Identification ofde novovariants from parent-proband duos via long-read sequencing

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 26, 2025

While de novo variants cause many Mendelian disorders, their detection currently requires sequencing of the proband and both biological parents. This is not feasible when only one parent available, a limitation for millions families. We developed duoNovo , which identifies from single parent-proband duos using long-read followed by haplotype reconstruction identical-by-descent blocks. sequenced 40 trios applied to each 80 constructed masking parent, classifying over 20 million variants. evaluated 's performance against classifications obtained full (which included 1,900 variants), demonstrating very high precision low error rate, perfect accuracy among absent gnomAD. freely available community as an R package, may represent example where provides clear diagnostic benefit short-read sequencing.

Language: Английский

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Mechanistic insights into CDCA gene family-mediated glioblastoma progression: implications for diagnosis, prognosis, and therapeutic targeting

Hereditas, Journal Year: 2025, Volume and Issue: 162(1)

Published: March 20, 2025

Abstract Background Glioblastoma (GBM) is a highly aggressive brain tumor characterized by poor prognosis and limited therapeutic options. Understanding the molecular mechanisms driving GBM progression essential for developing more effective diagnostic approaches. Specifically, investigating Cell Division Cycle-Associated (CDCA) genes offers new perspectives on cell cycle regulation proliferation of cells, which are key factors in growth resistance to treatment. These have not been extensively studied GBM, making them promising area targeted research potential interventions. This project was launched elucidate pathogenic, diagnostic, roles CDCA GBM. Methodology Total RNA extracted from lines followed RT-qPCR analyze expression genes. The validation, prognostic significance, mutational analysis were performed using various databases. Functional assays, including gene knockdown, colony formation, proliferation, wound healing, conducted U87MG cells assess role CDCA7 CDCA8 Results 12 6 normal revealed significant overexpression these ROC curve demonstrated excellent potential, with AUC values 1 most indicates that effectively distinguishes cells. Validation additional TCGA data confirmed upregulation tumors, association cancer-related pathways. Survival showed higher correlated patients. Mutation, CNV, methylation analyses alterations genes, further supporting their Additionally, linked immune modulation cycle-related functions, suggesting involvement evasion proliferation. Knockdown experiments reduction migration, highlighting as targets. Conclusion Overall, our findings suggest could serve both biomarkers targets

Language: Английский

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Redox-Driven Epigenetic Modifications in Sperm: Unraveling Paternal Influences on Embryo Development and Transgenerational Health

Antioxidants, Journal Year: 2025, Volume and Issue: 14(5), P. 570 - 570

Published: May 9, 2025

Male-factor infertility accounts for nearly half of all cases, and mounting evidence points to oxidative stress as a pivotal driver sperm dysfunction, genetic instability, epigenetic dysregulation. In particular, the DNA lesion 8-hydroxy-2′-deoxyguanosine (8-OHdG) has emerged central mediator at interface damage regulation. We discuss how this can disrupt key mechanisms such methylation, histone modifications, small non-coding RNAs, thereby influencing fertilization outcomes, embryo development, offspring health. propose that interplay between reprogramming is further exacerbated by aging in both paternal maternal germlines, creating “perfect storm” increases risk heritable (epi)mutations. The consequences unresolved lesions thus persist beyond fertilization, contributing transgenerational health risks. Finally, we explore promise potential pitfalls antioxidant therapy strategy mitigate damage. While supplementation may hold significant therapeutic value men with subfertility experiencing elevated stress, careful, personalized approach essential avoid reductive unintended disruptions. Recognizing dual role shaping genome epigenome underscores need integrating redox biology into reproductive medicine, aim improving fertility treatments safeguarding future generations.

Language: Английский

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Temporal analyses of germ cell mutations using the MutaMouse model support the recommended design in OECD test guideline 488

Archives of Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: May 21, 2025

Language: Английский

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