Abstract
Somatic mutation accumulation has been implicated as a major cause of cancer and aging. By using a transgenic mouse model with a chromosomally integrated lacZ reporter gene, mutational spectra were characterized at young and old age in two organs greatly differing in proliferative activity, i.e., the heart and small intestine. At young age the spectra were nearly identical, mainly consisting of G·C to A·T transitions and 1-bp deletions. At old age, however, distinct patterns of mutations had developed. In small intestine, only point mutations were found to accumulate, including G·C to T·A, G·C to C·G, and A·T to C·G transversions and G·C to A·T transitions. In contrast, in heart about half of the accumulated mutations appeared to be large genome rearrangements, involving up to 34 centimorgans of chromosomal DNA. Virtually all other mutations accumulating in the heart appeared to be G·C to A·T transitions at CpG sites. These results suggest that distinct mechanisms lead to organ-specific genome deterioration and dysfunction at old age.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8403-8408 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 97 |
| Issue number | 15 |
| DOIs | |
| State | Published - Jul 18 2000 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
- General
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Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. / Dollé, Martijn E T; Snyder, Wendy K.; Gossen, Jan A.; Lohman, Paul H M; Vijg, Jan.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 15, 18.07.2000, p. 8403-8408.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine
AU - Dollé, Martijn E T
AU - Snyder, Wendy K.
AU - Gossen, Jan A.
AU - Lohman, Paul H M
AU - Vijg, Jan
PY - 2000/7/18
Y1 - 2000/7/18
N2 - Somatic mutation accumulation has been implicated as a major cause of cancer and aging. By using a transgenic mouse model with a chromosomally integrated lacZ reporter gene, mutational spectra were characterized at young and old age in two organs greatly differing in proliferative activity, i.e., the heart and small intestine. At young age the spectra were nearly identical, mainly consisting of G·C to A·T transitions and 1-bp deletions. At old age, however, distinct patterns of mutations had developed. In small intestine, only point mutations were found to accumulate, including G·C to T·A, G·C to C·G, and A·T to C·G transversions and G·C to A·T transitions. In contrast, in heart about half of the accumulated mutations appeared to be large genome rearrangements, involving up to 34 centimorgans of chromosomal DNA. Virtually all other mutations accumulating in the heart appeared to be G·C to A·T transitions at CpG sites. These results suggest that distinct mechanisms lead to organ-specific genome deterioration and dysfunction at old age.
AB - Somatic mutation accumulation has been implicated as a major cause of cancer and aging. By using a transgenic mouse model with a chromosomally integrated lacZ reporter gene, mutational spectra were characterized at young and old age in two organs greatly differing in proliferative activity, i.e., the heart and small intestine. At young age the spectra were nearly identical, mainly consisting of G·C to A·T transitions and 1-bp deletions. At old age, however, distinct patterns of mutations had developed. In small intestine, only point mutations were found to accumulate, including G·C to T·A, G·C to C·G, and A·T to C·G transversions and G·C to A·T transitions. In contrast, in heart about half of the accumulated mutations appeared to be large genome rearrangements, involving up to 34 centimorgans of chromosomal DNA. Virtually all other mutations accumulating in the heart appeared to be G·C to A·T transitions at CpG sites. These results suggest that distinct mechanisms lead to organ-specific genome deterioration and dysfunction at old age.
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U2 - 10.1073/pnas.97.15.8403
DO - 10.1073/pnas.97.15.8403
M3 - Article
VL - 97
SP - 8403
EP - 8408
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 15
ER -