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

Maher, GJ; Ralph, HK; Ding, Z; Koelling, N; Mlcochova, H; Giannoulatou, E; Dhami, P; ... Goriely, A; + view all (2018) Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes. Genome Research , 28 (12) pp. 1779-1790. 10.1101/gr.239186.118. Green open access

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Abstract

Mosaic mutations present in the germline have important implications for reproductive risk and disease transmission. We previously demonstrated a phenomenon occurring in the male germline, whereby specific mutations arising spontaneously in stem cells (spermatogonia) lead to clonal expansion, resulting in elevated mutation levels in sperm over time. This process, termed selfish spermatogonial selection, explains the high spontaneous birth prevalence and strong paternal age-effect of disorders such as achondroplasia, Apert, Noonan and Costello syndromes, with direct experimental evidence currently available for specific positions of six genes (FGFR2, FGFR3, RET, PTPN11, HRAS and KRAS). We present a discovery screen to identify novel mutations and genes showing evidence of positive selection in the male germline, by performing massively parallel simplex PCR using RainDance technology to interrogate mutational hotspots in 67 genes (51.5 kb in total) in 276 biopsies of testes from 5 men (median age: 83 years). Following ultra-deep sequencing (~16,000x), development of a low-frequency variant prioritization strategy and targeted validation, we identified 61 distinct variants present at frequencies as low as 0.06%, including 54 variants not previously directly associated with selfish selection. The majority (80%) of variants identified have previously been implicated in developmental disorders and/or oncogenesis and include mutations in six newly associated genes (BRAF, CBL, MAP2K1, MAP2K2, RAF1 and SOS1), all of which encode components of RAS-MAPK pathway and activate signaling. Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the ageing male germline is a repository for such deleterious mutations.

Type: Article
Title: Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1101/gr.239186.118
Publisher version: https://doi.org/10.1101/gr.239186.118
Language: English
Additional information: This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10061249
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