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Mapping genetic effects on cellular phenotypes with “cell villages”

Jana M. Mitchell, James Nemesh, Sulagna Ghosh, Robert E. Handsaker, Curtis J. Mello, Daniel Meyer, Kavya Raghunathan, Heather de Rivera, Matt Tegtmeyer, Derek Hawes, Anna Neumann, View ORCID ProfileRalda Nehme, Kevin Eggan, Steven A. McCarroll
doi: https://doi.org/10.1101/2020.06.29.174383
Jana M. Mitchell
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
2Department of Stem Cell and Regenerative Biology and The Harvard Stem Cell Institute, Harvard University, Cambridge MA, 02138, USA
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James Nemesh
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
3Department of Genetics, Harvard Medical School, Boston MA, 02115, USA
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Sulagna Ghosh
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
2Department of Stem Cell and Regenerative Biology and The Harvard Stem Cell Institute, Harvard University, Cambridge MA, 02138, USA
3Department of Genetics, Harvard Medical School, Boston MA, 02115, USA
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Robert E. Handsaker
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
3Department of Genetics, Harvard Medical School, Boston MA, 02115, USA
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Curtis J. Mello
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
3Department of Genetics, Harvard Medical School, Boston MA, 02115, USA
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Daniel Meyer
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
3Department of Genetics, Harvard Medical School, Boston MA, 02115, USA
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Kavya Raghunathan
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
2Department of Stem Cell and Regenerative Biology and The Harvard Stem Cell Institute, Harvard University, Cambridge MA, 02138, USA
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Heather de Rivera
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
3Department of Genetics, Harvard Medical School, Boston MA, 02115, USA
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Matt Tegtmeyer
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
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Derek Hawes
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
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Anna Neumann
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
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Ralda Nehme
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
2Department of Stem Cell and Regenerative Biology and The Harvard Stem Cell Institute, Harvard University, Cambridge MA, 02138, USA
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  • ORCID record for Ralda Nehme
Kevin Eggan
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
2Department of Stem Cell and Regenerative Biology and The Harvard Stem Cell Institute, Harvard University, Cambridge MA, 02138, USA
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  • For correspondence: eggan@mcb.harvard.edu mccarroll@hms.harvard.edu
Steven A. McCarroll
1Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge MA, 02142, USA
3Department of Genetics, Harvard Medical School, Boston MA, 02115, USA
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  • For correspondence: eggan@mcb.harvard.edu mccarroll@hms.harvard.edu
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Summary

Tens of thousands of genetic variants shape human phenotypes, mostly by unknown cellular mechanisms. Here we describe Census-seq, a way to measure cellular phenotypes in cells from many people simultaneously. Analogous to pooled CRISPR screens but for natural variation, Census-seq associates cellular phenotypes to donors’ genotypes by quantifying the presence of each donor’s DNA in cell “villages” before and after sorting or selection for cellular traits of interest. Census-seq enables population-scale cell-biological phenotyping with low cost and high internal control. We demonstrate Census-seq through investigation of genetic effects on the SMN protein whose deficiency underlies spinal muscular atrophy (SMA). Census-seq quantified and mapped effects of many common alleles on SMN protein levels and response to SMN-targeted therapeutics, including a common, cryptic non-responder allele. We provide tools enabling population-scale cell experiments and explain how Census-seq can be used to map genetic effects on diverse cell phenotypes.

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Highlights

  • Census-seq reveals how inherited genetic variation affects cell phenotypes

  • Genetic analysis of cellular traits in cell villages of >100 donors

  • Characterizing human alleles that shape SMN protein expression and drug responses

  • Development of protocols and software to enable cellular population genetics

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 29, 2020.
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Mapping genetic effects on cellular phenotypes with “cell villages”
Jana M. Mitchell, James Nemesh, Sulagna Ghosh, Robert E. Handsaker, Curtis J. Mello, Daniel Meyer, Kavya Raghunathan, Heather de Rivera, Matt Tegtmeyer, Derek Hawes, Anna Neumann, Ralda Nehme, Kevin Eggan, Steven A. McCarroll
bioRxiv 2020.06.29.174383; doi: https://doi.org/10.1101/2020.06.29.174383
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Mapping genetic effects on cellular phenotypes with “cell villages”
Jana M. Mitchell, James Nemesh, Sulagna Ghosh, Robert E. Handsaker, Curtis J. Mello, Daniel Meyer, Kavya Raghunathan, Heather de Rivera, Matt Tegtmeyer, Derek Hawes, Anna Neumann, Ralda Nehme, Kevin Eggan, Steven A. McCarroll
bioRxiv 2020.06.29.174383; doi: https://doi.org/10.1101/2020.06.29.174383

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