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Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline. | LitMetric

AI Article Synopsis

  • The HRAS gene, linked to several cancers and Costello syndrome, encodes a protein that helps control cell behavior and its mutations can be inherited or arise in tumors.
  • Researchers proposed that activating HRAS mutations may be favored in sperm, a concept termed selfish spermatogonial selection, and tested this by analyzing specific mutation levels in blood and sperm samples.
  • The study found that while HRAS mutations are indeed enriched in sperm, their prevalence doesn't perfectly align with cancer-associated mutations, indicating unique mutation patterns and a potential vulnerability in the germline.

Article Abstract

The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864328PMC
http://dx.doi.org/10.1073/pnas.1311381110DOI Listing

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