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Single-Cell Analysis of the 3D Topologies of Genomic Loci Using Genome Architecture Mapping

Lonnie R. Welch, Catherine Baugher, Yingnan Zhang, Trenton Davis, William F. Marzluff, Joshua D. Welch, Ana Pombo
doi: https://doi.org/10.1101/2020.02.10.941047
Lonnie R. Welch
1School of Computer Science and Electrical Engineering, Ohio University, Athens, Ohio, USA
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  • For correspondence: welch@ohio.edu
Catherine Baugher
1School of Computer Science and Electrical Engineering, Ohio University, Athens, Ohio, USA
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Yingnan Zhang
1School of Computer Science and Electrical Engineering, Ohio University, Athens, Ohio, USA
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Trenton Davis
1School of Computer Science and Electrical Engineering, Ohio University, Athens, Ohio, USA
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William F. Marzluff
2Dept. of Biochemistry and Biophysics and Integrative Pgm. in Biological and Genome Sciences, University of North Carolina, Chapel Hill, NC 27599
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Joshua D. Welch
3Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA
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Ana Pombo
4Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine and Humboldt University of Berlin, Berlin, Germany
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Abstract

Although each cell within an organism contains a nearly identical genome sequence, the three-dimensional (3D) packing of the genome varies among individual cells, influencing cell-type-specific gene expression. Genome Architecture Mapping (GAM) is the first genome-wide experimental method for capturing 3D proximities between any number of genomic loci without ligation. GAM overcomes several limitations of 3C-based methods by sequencing DNA from a large collection of thin sections sliced from individual nuclei. The GAM technique measures locus co-segregation, extracts radial positions, infers chromatin compaction, requires small numbers of cells, does not depend on ligation, and provides rich single-cell information. However, previous analyses of GAM data focused exclusively on population averages, neglecting the variation in 3D topology among individual cells.

We present the first single-cell analysis of GAM data, demonstrating that the slices from individual cells reveal intercellular heterogeneity in chromosome conformation. By simultaneously clustering both slices and genomic loci, we identify topological variation among single cells, including differential compaction of cell cycle genes. We also develop a geometric model of the nucleus, allowing prediction of the 3D positions of each slice. Using GAM data from mouse embryonic stem cells, we make new discoveries about the structure of the major mammalian histone gene locus, which is incorporated into the Histone Locus Body (HLB), including structural fluctuations and putative causal molecular mechanisms. Our methods are packaged as SluiceBox, a toolkit for mining GAM data. Our approach represents a new method of investigating variation in 3D genome topology among individual cells across space and time.

Footnotes

  • Added acknowledgements to sponsors.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 13, 2020.
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Single-Cell Analysis of the 3D Topologies of Genomic Loci Using Genome Architecture Mapping
Lonnie R. Welch, Catherine Baugher, Yingnan Zhang, Trenton Davis, William F. Marzluff, Joshua D. Welch, Ana Pombo
bioRxiv 2020.02.10.941047; doi: https://doi.org/10.1101/2020.02.10.941047
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Single-Cell Analysis of the 3D Topologies of Genomic Loci Using Genome Architecture Mapping
Lonnie R. Welch, Catherine Baugher, Yingnan Zhang, Trenton Davis, William F. Marzluff, Joshua D. Welch, Ana Pombo
bioRxiv 2020.02.10.941047; doi: https://doi.org/10.1101/2020.02.10.941047

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