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An Isogenic Trisomic–Disomic Model System Using Cells from People with Mosaic Down Syndrome Unmasks Trisomy 21 Associated Increases in Age-Related Chromosomal Instability, Senescence Associated Distension of Satellites, and Telomere Shortening

      We hypothesize that cellular changes leading to premature aging in Down syndrome (Ds) include: (1) increases in somatic chromosomal instability frequencies (SCINF); (2) increases in senescence associated distension of satellites (SADS); and (3) decreases in telomere length. Given that the trisomic/normal cells from people with mosaic Ds (mDs) are identical with regard to environmental exposures and genes (except chromosome 21 copy number), comparisons of these isogenic cells allow one to “unmask” cellular consequences of trisomy 21. Thus, we evaluated the trisomic/normal cells from 31 people with mDs (ages 1–44) to quantify: (1) SCINF (scored 1000 cells/person using a micronucleus [MN] assay); (2) SADS (scored 100 cells/person with probes for chromosomes 8 and 21; and (3) telomere lengths (scored 10 disomic and 10 trisomic cells/person using a chromosome-specific assay). In children (ages 1–11; n = 20), no difference was observed in SCINF in disomic (0.16 mean ± 0.02 SEM) compared to trisomic (0.17 ± 0.02) cells (p > 0.05), but in teens/adults (ages 15–44; n = 11), trisomic binucleates showed a significant increase in SCINF (0.32 ± 0.05) when compared to disomic (0.17 ± 0.02) cells (p = 0.006). MN containing chromosome 21 occurred more often than expected by chance (p < 0.01), but accounted for only 12% of the total MN detected. Preliminary data suggest that SADS are also present in a higher frequency in the trisomic cells of older probands. Trisomic cells also had significantly shorter telomeres across all chromosomes when compared to disomic cells (to date, n = 13; p < 0.001), with this difference appearing by age 2. Collectively, these results suggest that age-related, trisomy 21-associated cellular changes arise from a “network” involving multiple acquired chromosomal findings and are not limited to alterations involving chromosome 21. They also support the use of this isogenic mDs model system for providing insight about cellular changes arising from a trisomy 21 imbalance.
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