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

Area of Science:

• Genetics
• Reproductive Biology
• Developmental Biology

Background:

• Germline mosaic mutations have significant implications for reproductive risks and disease transmission.
• Selfish spermatogonial selection, a phenomenon of clonal expansion of mutated stem cells, explains paternal age effects in certain genetic disorders.

Purpose of the Study:

• To discover novel mutations and genes exhibiting positive selection in the aging male germline.
• To investigate the role of the RAS-MAPK pathway in selfish spermatogonial selection.

Main Methods:

• Massively parallel simplex PCR and ultradeep sequencing of 67 genes in 276 testicular biopsies from elderly men.
• Development of a low-frequency variant prioritization strategy for variant identification.
• Targeted validation of identified variants.

Main Results:

• Identified 61 distinct variants, including 54 novel ones associated with selfish selection, at frequencies as low as 0.06%.
• 80% of variants are linked to developmental disorders or oncogenesis.
• Discovered mutations in six new genes (BRAF, CBL, MAP2K1, MAP2K2, RAF1, SOS1), all part of the RAS-MAPK pathway.

Conclusions:

• The study extends the association between RAS-MAPK pathway dysregulation and selfish selection in the male germline.
• The aging male germline acts as a reservoir for deleterious mutations driving selfish selection.