Single-Cell Whole-Genome Sequencing Reveals B Lymphocyte Mutational Landscapes Across the Human Lifespan

Using a recently developed, highly accurate single-cell whole-genome sequencing method we analyzed the somatic mutational landscape of human B lymphocytes, from birth to over 100 years. Mutations increased with age from less than 500 in cord blood to over 3,000 per cell on average in individuals over 100. Distinct B cell-specific mutation signatures specific for age and function were identified, as well as a total of 24 hotspot regions, five of which were part of Immunoglobulin variable regions subject to somatic hypermutation. Functional annotation of all mutations demonstrated that cells from aged individuals contain on average 6.5 deleterious mutations per cell in transcribed genes, 18.5 mutations in transcribed UTR regions, and 24.5 mutations in proximate transcription factor binding sites. These results suggest that spontaneous somatic mutations accumulating with age reach high enough levels to contribute to age-related, intrinsic functional decline, such as the well documented degenerative changes in B lymphocytes.