Orion: Detecting regions of the human non-coding genome that are intolerant to variation using population genetics

There is broad agreement that genetic mutations occurring outside of the protein-coding regions play a key role in human disease. Despite this consensus, we are not yet capable of discerning which portions of non-coding sequence are important in the context of human disease. Here, we present Orion, an approach that detects regions of the non-coding genome that are depleted of variation, suggesting that the regions are intolerant of mutations and subject to purifying selection in the human lineage. We show that Orion is highly correlated with known intolerant regions as well as regions that harbor putatively pathogenic variation. This approach provides a mechanism to identify pathogenic variation in the human non-coding genome and will have immediate utility in the diagnostic interpretation of patient genomes and in large case control studies using whole-genome sequences.学界已达成广泛共识：蛋白质编码区之外发生的基因突变在人类疾病发生中发挥关键作用。尽管存在这一共识，但目前我们仍无法甄别出与人类疾病相关的非编码序列区域。为此，我们提出了Orion方法，该方法可检测人类非编码基因组中变异匮乏的区域，提示这些区域无法耐受突变，在人类演化谱系中受到纯化选择作用。我们证实，Orion的检测结果与已知的突变不耐受区域，以及携带疑似致病性变异的区域均呈现高度相关性。该方法为人类非编码基因组中致病性变异的识别提供了可行路径，可直接应用于患者基因组的诊断解读，以及基于全基因组序列的大规模病例对照研究中。