Αlpha¹ Record ID: 66782BBF
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Sydney B. Blattman, Nabih Maslah, Austin A. Varela, Karolis Kumpaitis, Benan Nalbant, Catherine Snopkowski, Marisa Mariani, Laura C. Kida, Meril Takizawa, Nalin Ratnayeke et al.
Single-cell transcriptomics has revolutionized our understanding of heterogeneous cell populations. However, technical limitations of widely-used platforms have limited our ability to link transcriptional states to somatic mutations within the same cells at scale. Here, we introduce Genotyping in Fixed Transcriptomes (GIFT), a novel assay for simultaneous detection of hundreds of targeted genetic variants and whole transcriptome profiles in single cells. The core innovation of GIFT is a rationally designed gapfilling reaction between adjacent single-stranded DNA (ssDNA) probes that barcodes native transcript sequence to enable highly-specific targeted mutation detection. GIFT achieves >99% genotyping accuracy and flexible capture of hundreds of mutations per cell, including in FFPE (Formalin-Fixed Paraffin-Embedded) tissue, enabling clonal lineage tracing in heterogeneous settings. We demonstrate the unique scalability of GIFT by profiling >700,000 cells from 35 donors with myeloproliferative neoplasms (MPN), revealing mutation-dependent hematopoietic responses to systemic inflammation associated with the characteristic JAK2V617 mutation, including an allelic dose gradient of interferon-associated transcriptional programs and transcriptional priming of hematopoietic stem cells that develop into divergent disease states. Together, the unique technical advantages of GIFT enable direct resolution of genotype-to-phenotype relationships via clonal lineage tracing with comprehensive cell state measurements at single-cell resolution.
GIFT genotypes hundreds of mutations while reading the full transcriptome from fixed single cells. It's like giving old FFPE samples a high-tech DNA barcode upgrade, revealing how mutant clones drive inflammation in blood cancers.
Posted by PI Caleb Lareau (@CalebLareau) with co-authors from MSKCC and 10x Genomics. Drew excitement from single-cell and cancer genomics communities for scalability and clonal tracing power
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CD4⁺ T cells confer transplantable rejuvenation via Rivers of telomeres
Lanna, A.; Valvo, S.; Dustin, M.; Rinaldi, F.
Using a GPT-5-driven autonomous lab to optimize the cost and titer of cell-free protein synthesis
Smith, A. A.; Wong, E. L.; Donovan, R. C.; Chapman, B. A.; Harry, R.; Tirandazi, P.; Kanigowska, P.; Gendreau, E. A.; Dahl, R. H.; Jastrzebski, M.; Cortez, J. E.; Bremner, C. J.; Hemuda, J. C. M.; Dooner, J.; Graves, I.; Karandikar, R.; Lionetti, C.; Christopher, K.; Consiglio, A. L.; Tran, A.; McCusker, W.; Nguyen, D. X.; Nunes da Silva, I. B.; Bautista-Ayala, A. R.; McNerney, M. P.; Atkins, S.; McDuffie, M.; Serber, W.; Barber, B. P.; Thanongsinh, T.; Nesson, A.; Lama, B.; Nichols, B.; LaFrance, C.; Nyima, T.; Byrn, A.; Thornhill, R.; Cai, B.; Ayala-Valdez, L.; Wong, A.; Che, A. J.; Thavaraj
A Single-Cell and Spatial 3D Multi-omic Atlas of Developing Human Basal Ganglia and Inhibitory Neurons
Heffel, M. G.; Xu, H.; Pastor-Alonso, O.; Li, X.; Baig, M. S.; Irfan Ghoor, R.; Li, R.; Kern, C.; Kum, J.; Zhang, Y.; Paino, J.; Tsai, M. J.; Tai, C.-Y.; Tucker, G.; Zhao, Z.; Hou, A.; von Behren, Z.; Bhade, M.; Li, S.; Sandoval, K.; Scholes, J.; Codrea, F.; Calimlim, J.; Liao, E. K.; Leung, G.; Kim, J.; Eskin, E.; Flint, J.; Cotter, J. A.; Pasaniuc, B.; Bintu, B.; Zhu, Q.; Mukamel, E. A.; Ernst, J.; Paredes, M. F.; Luo, C.
Prediction of transformative breakthroughs in biomedical research
Davis, M. T.; Busse, B. L.; Arabi, S.; Meyer, P.; Hoppe, T. A.; Meseroll, R. A.; Hutchins, B. I.; Willis, K. A.; Santangelo, G. M.