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; Soumya Raychaudhuri

doi:10.1038/s41467-023-44045-w

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

Nat Commun. 2024 Jan 6;15(1):347. doi: 10.1038/s41467-023-44045-w.

Authors

Matthew Tegtmeyer^#^{1

2

3}, Jatin Arora^#^{4

5

6

7}, Samira Asgari^#^{4

5

6

7

8

9}, Beth A Cimini¹⁰, Ajay Nadig^{1

7

11}, Emily Peirent¹, Dhara Liyanage¹, Gregory P Way¹⁰, Erin Weisbart¹⁰, Aparna Nathan^{4

5

6

7

8}, Tiffany Amariuta^{8

12

13

14}, Kevin Eggan^{1

2}, Marzieh Haghighi¹⁰, Steven A McCarroll^{1

8

15}, Luke O'Connor^{7

8}, Anne E Carpenter¹⁰, Shantanu Singh¹⁶, Ralda Nehme^{17

18}, Soumya Raychaudhuri^{19

20

21

22

23

24}

Affiliations

¹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
³ Centre for Gene Therapy and Regenerative Medicine, King's College, London, UK.
⁴ Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁸ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
⁹ Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰ Imaging Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹¹ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹³ Halıcıoğlu Data Science Institute, University of California, La Jolla, CA, USA.
¹⁴ Department of Medicine, University of California, La Jolla, CA, USA.
¹⁵ Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁶ Imaging Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA. shsingh@broadinstitute.org.
¹⁷ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. rnehme@broadinstitute.org.
¹⁸ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. rnehme@broadinstitute.org.
¹⁹ Center for Data Sciences, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
²⁰ Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
²¹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
²² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. soumya@broadinstitute.org.
²³ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. soumya@broadinstitute.org.
²⁴ Centre for Genetics and Genomics Versus Arthritis, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK. soumya@broadinstitute.org.

^# Contributed equally.

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 < 10^-6) of association with one or more morphology traits. We then use these data to make predictions about sample size requirements for increasing discovery in cellular genetic studies. We conclude that, similar to molecular phenotypes, morphological profiling can yield insight about the function of genes and variants.

MeSH terms

Cell Nucleus
Cell Shape
Chromosome Mapping
Induced Pluripotent Stem Cells*
Mutant Proteins
Quantitative Trait Loci* / genetics

Substances

Mutant Proteins

Abstract

MeSH terms

Substances

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