Transcriptional and epigenetic changes from the genesis of the human male germline through to adulthood provide a map of prenatal and postnatal molecular drivers of differentiation and reveal the developmental origin of seminoma.

Aberrancies in male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping of seminoma transcriptomes and open chromatin landscape onto our normal human male germline trajectory, we find that seminoma resembles premigratory/migratory primordial germ cells, but exhibit enhanced germline and pluripotency programs and upregulate genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. By modeling seminoma using pluripotent stem cell-derived primordial germ cells from Pallister Killian syndrome patients mosaic for i(12p), we identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide insights into genetic, cellular and signaling programs driving seminoma transformation and our in vitro platform will permit future evaluation of additional signals required for seminoma tumorigenesis. Overall design: Human pre- and post-natal testis samples were recovered along with seminoma samples and subjected to single-cell RNA sequencing (10X genomics) and/or single-cell RNA/ATAC ("multiome", 10X Genomics). The goal of this study was to develop the human trajectory of germ cell development and then map the seminoma samples onto it.