Previous studies have surveyed the potential impact of loss-of-function (LoF) variants and identified LoF-tolerant protein-coding genes. However, the tolerance of human genomes to losing enhancers has not yet been evaluated. Here we present the catalog of LoF-tolerant enhancers using structural variants from whole-genome sequences. Using a conservative approach, we estimate that individual human genomes possess at least 28 LoF-tolerant enhancers on average. We assessed the properties of LoF-tolerant enhancers in a unified regulatory network constructed by integrating tissue-specific enhancers and gene-gene interactions. We find that LoF-tolerant enhancers tend to be more tissue-specific and regulate fewer and more dispensable genes relative to other enhancers. They are enriched in immune-related cells while enhancers with low LoF-tolerance are enriched in kidney and brain/neuronal stem cells. We developed a supervised learning approach to predict the LoF-tolerance of all enhancers, which achieved an area under the receiver operating characteristics curve (AUROC) of 98%. We predict 3,519 more enhancers would be likely tolerant to LoF and 129 enhancers that would have low LoF-tolerance. Our predictions are supported by a known set of disease enhancers and novel deletions from PacBio sequencing. The LoF-tolerance scores provided here will serve as an important reference for disease studies.

中文翻译：

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人类基因组中增强子的功能丧失耐受性。

先前的研究调查了功能丧失（LoF）变异体的潜在影响，并确定了LoF耐受蛋白编码基因。然而，尚未评估人类基因组对丢失增强子的耐受性。在这里，我们使用来自全基因组序列的结构变体介绍了LoF耐受增强子的目录。使用保守的方法，我们估计每个人的基因组平均拥有至少28个LoF耐受增强子。我们在通过整合组织特异性增强子和基因-基因相互作用构建的统一监管网络中评估了LoF耐受增强子的特性。我们发现，相对于其他增强子，耐受LoF的增强子倾向于更具组织特异性，并且调控着越来越少的可分配基因。它们富含免疫相关细胞，而低LoF耐受性的增强剂富含肾和脑/神经元干细胞。我们开发了一种有监督的学习方法来预测所有增强子的LoF容差，该区域在接收器工作特性曲线（AUROC）下的面积达到98％。我们预测，可能有3,519个增强子可能耐受LoF，而129个增强子可能具有较低的LoF耐受性。我们的预测得到PacBio测序已知的一组疾病增强剂和新缺失的支持。此处提供的LoF耐受性评分将为疾病研究提供重要参考。在接收器工作特性曲线（AUROC）下的面积达到了98％。我们预测，可能有3,519个增强子可能耐受LoF，而129个增强子可能具有较低的LoF耐受性。我们的预测得到PacBio测序已知的一组疾病增强剂和新缺失的支持。此处提供的LoF耐受性评分将为疾病研究提供重要参考。在接收器工作特性曲线（AUROC）下的面积达到了98％。我们预测，可能有3,519个增强子可能耐受LoF，而129个增强子可能具有较低的LoF耐受性。我们的预测得到PacBio测序已知的一组疾病增强剂和新缺失的支持。此处提供的LoF耐受性评分将为疾病研究提供重要参考。