当前位置： SCI文献检索 > GENOME RESEARCH期刊下所有文献 > Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes.

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

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 and 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 five men (median age, 83 yr). Following ultradeep sequencing (about 16,000×), 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 the 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 aging male germline is a repository for such deleterious mutations.

journal_name

Genome Res

journal_title

Genome research

authors

Maher GJ,Ralph HK,Ding Z,Koelling N,Mlcochova H,Giannoulatou E,Dhami P,Paul DS,Stricker SH,Beck S,McVean G,Wilkie AOM,Goriely A

doi

10.1101/gr.239186.118

subject

Has Abstract

pub_date

2018-12-01 00:00:00

pages

1779-1790

issue

eissn

1088-9051

issn

1549-5469

pii

gr.239186.118

journal_volume

pub_type

杂志文章

在线工具

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