Journal
SCIENCE
Volume 361, Issue 6405, Pages 924-928Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aat5641
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Funding
- Beijing Advanced Innovation Center for Genomics at Peking University
- Harvard Brain Initiative (HBI) Collaborative Seed Grant
- National Science Foundation of China [21390412, 21327808]
- HHMI International Student Research Fellowship
- NHGRI [R01 HG010040]
- NIH Director's Pioneer Award [DP1 CA186693]
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Three-dimensional genome structures play a key role in gene regulation and cell functions. Characterization of genome structures necessitates single-cell measurements. This has been achieved for haploid cells but has remained a challenge for diploid cells. We developed a single-cell chromatin conformation capture method, termed Dip-C, that combines a transposon-based whole-genome amplification method to detect many chromatin contacts, called META (multiplex end-tagging amplification), and an algorithm to impute the two chromosome haplotypes linked by each contact. We reconstructed the genome structures of single diploid human cells from a lymphoblastoid cell line and from primary blood cells with high spatial resolution, locating specific single-nucleotide and copy number variations in the nucleus. The two alleles of imprinted loci and the two X chromosomes were structurally different. Cells of different types displayed statistically distinct genome structures. Such structural cell typing is crucial for understanding cell functions.
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