High-dimensional phenotyping to define the genetic basis of cellular morphology

Matthew Tegtmeyer, Jatin Arora, Samira Asgari, Beth A. Cimini, Ajay Nadig, Emily Peirent, Dhara Liyanage, Gregory P. Way, Erin Weisbart, Aparna Nathan, Tiffany Amariuta, Kevin Eggan, Marzieh Haghighi, Steven A. McCarroll, Luke O’Connor, Anne E. Carpenter, Shantanu Singh (), Ralda Nehme () and Soumya Raychaudhuri ()
Additional contact information
Matthew Tegtmeyer: Broad Institute of MIT and Harvard
Jatin Arora: Brigham and Women’s Hospital and Harvard Medical School
Samira Asgari: Brigham and Women’s Hospital and Harvard Medical School
Beth A. Cimini: Imaging Platform, Broad Institute of MIT and Harvard
Ajay Nadig: Broad Institute of MIT and Harvard
Emily Peirent: Broad Institute of MIT and Harvard
Dhara Liyanage: Broad Institute of MIT and Harvard
Gregory P. Way: Imaging Platform, Broad Institute of MIT and Harvard
Erin Weisbart: Imaging Platform, Broad Institute of MIT and Harvard
Aparna Nathan: Brigham and Women’s Hospital and Harvard Medical School
Tiffany Amariuta: Harvard Medical School
Kevin Eggan: Broad Institute of MIT and Harvard
Marzieh Haghighi: Imaging Platform, Broad Institute of MIT and Harvard
Steven A. McCarroll: Broad Institute of MIT and Harvard
Luke O’Connor: Broad Institute of MIT and Harvard
Anne E. Carpenter: Imaging Platform, Broad Institute of MIT and Harvard
Shantanu Singh: Imaging Platform, Broad Institute of MIT and Harvard
Ralda Nehme: Broad Institute of MIT and Harvard
Soumya Raychaudhuri: Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract The morphology of cells is dynamic and mediated by genetic and environmental factors. Characterizing how genetic variation impacts cell morphology can provide an important link between disease association and cellular function. Here, we combine genomic sequencing and high-content imaging approaches on iPSCs from 297 unique donors to investigate the relationship between genetic variants and cellular morphology to map what we term cell morphological quantitative trait loci (cmQTLs). We identify novel associations between rare protein altering variants in WASF2, TSPAN15, and PRLR with several morphological traits related to cell shape, nucleic granularity, and mitochondrial distribution. Knockdown of these genes by CRISPRi confirms their role in cell morphology. Analysis of common variants yields one significant association and nominate over 300 variants with suggestive evidence (P

Date: 2024
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DOI: 10.1038/s41467-023-44045-w

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