ArticleProceedings of the National Academy of Sciences of the United States of America2016
Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39 citing papers in PubMed, 57 citations in OpenAlex.
- Large-scale whole-genome sequencing reveals the landscape and health implications of de novo mutations.Nature medicine · 2026Article
- Long-term survival without high cancer risk in a cohort of 24 patients with Apert syndrome.European journal of human genetics : EJHG · 2026Article
- Stem cell competition.Current topics in developmental biology · 2026Review
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- Development of a Clinically Applicable High-Resolution Assay for Sperm Mosaicism.The Journal of molecular diagnostics : JMD · 2025Article
- Male aging in germ cells: What are we inheriting?Genetics and molecular biology · 2025Article
- Single-cell RNA sequencing reveals transcriptomic landscape and potential targets for human testicular ageing.Human reproduction (Oxford, England) · 2024Article
- SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.American journal of human genetics · 2024Article
- Genetic variation across and within individuals.Nature reviews. Genetics · 2024Review
- Exploring FGFR3 Mutations in the Male Germline: Implications for Clonal Germline Expansions and Paternal Age-Related Dysplasias.Genome biology and evolution · 2024Article
- Exploring the Micro-Mosaic Landscape ofGenes · 2024Article
- Paternal age and 13 psychiatric disorders in the offspring: a population-based cohort study of 7 million children in Taiwan.Molecular psychiatry · 2022Article
- The impact of paternal age on new mutations and disease in the next generation.Fertility and sterility · 2022Review
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- Decoding the Spermatogenesis Program: New Insights from Transcriptomic Analyses.Annual review of genetics · 2022Review
- The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging-related disease.Molecular oncology · 2022Review
- Discovery of an unusually high number of de novo mutations in sperm of older men using duplex sequencing.Genome research · 2022Article
- Pathogenic postzygotic mosaicism in the tyrosine receptor kinase pathway: potential unidentified human disease hidden away in a few cells.The FEBS journal · 2021Review
- Molecular mechanisms underlying cellular effects of human MEK1 mutations.Molecular biology of the cell · 2021Article
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6 authors at 3 institutions in 1 country.
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Abstract
De novo point mutations arise predominantly in the male germline and increase in frequency with age, but it has not previously been possible to locate specific, identifiable mutations directly within the seminiferous tubules of human testes. Using microdissection of tubules exhibiting altered expression of the spermatogonial markers MAGEA4, FGFR3, and phospho-AKT, whole genome amplification, and DNA sequencing, we establish an in situ strategy for discovery and analysis of pathogenic de novo mutations. In 14 testes from men aged 39-90 y, we identified 11 distinct gain-of-function mutations in five genes (fibroblast growth factor receptors FGFR2 and FGFR3, tyrosine phosphatase PTPN11, and RAS oncogene homologs HRAS and KRAS) from 16 of 22 tubules analyzed; all mutations have known associations with severe diseases, ranging from congenital or perinatal lethal disorders to somatically acquired cancers. These results support proposed selfish selection of spermatogonial mutations affecting growth factor receptor-RAS signaling, highlight its prevalence in older men, and enable direct visualization of the microscopic anatomy of elongated mutant clones.
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