Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes

Maher, Geoffrey J.; Ralph, Hannah K; Ding, Zhihao; Koelling, Nils; Mlčochová, Hana; Giannoulatou, Eleni; Dhami, Pawan; Paul, Dirk S.; Stricker, Stefan H.; Beck, Stephan; McVean, Gil; Wilkie, Andrew O.M.; Goriely, Anne

doi:10.1101/gr.239186.118

Cited by 66 publications

(80 citation statements)

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“…Hras G12V has been detected in human sperm of healthy donors and is allelic to Hras G12S , the most common mutation in Costello syndrome, which increases with sperm donor age [9]. Given that gain-of-function mutations in the RAS pathway mediate positive selection of human SSCs [26, 27] and that overexpression of an Hras G12V cDNA is tumorigenic [23], we hypothesized that an increasing burden of Hras G12V would be detectable over time following induction in the adult testis. To test this hypothesis, our inducible mutation model enabled us to follow the fate of Hras G12V -positive A undiff over time.…”

Section: Resultsmentioning

confidence: 99%

Functional robustness of adult spermatogonial stem cells after induction of hyperactive Hras

et al. 2019

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Accumulating evidence indicates that paternal age correlates with disease risk in children. De novo gain-of-function mutations in the FGF-RAS-MAPK signaling pathway are known to cause a subset of genetic diseases associated with advanced paternal age, such as Apert syndrome, achondroplasia, Noonan syndrome, and Costello syndrome. It has been hypothesized that adult spermatogonial stem cells with pathogenic mutations are clonally expanded over time and propagate the mutations to offspring. However, no model system exists to interrogate mammalian germline stem cell competition in vivo. In this study, we created a lineage tracing system, which enabled undifferentiated spermatogonia with endogenous expression of Hras G12V , a known pathogenic gain-of-function mutation in RAS-MAPK signaling, to compete with their wild-type counterparts in the mouse testis. Over a year of fate analysis, neither Hras G12V -positive germ cells nor sperm exhibited a significant expansion compared to wild-type neighbors. Short-term stem cell capacity as measured by transplantation analysis was also comparable between wild-type and mutant groups. Furthermore, although constitutively active HRAS was detectable in the mutant cell lines, they did not exhibit a proliferative advantage or an enhanced response to agonist-evoked pERK signaling. These in vivo and in vitro results suggest that mouse spermatogonial stem cells are functionally resistant to a heterozygous Hras G12V mutation in the endogenous locus and that mechanisms could exist to prevent such harmful mutations from being expanded and transmitted to the next generation.

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Section: Resultsmentioning

confidence: 99%

Functional robustness of adult spermatogonial stem cells after induction of hyperactive Hras

et al. 2019

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“…Thus, Goriely et al coined the term "selfish spermatogonial selection" to describe the increase in the number of mutant sperm over time (i.e. male aging) caused by the mutation-driven clonal expansion process (Maher et al, 2018). Of note, Maher et al (2018) identified a mutational clone in human testes for the FGFR2 Ser372Cys, one of the mutations known to cause BSS.…”

Section: Discussionmentioning

confidence: 99%

“…male aging) caused by the mutation-driven clonal expansion process (Maher et al, 2018). Of note, Maher et al (2018) identified a mutational clone in human testes for the FGFR2 Ser372Cys, one of the mutations known to cause BSS. In situations like advanced paternal age and CBAVD, which are both characterized by poor spermogram parameters, the before-mentioned clonal expansion process would lead to a relative increase in the number of mutated sperm, compared to situations consistent with normal spermatogenesis.…”

Section: Discussionmentioning

confidence: 99%

Report of a Father With Congenital Bilateral Absence of the Vas Deferens Fathering a Child With Beare–Stevenson Syndrome

Ferreira

Dantas

2020

Front. Genet.

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Background: Apert, Pfeiffer, and Crouzon syndromes are autosomal dominant diseases characterized by craniosynostosis. They are paternal age effect disorders. The association between paternal age and Beare-Stevenson syndrome (BSS), a very rare and severe craniosynostosis, is uncertain. Gain-of-function mutations in FGFR2 become progressively enriched in testes as men age and were shown to cause these syndromes. Case report: Here, we describe a child affected with BSS, whose father was 36 years old and had congenital bilateral absence of the vas deferens (CBAVD). The child was heterozygous for the pathogenic FGFR2 variant c.1124A > G p.Tyr375Cys. By reviewing the literature, we found that BSS fathers are older than BSS mothers (mean age in years: 39 ± 10 vs 30 ± 6, p = 0.006). Male age greater than 34 years and CBAVD are both factors associated with poor spermogram parameters, which may represent an additional selective pressure to sperm carrying FGFR2 gain-of-function mutations. Conclusion: These findings are consistent with the hypothesis that BSS is a paternalorigin genetic disorder. Further experimental studies would be needed to confirm this hypothesis.

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“…Studies have suggested that most de novo point mutations or small indels have a paternal origin [37], whereas large deletions are predominantly of maternal origin, as is the case with NF1 [38]. Advanced paternal age can substantially increase this tendency for de novo point mutations, particularly for mutations occurring in genes implicated in the RAS pathway [39,40]. Indeed, such mutations stimulate selfish selection during spermatogenesis in a process close to oncogenesis, leading to an over-representation of spermatozoids carrying these alterations over time.…”

Section: Discussionmentioning

confidence: 99%

One NF1 Mutation may Conceal Another

Pacot

Laurendeau

Briand-Suleau

et al. 2019

Genes

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Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the NF1 gene, a negative regulator of the RAS-MAPK pathway. The NF1 gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the NF1 and SPRED1 genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent NF1 variants. All NF1 variants were classified as pathogenic, according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. In the sixth family, one sibling inherited a complete deletion of the NF1 gene from her mother and carried a variant of unknown significance in the SPRED1 gene. This variant was also present in her brother, who was diagnosed with Legius syndrome, a differential diagnosis of NF1. This work illustrates the complexity of molecular diagnosis in a not-so-rare genetic disease.

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Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes

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Cited by 66 publications

References 68 publications

Functional robustness of adult spermatogonial stem cells after induction of hyperactive Hras

Functional robustness of adult spermatogonial stem cells after induction of hyperactive Hras

Report of a Father With Congenital Bilateral Absence of the Vas Deferens Fathering a Child With Beare–Stevenson Syndrome

One NF1 Mutation may Conceal Another

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