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Genome-wide discovery of lupus genetic risk variant allelic regulatory activity
bioRxiv - Genomics Pub Date : 2021-01-21 , DOI: 10.1101/2020.01.20.906701
Xiaoming Lu , Xiaoting Chen , Carmy Forney , Omer Donmez , Daniel Miller , Sreeja Parameswaran , Ted Hong , Yongbo Huang , Mario Pujato , Tareian Cazares , Emily R. Miraldi , John P. Ray , Carl G. de Boer , John B. Harley , Matthew T. Weirauch , Leah C. Kottyan

Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3,073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we constructed a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into EBV-infected B cells revealed 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around these 51 variants identified one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second, larger class of TFs that also bind allelically but do not have their motifs directly altered by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.

中文翻译:

狼疮遗传风险变异等位基因调控活性的全基因组发现

系统性红斑狼疮(SLE)的全基因组关联研究在91个风险基因座上提名了3,073个遗传变异。为了系统地筛选这些变体的等位基因转录增强子活性,我们构建了一个大规模平行报告基因分析(MPRA)文库,该库包含12,396个DNA寡核苷酸,其中包含每个SLE变体的每个等位基因周围的基因组背景。转染到EBV感染的B细胞中后,发现有482个具有增强子活性的变体,其中有51个变体在27个风险基因座上显示了基因型依赖性(等位基因)增强子活性。对这51个变体及其周围的等位基因转录因子(TF)结合的深入分析,确定了一类TF,其DNA结合基序往往会被风险变体直接改变,而第二个,较大类型的TF,它们也具有等位基因结合作用,但其基序没有被变体直接改变。总之,我们的方法为发现任何疾病风险基因座的等位基因调控提供了一个蓝图,并为SLE的转录调控机制提供了见识。
更新日期:2021-01-22
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