biostudies-literatureKircher MBerlin Institute of Health (BIH), Berlin, GermanyHoward Hughes Medical InstituteU.S. Department of Health & Human Services | NIH | National Cancer InstituteNIMH NIH HHSNHGRI NIH HHSNCI NIH HHSU.S. Department of Health & Human Services | NIH | National Human Genome Research InstituteU.S. Department of Health & Human Services | NIH | National Institute of Mental HealthNIGMS NIH HHS3583https://www.ebi.ac.uk/biostudies/studies/S-EPMC6687891biostudies-literatureUnknown10(1)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.Nature communicationsSaturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution.PMC6687891R01 CA1971391U01MH1164381R01HG006768UM1 HG009408R01 MH109907R01 HG0067681R01CA197139U01 MH116438T32 GM0085681R01HG009136R01 HG0091361UM1HG009408Kircher MSchubach MShendure JXiong CCostello JFAhituv NBell RJAMartin BInoue FfalseSaturation mutagenesis of twenty disease-associated regulatory elements at single base-pair resolution.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.2019-01-01T00:00:00Z2019 Aug2024-11-20T06:47:33.717Z2019-08-16T07:02:22ZS-EPMC66878913139586510.1038/s41467-019-11526-w