Non-coding "ultraconserved" regions containing hundreds of consecutive bases of perfect sequence conservation across mammalian genomes can function as distant-acting enhancers. However, initial deletion studies in mice revealed that loss of such extraordinarily constrained sequences had no immediate impact on viability. Here, we show that ultraconserved enhancers are required for normal development. Focusing on some of the longest ultraconserved sites genome wide, located near the essential neuronal transcription factor Arx, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved enhancers. Mice with single or pairwise deletions of ultraconserved enhancers were viable and fertile but in nearly all cases showed neurological or growth abnormalities, including substantial alterations of neuron populations and structural brain defects. Our results demonstrate the functional importance of ultraconserved enhancers and indicate that remarkably strong sequence conservation likely results from fitness deficits that appear subtle in a laboratory setting.

中文翻译：

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正常开发需要超保守的增强子。

包含数百个跨哺乳动物基因组的完美序列保守序列的连续碱基的非编码“超保守”区域，可以充当远距离增强子。但是，在小鼠中进行的初步删除研究表明，此类异常受限制的序列的丢失对生存力没有立即的影响。在这里，我们表明正常发展需要超保守的增强子。着眼于全基因组中最长的超保守位点，位于基本神经元转录因子Arx附近，我们使用基因组编辑来创建一系列扩展的基因敲除小鼠，这些小鼠缺乏超保守增强剂的个体或组合。单个或成对缺失超保守增强子的小鼠是可行的和可育的，但几乎在所有情况下均显示神经系统或生长异常，包括神经元种群的大量变化和大脑结构的缺陷。我们的研究结果证明了超保守增强子的功能重要性，并表明非常强的序列保守性很可能是由于在实验室环境下出现的适应性缺陷而导致的。