Radio, S. | bioRxiv Science

bioRxiv2024

An iPSC-based model of Jacob Syndrome reveals a DNA methylation-independent transcriptional dysregulation shared with X aneuploid cells.

Male sex chromosome aneuploidies are frequent genetic aberrations in humans characterized by additional Y or X chromosome complements. Jacob (JS) and Klinefelter syndromes (KS), carrying 47,XYY and 47,XXY chromosomes, respectively, share several clinical features, including sterility, hormonal deficits, neurocognitive delay, and skeletal-muscle defects. Despite the high incidence, a complete understanding of the molecular mechanisms underlying the clinical manifestations in sex aneuploid patients is still elusive. In this study, we generated and characterized the inaugural cohort of 47,XYY human induced pluripotent stem cells (iPSCs). We performed a comprehensive transcriptional analysis, including JS primary fibroblasts, iPSCs, and neural stem cells (NSCs) alongside KS cells. Our study revealed a transcriptional feedback mechanism tuning non-PAR X chromosome genes (NPX) homologs in Y supernumerary cells, a phenomenon not detected in X aneuploid iPSCs. By ectopically modulating the expression of selected NPY genes, we demonstrated a direct transcriptional link between the UTY-UTX gene pair. Furthermore, our analyses identified a shared transcriptomic signature between JS and KS, discernible already at the iPSC stage, with a notable enrichment for processes related to neurological functions. This transcriptomic convergence underscores potential commonalities in the molecular pathways underpinning the pathophysiology of male sex chromosome aneuploidies. Finally, through genome-wide DNA methylation profiling of JS iPSCs, we demonstrated that a supernumerary Y chromosome only minimally impacts the methylation status of 47,XYY cells at the pluripotent stage. Our work reveals critical transcriptional feedback mechanisms and shared gene expression signatures in male sex chromosome aneuploidies, paving the way for a better understanding of their common phenotypic features.

cell biology↗

bioRxiv2021

Population-scale long-read sequencing uncovers transposable elements contributing to gene expression variation and associated with adaptive signatures in Drosophila melanogaster

High quality reference genomes are crucial to understanding genome function, structure and evolution. The availability of reference genomes has allowed us to start inferring the role of genetic variation in biology, disease, and biodiversity conservation. However, analyses across organisms demonstrate that a single reference genome is not enough to capture the global genetic diversity present in populations. In this work, we generated 32 high-quality reference genomes for the well-known model species D. melanogaster and focused on the identification and analysis of transposable element variation as they are the most common type of structural variant. We showed that integrating the genetic variation across natural populations from five climatic regions increases the number of detected insertions by 58%. Moreover, 26% to 57% of the insertions identified using long-reads were missed by short-reads methods. We also identified hundreds of transposable elements associated with gene expression variation and new TE variants likely to contribute to adaptive evolution in this species. Our results highlight the importance of incorporating the genetic variation present in natural populations to genomic studies, which is essential if we are to understand how genomes function and evolve.

evolutionary biology↗