Whole-genome analysis of human embryonic stem cells enables rational line selection based on genetic variation

Florian T Merkle; Sulagna Ghosh; Giulio Genovese; Robert E Handsaker; Seva Kashin; Daniel Meyer; Konrad J Karczewski; Colm O'Dushlaine; Carlos Pato; Michele Pato; Daniel G MacArthur; Steven A McCarroll; Kevin Eggan

doi:10.1016/j.stem.2022.01.011

Whole-genome analysis of human embryonic stem cells enables rational line selection based on genetic variation

Cell Stem Cell. 2022 Mar 3;29(3):472-486.e7. doi: 10.1016/j.stem.2022.01.011. Epub 2022 Feb 16.

Authors

Affiliations

¹ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Wellcome - MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK; Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK. Electronic address: fm436@medschl.cam.ac.uk.
² Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁷ Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA; Department of Psychiatry, New Jersey Medical School, Rutgers University, Newark, NJ 07103, USA.
⁸ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, NSW, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: mccarroll@genetics.med.harvard.edu.
¹⁰ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: kevin.eggan@bmrn.com.

Abstract

Despite their widespread use in research, there has not yet been a systematic genomic analysis of human embryonic stem cell (hESC) lines at a single-nucleotide resolution. We therefore performed whole-genome sequencing (WGS) of 143 hESC lines and annotated their single-nucleotide and structural genetic variants. We found that while a substantial fraction of hESC lines contained large deleterious structural variants, finer-scale structural and single-nucleotide variants (SNVs) that are ascertainable only through WGS analyses were present in hESC genomes and human blood-derived genomes at similar frequencies. Moreover, WGS allowed us to identify SNVs associated with cancer and other diseases that could alter cellular phenotypes and compromise the safety of hESC-derived cellular products transplanted into humans. As a resource to enable reproducible hESC research and safer translation, we provide a user-friendly WGS data portal and a data-driven scheme for cell line maintenance and selection.

Keywords: embryonic stem cell; genetic variant; genomics; pluripotent; rational selection; resource; whole-genome sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Genetic Variation
Genome, Human / genetics
Human Embryonic Stem Cells*
Humans
Nucleotides
Whole Genome Sequencing

Substances

Nucleotides

Abstract

Publication types

MeSH terms

Substances

Grants and funding