The evolution of polyclonal competition in aging hematopoiesis

Area of Science:

• Somatic evolution and hematopoiesis.
• Genetics and molecular biology.
• Computational biology and evolutionary modeling.

Background:

• Clonal hematopoiesis (CH) involves genetic variant expansion in blood, a key aspect of somatic evolution.
• While CH often precedes malignant transformation, its underlying dynamics remain incompletely understood.
• Understanding CH is crucial for identifying early signs of hematologic malignancies.

Purpose of the Study:

• To explain the dynamics of clonal hematopoiesis (CH) throughout human life using a competitive model.
• To quantify the fitness distribution and occurrence rate of clonal expansions.
• To investigate the evolutionary patterns of specific genetic variants associated with CH.

Main Methods:

• Development and application of a polyclonal competition model to explain CH dynamics.
• Quantification of clonal expansion fitness and occurrence rates using variant trajectories and HSC genetic heterogeneity.
• Analysis of variant enrichment patterns (single-hit vs. multi-hit) for specific genes (DNMT3A, TET2, ASXL1, JAK2, SF3B1, SRSF2).

Main Results:

• The model of polyclonal competition accurately explains observed CH dynamics across the human lifespan.
• Approximately three fit clones emerge annually in the HSC pool, with rarely more than five exceeding 1.5% frequency.
• Fittest clones predominantly emerge later in life, consistent with multistep evolutionary processes.
• DNMT3A variants showed enrichment for single-hit clones, while TET2, ASXL1, JAK2, SF3B1, and SRSF2 variants were enriched for multi-hit evolution.

Conclusions:

• CH dynamics can be effectively modeled by polyclonal competition, offering insights into somatic evolution in blood.
• Specific genetic variants exhibit distinct evolutionary patterns, suggesting different pathways to clonal expansion.
• Precursors to hematologic malignancies are potentially identifiable before transformation, paving the way for early intervention strategies.