DOI: 10.1101/461251Nov 4, 2018Paper

Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype

BioRxiv : the Preprint Server for Biology
Jon LaurentJef D Boeke


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 development. Recently, 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. The 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 variation. To 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 variation. In order to efficiently decipher which sites are functional in AMD phenotypes, we describe a general framework for combinatorial assembly and delivery of large "synthetic haplotypes" to relevant disease cell types for downstream functional analysis. We demonstrate the successful and highly efficient assembly of a 119kb wild-type "assemblon" covering the HTRA1/ARMS2 risk region. We further propose the parallelized assembly of a library of combinatorial variant a...Continue Reading

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