Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype
作者机构：Institute for Systems Genetics Department of Biochemistry and Molecular Pathology Department of PathologyNYU Langone Health Shiley Eye InstituteUCSD School of Medicine
出 版 物：《Precision Clinical Medicine》 (精准临床医学（英文）)
年 卷 期：2019年第2卷第1期
页 面：1-7页
学科分类：08[工学] 0812[工学-计算机科学与技术（可授工学、理学学位）]
基 金：supported in part by National Institutes of Health grants 1RM1HG009491 HG008135 EY025090 and CA217642
主 题：CRISPR gene editing synthetic biology age related macular degeneration HTRA1
摘 要：Age-related Macular Degeneration(AMD)is a leading cause of blindness in the developed world,especially in aging populations,and is therefore an important target for new therapeutic ***,there have been several studies demonstrating strong associations between AMD and sites of heritable genetic variation at multiple loci,including a highly significant association at *** 10q26 risk region contains two genes,HTRA1 and ARMS2,both of which have been separately implicated as causative for the disease,as well as dozens of sites of non-coding *** date,no studies have successfully pinpointed which of these variant sites are functional in AMD,nor definitively identified which genes in the region are targets of such regulatory *** order to efficiently decipher which sites are functional in AMD phenotypes,we describe a general framework for combinatorial assembly of large‘synthetic haplotypes’along with delivery to relevant disease cell types for downstream functional *** demonstrate the successful and highly efficient assembly of a first-draft 119kb wild-type‘assemblon’covering the HTRA1/ARMS2 risk *** further propose the parallelized assembly of a library of combinatorial variant synthetic haplotypes covering the region,delivery and analysis of which will identify functional sites and their effects,leading to an improved understanding of AMD *** anticipate that the methodology proposed here is highly generalizable towards the difficult problem of identifying truly functional variants from those discovered via GWAS or other genetic association studies.
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