The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations

Area of Science:

• Genetics
• Genomics
• Hematology

Background:

• Clonal hematopoiesis (CH) involves genetically identical cell expansion in blood.
• Known genetic lesions often drive CH, but CH can occur without them.
• Characterizing CH without known driver mutations is crucial for understanding hematologic health.

Purpose of the Study:

• To characterize CH in individuals lacking leukemogenic point mutations (CH-LPMneg).
• To develop a method for quantifying mutation burden from whole genomes without paired tissue.
• To identify genetic, genomic, and phenotypic correlates of CH-LPMneg.

Main Methods:

• Analyzed 51,399 whole genomes from the NHLBI TOPMed initiative.
• Developed the Genomic and Epigenomic informed Mutation (GEM) rate to quantify somatic mutation burden.
• Performed genome-wide association studies, fine-mapping, variant-to-gene analyses, and multi-tissue transcriptomic analyses.

Main Results:

• Identified seven genes (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1) associated with CH-LPMneg.
• GEM rate is linked to increased white blood cell count and peripheral artery disease risk.
• Functional analyses implicated SMC4 and NRIP1 in HSC self-renewal and proliferation.

Conclusions:

• The GEM rate effectively quantifies mutation burden from whole genomes.
• Discovered novel genetic determinants and phenotypic associations of CH-LPMneg.
• This work provides insights into the mechanisms and health implications of CH without known driver mutations.