Abstract
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 language | English |
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Article number | 110573 |
Journal | Cell Reports |
Volume | 38 |
Issue number | 13 |
DOIs | |
State | Published - 29 Mar 2022 |
Bibliographical note
Publisher Copyright:© 2022 The Authors
Keywords
- CP: Cell Biology
- CP: Stem Cell Research
- essential genes
- genetic screening
- haploinsufficiency
- human embryonic stem cells
- signaling pathways