In situ genome sequencing resolves DNA sequence and structure in intact biological samples

Andrew C. Payne, Zachary D. Chiang, Paul L. Reginato, Sarah M. Mangiameli, Evan M. Murray, Chun Chen Yao, Styliani Markoulaki, Andrew S. Earl, Ajay S. Labade, Rudolf Jaenisch, George M. Church, Edward S. Boyden*, Jason D. Buenrostro, Fei Chen

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


Understanding genome organization requires integration of DNA sequence and three-dimensional spatial context; however, existing genome-wide methods lack either base pair sequence resolution or direct spatial localization. Here, we describe in situ genome sequencing (IGS), a method for simultaneously sequencing and imaging genomes within intact biological samples. We applied IGS to human fibroblasts and early mouse embryos, spatially localizing thousands of genomic loci in individual nuclei. Using these data, we characterized parent-specific changes in genome structure across embryonic stages, revealed single-cell chromatin domains in zygotes, and uncovered epigenetic memory of global chromosome positioning within individual embryos. These results demonstrate how IGS can directly connect sequence and structure across length scales from single base pairs to whole organisms.

Original languageEnglish (US)
Article numberaay3446
Issue number6532
StatePublished - Feb 26 2021

ASJC Scopus subject areas

  • General


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