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Mapping genetic effects on cellular phenotypes with "cell villages"

Jana M. MitchelliD, James C. Nemesh, Sulagna Dia GhoshiD, Robert E. HandsakeriD, Curtis J. MelloiD, Daniel MeyeriD, Kavya Raghunathan, Heather de RiveraiD, Matthew TegtmeyeriD, Derek Hawes, Anna NeumanniD, Ralda NehmeiD, Kevin C. EgganiD, Steven A. McCarrolliD

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Abstract

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 donors 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. O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/174383v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@169bf4borg.highwire.dtl.DTLVardef@18dd9c0org.highwire.dtl.DTLVardef@1d30ca5org.highwire.dtl.DTLVardef@e35bf0_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICensus-seq reveals how inherited genetic variation affects cell phenotypes C_LIO_LIGenetic analysis of cellular traits in cell villages of >100 donors C_LIO_LICharacterizing human alleles that shape SMN protein expression and drug responses C_LIO_LIDevelopment of protocols and software to enable cellular population genetics C_LI

Abstract summary

Claude Opus 5.5 · xhigh effort · 2 Nov 2026 · from the abstract

Census-seq pools cells from >100 human donors into "cell villages" and quantifies donor DNA before and after selection to map genetic effects on cellular traits.

Tens of thousands of genetic variants shape human phenotypes through largely unknown cellular mechanisms. Analogous to pooled CRISPR screens, Census-seq measures cellular traits across cells from >100 donors simultaneously with low cost and high internal control by quantifying each donor's DNA in "cell villages" before and after phenotypic sorting or selection.

Key results

  1. ShownCensus-seq maps the effects of inherited genetic variation on cellular traits across pooled "cell villages" of >100 human donors by quantifying each donor's DNA before and after phenotypic sorting or selection.

    Demonstrated as a pooled population-scale cellular phenotyping assay and accompanying software toolkit. · Abstract

  2. ShownApplying Census-seq to the SMN protein (whose deficiency underlies spinal muscular atrophy) mapped common alleles affecting SMN protein levels and response to SMN-targeted therapeutics, uncovering a common cryptic non-responder allele.

    Measured in human donor cell villages sorted or selected for SMN protein abundance and therapeutic response (specific effect sizes and allele identifiers are not stated in the abstract). · Abstract

Methods, data and reproducibility

Cells from >100 human donors are pooled into "cell villages" and subjected to sorting or selection for a cellular trait of interest; Census-seq quantifies the presence of each donor's DNA before and after selection to associate donor genotypes with cellular phenotypes and drug responses.

  • Pooled human donor cell villages assayed for SMN protein levels and response to SMN-targeted therapeutics · human · n = >100 donors
Methods & tools
Census-seq
Reproducibility gaps
Although the abstract states that protocols and software tools are provided, no repository URLs or data accessions appear in the abstract.
Limitations (2)
  • The abstract does not specify the cell types used, exact donor count, or quantitative effect sizes and allele identifiers from the SMN screen. · noted in this summary
  • Pooled cell village assays are limited to cell-autonomous phenotypes amenable to physical sorting or survival selection. · noted in this summary

Read this if you want to map natural human genetic variation or pharmacogenomic responses onto cellular phenotypes using pooled multi-donor cell culture screens.

Citations
79

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