Human and mouse essentiality screens as a resource for disease gene discovery
Human and mouse essentiality screens as a resource for disease gene discovery
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DOI：
10.1038/s41467-020-14284-2
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发表时间：
2020-01-31
影响因子：
16.6
通讯作者：
Kane, Coleen
中科院分区：
文献类型：
--
作者：
Cacheiro, Pilar;Munoz-Fuentes, Violeta;Kane, Coleen
在测序研究中鉴定致病变异仍然是一个相当大的挑战，可以通过新的基因特异性知识部分解决。在这里，我们整合的措施是多么重要的基因是支持生命，推断从生存能力和表型筛选敲除小鼠进行的国际小鼠表型协会和必要性筛选人类细胞系。我们提出了一个跨物种的基因分类的功能丧失（FUSIL）的不耐受性的全谱，并证明在五个相互排斥的FUSIL类别的基因具有不同的生物学特性。最值得注意的是，孟德尔疾病基因，特别是与发育障碍相关的基因，在细胞生存非必需但生物体发育所需的基因中高度过度表达。在从三个独立的疾病测序联盟中筛选发育障碍病例后，我们发现了以前与罕见疾病无关的基因中的潜在致病性变异。因此，我们提出FUSIL作为一种有效的方法，疾病基因discovery.Discovery的致病变异单基因疾病已被促进了全外显子组和基因组测序，但并不提供一个诊断为所有患者。在这里，作者提出了一种功能丧失不耐受性全谱（FUSIL）分类，该分类整合了基因必要性信息，以帮助发现疾病基因。
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.