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Comprehensive In Vivo Interrogation Reveals Phenotypic Impact of Human Enhancer Variants.
Cell ( IF 64.5 ) Pub Date : 2020-03-12 , DOI: 10.1016/j.cell.2020.02.031
Evgeny Z Kvon 1 , Yiwen Zhu 1 , Guy Kelman 1 , Catherine S Novak 1 , Ingrid Plajzer-Frick 1 , Momoe Kato 1 , Tyler H Garvin 1 , Quan Pham 1 , Anne N Harrington 1 , Riana D Hunter 1 , Janeth Godoy 1 , Eman M Meky 1 , Jennifer A Akiyama 1 , Veena Afzal 1 , Stella Tran 1 , Fabienne Escande 2 , Brigitte Gilbert-Dussardier 3 , Nolwenn Jean-Marçais 4 , Sanjarbek Hudaiberdiev 5 , Ivan Ovcharenko 5 , Matthew B Dobbs 6 , Christina A Gurnett 7 , Sylvie Manouvrier-Hanu 2 , Florence Petit 2 , Axel Visel 8 , Diane E Dickel 1 , Len A Pennacchio 9
Affiliation  

Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal lead to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knockin mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants.

中文翻译:

全面的体内审讯揭示了人类增强子变体的表型影响。

在非编码变体和人类表型之间建立因果关系是一个日益严峻的挑战。在这里,我们介绍了一种高通量的小鼠报告基因检测方法,用于评估体内人类增强子变异体的致病潜力,并检查与多指重复连接的增强子中的近千种变异体。我们显示71%的所有罕见非编码变体先前被提议作为因果关系导致报告基因表达的模式与其致病作用一致。进一步证实了观察到的改变增强子活性的变体在敲入小鼠中引起多指。我们还使用了组合诱变和单核苷酸诱变来评估影响增强子所有位置的突变对体内的影响,并确定了其他功能取代,包括迄今为止尚未在人类中观察到的潜在致病变体。我们的结果揭示了与表型相关的增强子中数百个突变的功能后果,并建立了可广泛应用的策略,用于对人类增强子变体进行系统的体内评估。
更新日期:2020-03-12
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