The human body accumulates somatic mutations throughout life, shaped by diverse mutational processes, environmental exposures, and tissue-specific dynamics. Using highly accurate single-molecule sequencing (NanoSeq), we have mapped the mutational landscape across over 50 human tissue types, revealing striking variability in mutation burden, mutational signatures, and clonal structure. While most somatic tissues accumulate mutations through both endogenous and exogenous processes, the male germline emerges as an evolutionary outlier. Spermatogonial stem cells exhibit the lowest mutation rates observed in any dividing human cell, accumulating just 2-4 single base substitutions per year, despite their lifelong proliferation.

In this talk, Dr Rahbari will present insights from their pan tissue analysis, with a focus on the unique features of the germline. She will discuss how its mutational restraint, signature spectrum, and evidence of positive selection distinguish it from somatic tissues, and explore the evolutionary pressures likely acting on the germline to preserve reproductive fidelity. Finally, she will discuss how rare exceptions, such as germline hypermutation, reveal vulnerabilities in this otherwise tightly constrained system, with important implications for heritable disease risk.