Modeling stochastic gene expression: Implications for haploinsufficiency
Modeling stochastic gene expression: Implications for haploinsufficiency
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DOI：
10.1073/pnas.95.26.15641
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发表时间：
1998-12-22
影响因子：
11.1
通讯作者：
Tapscott, SJ
中科院分区：
文献类型：
--
作者：
Cook, DL;Gerber, LN;Tapscott, SJ
人们越来越认识到，在发育生物体中，随机过程调节着高度可预测的基因表达模式，但随机基因表达对理解单倍功能不全的影响在很大程度上仍未被探索。我们已经使用随机基因表达的模拟来说明，基因拷贝数和表达失活率是实现可预测结果的重要变量。在非零表达失活率的基因表达系统中，二倍体系统比单倍体系统具有更高的不间断基因表达的可能性，并且更成功地将基因产物维持在非常低的阈值之上。表达失活率相对较快（不稳定基因表达）的系统比表达失活率较慢或为零（稳定基因表达）的系统对诱导剂梯度的反应更可预测，二倍体系统比单倍体系统更可预测，无论是否有剂量补偿。我们认为，二倍体生物中单个等位基因的零突变可能会降低基因表达的概率，并提出一些单倍不全综合征可能是由于基因启动随机延迟或基因表达中断的易感性增加所致。
There is increasing recognition that stochastic processes regulate highly predictable patterns of gene expression in developing organisms, but the implications of stochastic gene expression for understanding haploinsufficiency remain largely unexplored, We have used simulations of stochastic gene expression to illustrate that gene copy number and expression deactivation rates are important variables in achieving predictable outcomes, In gene expression systems with non-zero expression deactivation rates, diploid systems had a higher probability of uninterrupted gene expression than haploid systems and were more successful at maintaining gene product above a very low threshold. Systems with relatively rapid expression deactivation rates (unstable gene expression) had more predictable responses to a gradient of inducer than systems with slow or zero expression deactivation rates (stable gene expression), and diploid systems were more predictable than haploid, with or without dosage compensation. We suggest that null mutations of a single allele in a diploid organism could decrease the probability of gene expression and present the hypothesis that some haploinsufficiency syndromes might result from an increased susceptibility to stochastic delays of gene initiation or interruptions of gene expression.