Big DNA as a tool to dissect an age-related macular degeneration-associated haplotype
By
Jon M. Laurent,
Xin Fu,
Sergei German,
Matthew Maurano,
Kang Zhang,
Jef D Boeke
Posted 04 Nov 2018
bioRxiv DOI: 10.1101/461251
(published DOI: 10.1093/pcmedi/pby019)
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 assemblons covering the region, delivery and analysis of which will identify functional sites and their effects, leading to an improved understanding of AMD development. We anticipate that the methodology proposed here is highly generalizable towards the difficult problem of identifying truly functional variation discovered via GWAS or other genetic association studies.
Download data
- Downloaded 422 times
- Download rankings, all-time:
- Site-wide: 56,635
- In genetics: 2,731
- Year to date:
- Site-wide: 116,053
- Since beginning of last month:
- Site-wide: 119,715
Altmetric data
Downloads over time
Distribution of downloads per paper, site-wide
PanLingua
News
- 27 Nov 2020: The website and API now include results pulled from medRxiv as well as bioRxiv.
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!