Analysis of Somatic Mutations in Senescent Cells Using Single-Cell Whole-Genome Sequencing
Lei Zhang1,2, Marco De Cecco3, Moonsook Lee4
1Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
Aging Biology
|October 18, 2024
Summary
Cellular senescence, a hallmark of aging, doubles somatic mutations like single-nucleotide variants (SNVs) and small insertions/deletions (INDELs) due to increased cell divisions. However, deeply senescent cells exhibit a significant increase in aneuploidies, suggesting chromosomal instability is linked to senescence.
Area of Science:
- Genetics
- Cell Biology
- Aging Research
Background:
- Somatic mutations accumulate with age and contribute to cancer.
- Cellular senescence is implicated in aging and acts as an anticancer mechanism.
Purpose of the Study:
- To compare somatic mutation burden in early passage versus deeply senescent human fibroblasts.
- To investigate the types of mutations associated with cellular senescence.
Main Methods:
- Single-cell whole-genome sequencing was employed.
- Human fibroblasts at early passage and deep senescence were analyzed.
Main Results:
- Senescent cells showed a twofold increase in single-nucleotide variants (SNVs) and small insertions/deletions (INDELs) compared to early passage cells.
- Mutational signatures for SNVs and INDELs remained similar between early and senescent cells.
- A significant increase in aneuploidies was observed in deeply senescent cells, affecting approximately half of the analyzed cells.
Conclusions:
- The accumulation of SNVs and INDELs in senescent cells may result from increased replication errors.
- Large chromosomal events, specifically aneuploidies, are mechanistically linked to cellular senescence, distinct from small base substitution mutations.
