title: Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline.
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.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom.
authors.forename: Eleni
authors.initials: E
authors.lastname: Giannoulatou
authors.forename: Gilean
authors.initials: G
authors.lastname: McVean
authors.forename: Indira B
authors.initials: IB
authors.lastname: Taylor
authors.forename: Simon J
authors.initials: SJ
authors.lastname: McGowan
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Maher
authors.forename: Zamin
authors.initials: Z
authors.lastname: Iqbal
authors.forename: Susanne P
authors.initials: SP
authors.lastname: Pfeifer
authors.forename: Isaac
authors.initials: I
authors.lastname: Turner
authors.forename: Emma M M
authors.initials: EM
authors.lastname: Burkitt Wright
authors.forename: Jennifer
authors.initials: J
authors.lastname: Shorto
authors.forename: Aysha
authors.initials: A
authors.lastname: Itani
authors.forename: Karen
authors.initials: K
authors.lastname: Turner
authors.forename: Lorna
authors.initials: L
authors.lastname: Gregory
authors.forename: David
authors.initials: D
authors.lastname: Buck
authors.forename: Ewa
authors.initials: E
authors.lastname: Rajpert-De Meyts
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
authors.forename: Anne
authors.initials: A
authors.lastname: Goriely
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000097:blood / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics*; D003062:Codon / Q000235:genetics; D056685:Costello Syndrome / Q000235:genetics*; D005854:Germ Cells / Q000737:chemistry*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009154:Mutation / Q000235:genetics; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012641:Selection, Genetic / Q000235:genetics*
chemical_list: D003062:Codon; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: RASopathy; male mutation bias; paternal age effect; testis