While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.
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http://dx.doi.org/10.1016/j.ajhg.2024.07.006 | DOI Listing |
Toxicology
January 2025
Department of Chemical Toxicology, Norwegian Institute of Public Health, Oslo, Norway; Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway. Electronic address:
The safety and developmental neurotoxicity (DNT) potential of chemicals remain critically understudied due to limitations of current in vivo testing guidelines, which are low throughput, resource-intensive, and hindered by species differences that limit their relevance to human health. To address these issues, robust New Approach Methodologies (NAMs) using deeply characterized cell models are essential. This study presents the comprehensive transcriptomic characterization of two advanced human-induced pluripotent stem cell (hiPSC)-derived models: a 2D adherent and a 3D neurosphere model of human neural progenitor cells (hiNPCs) differentiated up to 21 days.
View Article and Find Full Text PDFInt J Orthop Trauma Nurs
November 2024
Department of Orthopaedic Surgery and Traumatology, Odense University Hospital, Odense, Denmark; Orthopaedic Research Unit, Department of Clinical Research, University of Southern Denmark, Denmark. Electronic address:
Am J Med Genet C Semin Med Genet
December 2024
Genetics, Children's Nebraska, University of Nebraska Medical Center, Omaha, Nebraska, USA.
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