Accumulation of mutations in somatic cells has been implicated as a cause of aging since the 1950s. However, attempts to establish a causal relationship between somatic mutations and aging have been constrained by the lack of methods to directly identify mutational events in primary human tissues. Here we provide genome-wide mutation frequencies and spectra of human B lymphocytes from healthy individuals across the entire human lifespan using a highly accurate single-cell whole-genome sequencing method. We found that the number of somatic mutations increases from <500 per cell in newborns to >3,000 per cell in centenarians. We discovered mutational hotspot regions, some of which, as expected, were located at Ig genes associated with somatic hypermutation (SHM). B cell–specific mutation signatures associated with development, aging, or SHM were found. The SHM signature strongly correlated with the signature found in human B cell tumors, indicating that potential cancer-causing events are already present even in B cells of healthy individuals. We also identified multiple mutations in sequence features relevant to cellular function (i.e., transcribed genes and gene regulatory regions). Such mutations increased significantly during aging, but only at approximately one-half the rate of the genome average, indicating selection against mutations that impact B cell function. This full characterization of the landscape of somatic mutations in human B lymphocytes indicates that spontaneous somatic mutations accumulating with age can be deleterious and may contribute to both the increased risk for leukemia and the functional decline of B lymphocytes in the elderly.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Apr 30 2019|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS. We thank the Molecular Cytogenetics Core and the Epigenomics Core at the Albert Einstein College of Medicine for B cell isolation and RNA/ATAC sequencing, respectively. We thank Drs. Bernice Morrow, Sofiya Milman, and Nir Barzilai for sharing human samples and assisting us with the human subjects part of the research. This study was supported by the National Institutes of Health (Grants P01 AG017242 to J.V., P01 AG047200 to J.V., and K99 AG056656 to X.D.), Einstein’s Nathan Shock Center of Excellence in Basic Biology of Aging (Grant P30 AG038072), and the Paul F. Glenn Center for the Biology of Human Aging.
© 2019 National Academy of Sciences. All rights reserved.
- B lymphocyte
- Functional genome
- Single-cell whole-genome
- Somatic DNA mutation