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Somatic mutations are frequent and increase with age in human kidney epithelial cells
G M Martin1, C E Ogburn, L M Colgin
1Department of Pathology, University of Washington, Seattle 98195, USA.
Abstract:
We have used a primary cloning assay to determine the frequency of 6-thioguanine (TG)-resistant tubular epithelial cells in kidney tissue from 72 human donors ranging in age from 2 to 94 years. The frequency of TG-resistant mutants ranged from approximately 5 x 10(-5) for donors in the first decade of life to approximately 2.5 x 10(-4) for donors in the eighth and later decades of life. Two different statistical analyses indicated that this increase in mutant frequency is exponential with age. We also observed a 2-fold higher TG-resistant mutant frequency in nephrectomy kidneys containing a coincident renal carcinoma. DNA sequence analyses revealed HPRT gene mutations in each of 14 TG-resistant mutants from seven unrelated donors. Thirteen of these 14 mutants resulted from independent mutational events. These results suggest that somatic mutations are common in renal--and perhaps in other human--epithelia, and thus could play an important role in the genesis of age-associated disease.
Insights
The frequency of 6-thioguanine-resistant kidney cells increases exponentially with age, suggesting somatic mutations are common in human epithelia. This accumulation may contribute to age-related diseases.
Area of Science:
- Genetics
- Gerontology
- Nephrology
Background:
- Somatic mutations accumulate in human tissues with age.
- Understanding mutation frequency in kidney cells is crucial for aging research.
Purpose of the Study:
- To determine the frequency of 6-thioguanine-resistant tubular epithelial cells in human kidney tissue across a wide age range.
- To investigate the relationship between age and mutation frequency in renal cells.
- To analyze the mutational spectrum in resistant cells.
Main Methods:
- Primary cloning assay to quantify 6-thioguanine-resistant cells.
- Analysis of kidney tissue from 72 human donors (ages 2-94).
- DNA sequencing to identify mutations in the HPRT gene.
Main Results:
- A significant, exponential increase in 6-thioguanine-resistant mutant frequency with age was observed.
- Mutant frequency ranged from 5 x 10(-5) in children to 2.5 x 10(-4) in older adults.
- A 2-fold higher mutant frequency was found in kidneys with renal carcinoma.
- HPRT gene mutations were identified in all analyzed resistant mutants, mostly from independent events.
Conclusions:
- Somatic mutations are common in human renal epithelia and accumulate exponentially with age.
- These mutations may play a significant role in the development of age-associated diseases.
- The findings support the role of accumulated somatic mutations in aging and disease pathogenesis.