PhD Student The Hebrew University of Jerusalem Jerusalem, Yerushalayim, Israel
Abstract: The only viable full monosomy in human pluripotent stem cells (hPSCs) in culture is X0, resulting from the loss of one of the sex chromosomes. Loss of chromosome Y (LOY) occurs in various cancers in males, but the extent and implications of LOY on hPSCs was not thoroughly studied. In this study, we performed a large-scale analysis of RNA-seq data from over 2,700 samples from around 140 independent studies, containing both hPSCs and their differentiated derivatives. We show that 12% of the samples have lost chromosome Y, either heterogeneously or fully, across different studies and cell lines. The LOY samples do not significantly differ from wildtype samples in other technical or genomic irregularities, such as read coverage, autosomal aneuploidies and TP53 mutations. Enrichment differential expression analysis revealed that the undifferentiated LOY samples show downregulated expression of major pluripotent markers, X-degenerate tumor suppressors and, most substantially, ribosomal protein genes. In addition to the downregulation of RPS4Y1, a Y-linked ribosomal protein genes, a significant decrease in expression of the majority of the autosomal ribosomal protein genes, both small- and large-ribosomal subunit proteins, was observed in LOY samples. We performed differential expression analysis on samples of Turner and Diamond-Blackfan anemia Syndromes, known for losing one allele in an autosomal ribosomal gene, and observed similar trend of downregulation in the expression of ribosomal protein genes, supporting our hypothesis of ribosomal haploinsufficiency mechanism. Overall, we present a wide, extensive analysis of LOY in hPSCs, detected samples across different studies and cell lines that have lost their chromosome Y and identified the downstream molecular effects of this chromosomal aberration, mainly downregulation in pluripotency and in ribosomal protein transcription. Thus, we shed light on the implications of LOY and may provide a possible dosage-dependent explanation for the phenotypes underlying other ribosomal-deficiency diseases.
