کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2035041 1072125 2016 16 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Systematic Functional Dissection of Common Genetic Variation Affecting Red Blood Cell Traits
ترجمه فارسی عنوان
توزیع سیستماتیک عملکرد تغییرات ژنتیکی مشترک که بر ویژگی های سلول های قرمز خون تاثیر می گذارد
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی بیوشیمی، ژنتیک و زیست شناسی مولکولی (عمومی)
چکیده انگلیسی


• A massively parallel reporter assay was developed to screen for functional variation
• Variants identified by this assay are enriched for orthogonal measures of function
• Functional GWAS variants alter activity of master transcription factors
• The target gene RBM38 was linked to its GWAS phenotype and regulates mRNA splicing

SummaryGenome-wide association studies (GWAS) have successfully identified thousands of associations between common genetic variants and human disease phenotypes, but the majority of these variants are non-coding, often requiring genetic fine-mapping, epigenomic profiling, and individual reporter assays to delineate potential causal variants. We employ a massively parallel reporter assay (MPRA) to simultaneously screen 2,756 variants in strong linkage disequilibrium with 75 sentinel variants associated with red blood cell traits. We show that this assay identifies elements with endogenous erythroid regulatory activity. Across 23 sentinel variants, we conservatively identified 32 MPRA functional variants (MFVs). We used targeted genome editing to demonstrate endogenous enhancer activity across 3 MFVs that predominantly affect the transcription of SMIM1, RBM38, and CD164. Functional follow-up of RBM38 delineates a key role for this gene in the alternative splicing program occurring during terminal erythropoiesis. Finally, we provide evidence for how common GWAS-nominated variants can disrupt cell-type-specific transcriptional regulatory pathways.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: - Volume 165, Issue 6, 2 June 2016, Pages 1530–1545
نویسندگان
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