Saturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution
Year: 2019
Type: article
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 perform 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 substitutions and deletions. 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 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 comprise a rich dataset for the further development of algorithms that aim to predict the regulatory effects of noncoding mutations.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G1431274088, Massively parallel, in vivo functional testing of regulatory elements, G2902703691, Integrative interpretation of the organismal consequences of non-coding variation, Predictive Modeling of Alternative Splicing and Polyadenylation from Millions of Random Sequences, G602949188, Massively parallel reporter assays and genome editing of ENCODE predicted regulatory elements, G703633553, Massively parallel dissection of psychiatric regulatory networks, Predoctoral Training in Biomedical Sciences, Massively parallel characterization of psychiatric disease associated regulatory elements in defined cell types, G963685695
OpenAlex ID: W2967059818