Whole-genome and exome sequencing in human populations has revealed the tolerance of each gene for loss-of-function variation. By understanding this tolerance, it has become increasingly possible to identify genes that would make safe therapeutic targets and to identify rare genetic risk factors and phenotypes at the scale of individual genomes. To date, the vast majority of surveyed loss-of-function variants are in protein-coding regions of the genome mainly due to the focus on these regions by exome-based sequencing projects and their relative ease of interpretability. As whole-genome sequencing becomes more prevalent, new strategies will be required to uncover impactful variation in non-coding regions of the genome where the architecture of genome function is more complex. In this review, we investigate recent studies of loss-of-function variation and emerging approaches for interpreting whole-genome sequencing data to identify rare and impactful non-coding loss-of-function variants.

中文翻译：

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人类基因组中的非编码功能丧失变异。


人群的全基因组和外显子组测序揭示了每个基因对功能丧失变异的耐受性。通过了解这种耐受性，越来越有可能识别出可作为安全治疗靶点的基因，并在个体基因组范围内识别罕见的遗传风险因素和表型。迄今为止，绝大多数调查的功能丧失变异都位于基因组的蛋白质编码区域，这主要是由于基于外显子组的测序项目对这些区域的关注及其相对容易解释。随着全基因组测序变得越来越普遍，需要新的策略来揭示基因组非编码区域的有影响力的变异，这些区域的基因组功能结构更加复杂。在这篇综述中，我们调查了最近关于功能丧失变异的研究以及解释全基因组测序数据的新兴方法，以识别罕见且有影响力的非编码功能丧失变异。