Batada Nizar N, Hurst Laurence D
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
Nat Genet. 2007 Aug;39(8):945-9. doi: 10.1038/ng2071.
The distribution of genes on eukaryotic chromosomes is nonrandom, but the reasons behind this are not well understood. The commonly observed clustering of essential genes is a case in point. Here we model and test a new hypothesis. Essential proteins are unusual in that random fluctuations in abundance (noise) can be highly deleterious. We hypothesize that persistently open chromatin domains are sinks for essential genes, as they enable reduced noise by avoidance of transcriptional bursting associated with chromatin remodeling. Simulation of the model captures clustering and correctly predicts that (i) essential gene clusters are associated with low nucleosome occupancy (ii) noise-sensitive nonessential genes cluster with essential genes (iii) nonessential genes of similar knockout fitness are physically linked (iv) genes in domains rich in essential genes have low noise (v) essential genes are rare subtelomerically and (vi) essential gene clusters are preferentially conserved. We conclude that different noise characteristics of different genomic domains favors nonrandom gene positioning. This has implications for gene therapy and understanding transgenic phenotypes.
真核生物染色体上基因的分布并非随机，但背后的原因尚未完全明了。常见的必需基因成簇现象就是一个例子。在此，我们构建并测试了一个新假说。必需蛋白不同寻常之处在于其丰度的随机波动（噪音）可能具有高度有害性。我们推测，持续开放的染色质结构域是必需基因的汇聚点，因为它们能够通过避免与染色质重塑相关的转录爆发来降低噪音。该模型的模拟捕捉到了基因成簇现象，并正确预测出：（i）必需基因簇与低核小体占有率相关；（ii）对噪音敏感的非必需基因与必需基因成簇；（iii）具有相似敲除适应性的非必需基因在物理上相互连接；（iv）富含必需基因的结构域中的基因噪音较低；（v）必需基因在亚端粒区域很少见；（vi）必需基因簇优先保守。我们得出结论，不同基因组结构域的不同噪音特征有利于非随机的基因定位。这对基因治疗和理解转基因表型具有启示意义。
