Somatic Mutations Reveal Lineage Relationships and Age-Related Mutagenesis in Human Hematopoiesis

TLDR

Mutation accumulation during life can contribute to hematopoietic dysfunction, yet the underlying dynamics remain unclear; somatic mutations in blood progenitors can reveal the rate, processes, lineage tree, and stem‑cell division numbers. The study catalogs somatic mutations in the genomes of bone‑marrow– and cord‑blood–derived hematopoietic stem and progenitor cells. Mutations accrue gradually at roughly 14 substitutions per year, largely after birth due to endogenous mutagenic processes, and the mutation data enable construction of a developmental lineage tree that shows a polyclonal, multipotent architecture. These findings illuminate features of native human hematopoiesis and suggest mechanisms relevant to leukemogenesis.

Abstract

Mutation accumulation during life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. Somatic mutations in blood progenitors can provide insight into the rate and processes underlying this accumulation, as well as the developmental lineage tree and stem cell division numbers. Here, we catalog mutations in the genomes of human-bone-marrow-derived and umbilical-cord-blood-derived hematopoietic stem and progenitor cells (HSPCs). We find that mutations accumulate gradually during life with approximately 14 base substitutions per year. The majority of mutations were acquired after birth and could be explained by the constant activity of various endogenous mutagenic processes, which also explains the mutation load in acute myeloid leukemia (AML). Using these mutations, we construct a developmental lineage tree of human hematopoiesis, revealing a polyclonal architecture and providing evidence that developmental clones exhibit multipotency. Our approach highlights features of human native hematopoiesis and its implications for leukemogenesis.