{"doi":"10.1101/2025.02.18.638922","title":"Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart","abstract":"Abstract Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS has revealed the non-coding genome as a significant contributor to disease. However, prioritizing causal common and rare non-coding variants in human disease, and understanding how selective pressures have shaped the non-coding genome, remains a significant challenge. Here, we predicted the effects of 15 million variants with deep learning models trained on single-cell ATAC-seq across 132 cellular contexts in adult and fetal brain and heart, producing nearly two billion context-specific predictions. Using these predictions, we distinguish candidate causal variants underlying human traits and diseases and their context-specific effects. While common variant effects are more cell-type-specific, rare variants exert more cell-type-shared regulatory effects, with selective pressures particularly targeting variants affecting fetal brain neurons. To prioritize de novo mutations with extreme regulatory effects, we developed FLARE, a context-specific functional genomic model of constraint. FLARE outperformed other methods in prioritizing case mutations from autism-affected families near syndromic autism-associated genes; for example, identifying mutation outliers near CNTNAP2 that would be missed by alternative approaches. Overall, our findings demonstrate the potential of integrating single-cell maps with population genetics and deep learning-based variant effect prediction to elucidate mechanisms of development and disease–ultimately, supporting the notion that genetic contributions to neurodevelopmental disorders are predominantly rare.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":554864,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9373,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1161505,"name":"Soumya Kundu","orcid":"0000-0001-5182-5326","position":1,"is_corresponding":false},{"id":571222,"name":"Evin M. Padhi","orcid":"0000-0003-2578-2435","position":2,"is_corresponding":false},{"id":1173422,"name":"Salil Deshpande","orcid":"0009-0009-5776-8428","position":3,"is_corresponding":false},{"id":478696,"name":"Austin Wang","orcid":"0000-0001-6785-7912","position":4,"is_corresponding":false},{"id":1324906,"name":"E. Robb","orcid":"0009-0009-4103-7639","position":5,"is_corresponding":false},{"id":227588,"name":"Ying Sun","orcid":"0000-0002-2042-6514","position":6,"is_corresponding":false},{"id":1452734,"name":"Chang‐Ho Yun","orcid":"0000-0003-2204-8067","position":7,"is_corresponding":false},{"id":1453151,"name":"Diego Pomales-Matos","orcid":null,"position":8,"is_corresponding":false},{"id":493636,"name":"Yilin Xie","orcid":"0000-0003-1452-0800","position":9,"is_corresponding":false},{"id":29407,"name":"Daniel Nachun","orcid":"0000-0002-0271-1135","position":10,"is_corresponding":false},{"id":246704,"name":"Selin Jessa","orcid":"0000-0003-4192-6523","position":11,"is_corresponding":false},{"id":360,"name":"Anshul Kundaje","orcid":"0000-0003-3084-2287","position":12,"is_corresponding":false},{"id":52,"name":"Stephen B. Montgomery","orcid":"0000-0002-5200-3903","position":13,"is_corresponding":false},{"id":471635,"name":"Andrew R. Marderstein","orcid":"0000-0003-0859-4969","position":0,"is_corresponding":true}],"reference_count":129,"raw_metadata":null,"created_at":"2026-07-19T02:54:54.542303Z","pmid":"40027628","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}