multimodal data integration for comprehensive human reference atlas.

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Abstract

The integration of multimodal single-cell data enables comprehensive organ reference atlases, yet its impact remains largely unexplored, particularly in complex tissues. We generated a benchmarking dataset for the renal cortex by integrating 3 and 5 scRNA-seq with joint snRNA-seq and snATAC-seq, profiling 119,744 high-quality nuclei/cells from 19 donors. To align cell identities and enable consistent comparisons, we developed the interpretable machine learning tool scOMM (single-cell Omics Multimodal Mapping) and systematically assessed integration strategies. "Horizontal" integration of scRNA and snRNA-seq improved cell-type identification, while "vertical" integration of snRNA-seq and snATAC-seq had an additive effect, enhancing resolution in homogeneous populations and difficult-to-identify states. Global integration was especially effective in identifying adaptive states and rare cell types, including WFDC2-expressing Thick Ascending Limb and Norn cells, previously undetected in kidney atlases. Our work establishes a robust framework for multimodal reference atlas generation, advancing single-cell analysis and extending its applicability to diverse tissues.

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Acera-Mateos, M., Adiconis, X., Li, J.-K., Marchese, D., Caratu, G., Hon, C.-C., Tiwari, P., Kojima, M., Vieth, B., Murphy, M. A., Simmons, S. K., Lefevre, T., Claes, I., O'Connor, C. L., Menon, R., Otto, E. A., Ando, Y., Vandereyken, K., Kretzler, M., Bitzer, M., Fraenkel, E., Voet, T., Enard, W., Carnici, P., Heyn, H., Levin, J. Z., Mereu, E.. 2025-03-06. Systematic evaluation of single-cell multimodal data integration for comprehensive human reference atlas.. https://doi.org/10.1101/2025.03.06.637075

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