Year: 2018
Type: preprint
Abstract: The majority of common variants associated with common diseases, as well as an unknown proportion of causal mutations for rare diseases, fall in noncoding regions of the genome. Although catalogs of noncoding regulatory elements are steadily improving, we have a limited understanding of the functional effects of mutations within them. Here, we performed saturation mutagenesis in conjunction with massively parallel reporter assays on 20 disease-associated gene promoters and enhancers, generating functional measurements for over 30,000 single nucleotide substitution and deletion mutations. We find that the density of putative transcription factor binding sites varies widely between regulatory elements, as does the extent to which evolutionary conservation or various integrative scores predict functional effects. These data provide a powerful resource for interpreting the pathogenicity of clinically observed mutations in these disease-associated regulatory elements, and also comprise a gold-standard dataset for the further development of algorithms that aim to predict the regulatory effects of noncoding mutations.
DOI: 10.1101/505362
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Massively parallel, in vivo functional testing of regulatory elements, Integrative interpretation of the organismal consequences of non-coding variation, Predictive Modeling of Alternative Splicing and Polyadenylation from Millions of Random Sequences, Massively parallel reporter assays and genome editing of ENCODE predicted regulatory elements, Massively parallel dissection of psychiatric regulatory networks, Massively parallel characterization of psychiatric disease associated regulatory elements in defined cell types
OpenAlex ID: W2905877589