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

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Whole-genome analysis of human embryonic stem cells enables rational line selection based on genetic variation
Cell Stem Cell ( IF 23.9 ) Pub Date : 2022-02-16 , DOI: 10.1016/j.stem.2022.01.011
Florian T Merkle ₁ , Sulagna Ghosh ₂ , Giulio Genovese ₃ , Robert E Handsaker ₃ , Seva Kashin ₃ , Daniel Meyer ₄ , Konrad J Karczewski ₅ , Colm O'Dushlaine ₆ , Carlos Pato ₇ , Michele Pato ₇ , Daniel G MacArthur ₈ , Steven A McCarroll ₃ , Kevin Eggan ₂

Affiliation

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.
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.
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.
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.
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.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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.
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.

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.

中文翻译：

人类胚胎干细胞的全基因组分析使基于遗传变异的合理细胞系选择成为可能

尽管它们在研究中得到广泛使用，但尚未以单核苷酸分辨率对人类胚胎干细胞 (hESC) 系进行系统的基因组分析。因此，我们对 143 个 hESC 系进行了全基因组测序 (WGS)，并注释了它们的单核苷酸和结构遗传变异。我们发现，虽然很大一部分 hESC 系包含大的有害结构变异，但只有通过 WGS 分析才能确定的更精细结构和单核苷酸变异 (SNV) 以相似的频率存在于 hESC 基因组和人类血液衍生基因组中。此外，WGS 使我们能够识别与癌症和其他疾病相关的 SNV，这些 SNV 可能会改变细胞表型并损害移植到人体中的 hESC 衍生细胞产品的安全性。

更新日期：2022-02-16

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