Framework for microRNA variant annotation and prioritization using human population and disease datasets.
Framework for microRNA variant annotation and prioritization using human population and disease datasets.
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DOI：
10.1002/humu.23668
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发表时间：
2019-01
期刊：
影响因子：
3.9
通讯作者：
Plon SE
中科院分区：
文献类型：
--
作者：
Oak N;Ghosh R;Huang KL;Wheeler DA;Ding L;Plon SE
microRNA（miRNA）的表达在人类疾病中经常失调，相反，疾病相关的miRNA突变研究不足。我们开发了miRNA元件的注释数据库，ADmiRE，它结合了多种现有的和新的生物学注释，以帮助确定因果miRNA变异的优先级。我们注释了来自多个大型测序数据集的10，206个成熟（种子区域内3，257个）miRNA变体，包括gnomAD（15，496个基因组; 123，136个外显子组）。miRNA变异的模式与蛋白质编码外显子区非常相似，基因内和基因间miRNA之间没有差异（p=0.56），高置信度的miRNA表现出更高的序列约束（p<0.001）。对100种脊椎动物的保守性分析鉴定出765种高度保守的miRNA，这些miRNA在gnomAD中也具有有限的遗传变异。我们将ADmiRE应用于来自33种成人癌症的10，000多名个体的TCGA PanCancerAtlas WES数据集，并注释了1，267个种系（在gnomAD中罕见）和1，492个体细胞miRNA变体。在癌症中具有失调基因表达的几个miRNA家族具有低水平的体细胞和种系变体，例如let-7、miR-10。除了血液系统癌症中已知的体细胞miR-142突变外，我们还描述了食管癌中影响下游miRNA靶点的新型体细胞miR-21突变。通过ADmiRE的开发，我们提出了一个在疾病数据集中对miRNA变异进行注释和优先排序的框架。
MicroRNA (miRNA) expression is frequently deregulated in human disease, in contrast, disease-associated miRNA mutations are understudied. We developed Annotative Database of miRNA Elements, ADmiRE that combines multiple existing and new biological annotations to aid prioritization of causal miRNA variation. We annotated 10,206 mature (3,257 within seed region) miRNA variants from multiple large sequencing datasets including gnomAD (15,496 genomes; 123,136 exomes). The pattern of miRNA variation closely resembles protein-coding exonic regions, with no difference between intragenic and intergenic miRNAs (p=0.56), and high confidence miRNAs demonstrate higher sequence constraint (p<0.001). Conservation analysis across 100 vertebrates identified 765 highly conserved miRNAs that also have limited genetic variation in gnomAD. We applied ADmiRE to the TCGA PanCancerAtlas WES datasets from over 10,000 individuals across 33 adult cancers and annotated 1,267 germline (rare in gnomAD) and 1,492 somatic miRNA variants. Several miRNA families with deregulated gene expression in cancer have low levels of both somatic and germline variants, e.g. let-7, miR-10. In addition to known somatic miR-142 mutations in hematologic cancers, we describe novel somatic miR-21 mutations in esophageal cancers impacting downstream miRNA targets. Through the development of ADmiRE, we present a framework for annotation and prioritization of miRNA variation in disease datasets.
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影响因子：
3.7
作者：
Hill CG;Jabbari N;Matyunina LV;McDonald JF
通讯作者：
McDonald JF
DOI：
10.1146/annurev.pathol.4.110807.092222
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lee YS;Dutta A
通讯作者：
Dutta A
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
13.6
作者：
Chan E;Prado DE;Weidhaas JB
通讯作者：
Weidhaas JB
影响因子：
14.9
作者：
Altuvia Y;Landgraf P;Lithwick G;Elefant N;Pfeffer S;Aravin A;Brownstein MJ;Tuschl T;Margalit H
通讯作者：
Margalit H