Trisomy 21-associated increases in chromosomal instability are unmasked by comparing isogenic trisomic/disomic leukocytes from people with mosaic Down syndrome.
Trisomy 21-associated increases in chromosomal instability are unmasked by comparing isogenic trisomic/disomic leukocytes from people with mosaic Down syndrome.
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DOI：
10.1371/journal.pone.0254806
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Jackson-Cook C
中科院分区：
文献类型：
--
作者：
Rafferty K;Archer KJ;Turner K;Brown R;Jackson-Cook C
唐氏综合征是由21号染色体三体不平衡引起的，与80多个表型性状有关。然而，由于这种非整倍体条件而在体细胞中产生的细胞变化尚未完全了解。本研究的主要目的是确定生殖系21三体是否与自发性体细胞染色体不稳定频率（SCINF）增加相关。为了实现这一目标，我们量化的人与马赛克唐氏综合征SCINF使用微核阻断试验。通过比较其同基因三体/二体细胞中的值，我们获得了直接归因于21三体不平衡的SCINF差异的测量，因为归因于“背景”遗传因素和环境暴露的差异效应可以消除。对69名镶嵌性唐氏综合征患者（年龄1 - 44岁;平均年龄12.84岁）进行的横断面评估显示，与二体细胞（0.18 ± 0.11）相比，三体细胞（0.37 ± 0.35 [平均值±标准差]）的微核频率显著更高（P <0.0001）。在三体细胞中，子双核细胞的异常模式数（1.68 ± 1.21）显著高于二体细胞（0.35 ± 0.45）（P <0.0001）。此外，注意到显著的年龄X细胞类型相互作用（P = 0.0113），表明年龄和SCINF之间的关系在三体和二体细胞之间不同。同样，对18名参与者的纵向评估（平均时间间隔为3.9年;范围为2至6年）显示，随着时间的推移，三体细胞的SCINF平均增加1.63倍（P = 0.0186），而二体细胞的SCINF平均增加1.13倍（P = 0.0464）。总之，这些结果表明，21三体相关的，年龄相关的SCINF增加。他们还强调了同基因嵌合唐氏综合征模型系统的力量，用于“揭露”由21三体不平衡引起的细胞变化。
Down syndrome, which results from a trisomic imbalance for chromosome 21, has been associated with 80+ phenotypic traits. However, the cellular changes that arise in somatic cells due to this aneuploid condition are not fully understood. The primary aim of this study was to determine if germline trisomy 21 is associated with an increase in spontaneous somatic cell chromosomal instability frequencies (SCINF). To achieve this aim, we quantified SCINF in people with mosaic Down syndrome using a cytokinesis-blocked micronucleus assay. By comparing values in their isogenic trisomic/disomic cells, we obtained a measure of differences in SCINF that are directly attributable to a trisomy 21 imbalance, since differential effects attributable to “background” genetic factors and environmental exposures could be eliminated. A cross-sectional assessment of 69 people with mosaic Down syndrome (ages 1 to 44; mean age of 12.84 years) showed a significantly higher frequency of micronuclei in their trisomic (0.37 ± 0.35 [mean ± standard deviation]) compared to disomic cells (0.18 ± 0.11)(P <0.0001). The daughter binucleates also showed significantly higher levels of abnormal patterns in the trisomic (1.68 ± 1.21) compared to disomic (0.35 ± 0.45) cells (P <0.0001). Moreover, a significant Age x Cell Type interaction was noted (P = 0.0113), indicating the relationship between age and SCINF differed between the trisomic and disomic cells. Similarly, a longitudinal assessment (mean time interval of 3.9 years; range of 2 to 6 years) of 18 participants showed a mean 1.63-fold increase in SCINF within individuals over time for their trisomic cells (P = 0.0186), compared to a 1.13-fold change in their disomic cells (P = 0.0464). In summary, these results showed a trisomy 21-associated, age-related increase in SCINF. They also underscore the strength of the isogenic mosaic Down syndrome model system for “unmasking” cellular changes arising from a trisomy 21 imbalance.
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作者：
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