The aging genome exhibits organized vulnerability to somatic mutations

Abstract

Somatic mutations accumulate throughout life and have been hypothesized to drive organismal decline. Yet whether these mutations are distributed randomly or whether cells shield their most critical components has remained unresolved. Here we analyze over a million somatic mutations across thirteen human tis-sues, finding that the aging genome exhibits organized vulnerability, captured by the existence of hypo-mutated genes and longevity-associated pathways that have significantly lower mutation burden. Highly connected network hubs are systematically protected from mutation, while peripheral, condition-specific genes accumulate disproportionate burdens. We show that this organized vulnerability arises from the interplay of two independent mechanisms: transcription-coupled repair, and selective filtering. Finally, we validate our findings under experimental mutagenesis, demonstrating intrinsic mechanisms of protection rather than tissue-specific confounders. These findings reframe the somatic mutation hypothesis: organismal decline may not reflect total mutational burden, but where those mutations fall within the cellular network.