Genome-wide analysis of haploinsufficiency in human embryonic stem cells

Roni Sarel-Gallily, Tamar Golan-Lev, Atilgan Yilmaz, Ido Sagi, Nissim Benvenisty

Research output: Contribution to journalArticlepeer-review


Haploinsufficiency describes a phenomenon where one functioning allele is insufficient for a normal phenotype, underlying several human diseases. The effect of haploinsufficiency on human embryonic stem cells (hESC) has not been thoroughly studied. To establish a genome-wide loss-of-function screening for heterozygous mutations, we fuse normal haploid hESCs with a library of mutant haploid hESCs. We identify over 600 genes with a negative effect on hESC growth in a haploinsufficient manner and characterize them as genes showing less tolerance to mutations, conservation during evolution, and depletion from telomeres and X chromosome. Interestingly, a large fraction of these genes is associated with extracellular matrix and plasma membrane and enriched for genes within WNT and TGF-β pathways. We thus identify haploinsufficiency-related genes that show growth retardation in early embryonic cells, suggesting dosage-dependent phenotypes in hESCs. Overall, we construct a unique model for studying haploinsufficiency and identified important dosage-dependent pathways involved in hESC growth and survival.

Original languageAmerican English
Article number110573
JournalCell Reports
Issue number13
StatePublished - 29 Mar 2022


  • CP: Cell Biology
  • CP: Stem Cell Research
  • essential genes
  • genetic screening
  • haploinsufficiency
  • human embryonic stem cells
  • signaling pathways

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology


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