Precisely defining disease variant effects in CRISPR-edited single cells

Yuriy Baglaenko (), Zepeng Mu, Michelle Curtis, Hafsa M. Mire, Vidyashree Jayanthi, Majd Al Suqri, Cassidy Liu, Ryan Agnew, Aparna Nathan, Annelise Yoo Mah-Som, David R. Liu, Gregory A. Newby and Soumya Raychaudhuri ()
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Yuriy Baglaenko: Brigham and Women’s Hospital
Zepeng Mu: Brigham and Women’s Hospital
Michelle Curtis: Brigham and Women’s Hospital
Hafsa M. Mire: Brigham and Women’s Hospital
Vidyashree Jayanthi: Brigham and Women’s Hospital
Majd Al Suqri: Brigham and Women’s Hospital
Cassidy Liu: Brigham and Women’s Hospital
Ryan Agnew: Brigham and Women’s Hospital
Aparna Nathan: Brigham and Women’s Hospital
Annelise Yoo Mah-Som: Brigham and Women’s Hospital
David R. Liu: Broad Institute of MIT and Harvard
Gregory A. Newby: Broad Institute of MIT and Harvard
Soumya Raychaudhuri: Brigham and Women’s Hospital

Nature, 2025, vol. 646, issue 8083, 117-125

Abstract: Abstract Genetic studies have identified thousands of individual disease-associated non-coding alleles, but the identification of the causal alleles and their functions remains a critical bottleneck1. CRISPR–Cas editing has enabled targeted modification of DNA to introduce and test disease alleles. However, the combination of inefficient editing, heterogeneous editing outcomes in individual cells and nonspecific transcriptional changes caused by editing and culturing conditions limits the ability to detect the functional consequences of disease alleles2,3. To overcome these challenges, we present a multi-omic single-cell sequencing approach that directly identifies genomic DNA edits, assays the transcriptome and measures cell-surface protein expression. We apply this approach to investigate the effects of gene disruption, deletions in regulatory regions, non-coding single-nucleotide polymorphism alleles and multiplexed editing. We identify the effects of individual single-nucleotide polymorphisms, including the state-specific effects of an IL2RA autoimmune variant in primary human T cells. Multimodal functional genomic single-cell assays, including DNA sequencing, enable the identification of causal variation in primary human cells and bridge a crucial gap in our understanding of complex human diseases.

Date: 2025
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DOI: 10.1038/s41586-025-09313-3

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