Biological insights from the whole genome analysis of human embryonic stem cells

Merkle, F. T.; Ghosh, S.; Genovese, G.; Handsaker, R. E.; Kashin, S.; Karczewski, K.; O'Dushlaine, C.; Pato, C.; Pato, M.; MacArthur, D.; McCarroll, S. A.; Eggan, K.

doi:10.1101/2020.10.26.337352

bioRxiv · 10.1101/2020.10.26.337352

Biological insights from the whole genome analysis of human embryonic stem cells

Merkle, F. T.·Ghosh, S.·Genovese, G.·Handsaker, R. E.·Kashin, S.·Karczewski, K.·O'Dushlaine, C.·Pato, C.·Pato, M.·MacArthur, D.·McCarroll, S. A.·Eggan, K.

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Abstract

There has not yet been a systematic analysis of hESC whole genomes 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 hESCs genomes and human blood-derived genomes at similar frequencies. However, WGS did identify SNVs associated with cancer or other diseases that will likely alter cellular phenotypes and may 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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/337352v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1c28e3aorg.highwire.dtl.DTLVardef@7a07corg.highwire.dtl.DTLVardef@b95f2borg.highwire.dtl.DTLVardef@1732af_HPS_FORMAT_FIGEXP M_FIG C_FIG IN BRIEFMerkle and Ghosh et al. describe insights from the whole genome sequences of commonly used human embryonic stem cell (hESC) lines. Analyses of these sequences show that while hESC genomes had more large structural variants than humans do from genetic inheritance, hESCs did not have an observable excess of finer-scale variants. However, many hESC lines contained rare loss-of-function variants and combinations of common variants that may profoundly shape their biological phenotypes. Thus, genome sequencing data can be valuable to those selecting cell lines for a given biological or clinical application, and the sequences and analysis reported here should facilitate such choices. HIGHLIGHTSO_LIOne third of hESCs we analysed are siblings, and almost all are of European ancestry C_LIO_LILarge structural variants are common in hESCs, but finer-scale variation is similar to that human populations C_LIO_LIMany strong-effect loss-of-function mutations and cancer-associated mutations are present in specific hESC lines C_LIO_LIWe provide user-friendly resources for rational hESC line selection based on genome sequence C_LI

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Merkle, F. T., Ghosh, S., Genovese, G., Handsaker, R. E., Kashin, S., Karczewski, K., O'Dushlaine, C., Pato, C., Pato, M., MacArthur, D., McCarroll, S. A., Eggan, K.. 2020-10-26. Biological insights from the whole genome analysis of human embryonic stem cells. https://doi.org/10.1101/2020.10.26.337352

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