A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders DOI Creative Commons
Arthur S. Lee, Lauren J Ayers, Michael Kosicki

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 27, 2023

ABSTRACT Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis -regulatory elements subsequently nominate candidate variants in the congenital dysinnervation disorders (CCDDs), set of altering cMN development. We generated epigenomic profiles for ∼86,000 cMNs related types, identifying ∼250,000 accessible regulatory with cognate predictions ∼145,000 putative enhancers. Seventy-five percent (44 59) validated an vivo transgenic reporter assay, demonstrating that accessibility is strong predictor enhancer activity. Applying our atlas 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, achieved significant reduction variant search space nominated predicted regulate known disease genes MAFB, PHOX2A, CHN1, EBF3 – as well new candidates recurrently mutated enhancers through peak- gene-centric allelic aggregation. This work provides novel discoveries relevance CCDDs generalizable nominating potentially high functional impact other disorders.

Язык: Английский

Rapid and quantitative functional interrogation of human enhancer variant activity in live mice DOI Creative Commons
Ethan W. Hollingsworth, Taryn Audrey Liu, Joshua A. Alcantara

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 6, 2025

Abstract Functional analysis of non-coding variants associated with congenital disorders remains challenging due to the lack efficient in vivo models. Here we introduce dual-enSERT, a robust Cas9-based two-color fluorescent reporter system which enables rapid, quantitative comparison enhancer allele activities live mice less than two weeks. We use this technology examine and measure gain- loss-of-function effects previously linked limb polydactyly, autism spectrum disorder, craniofacial malformation. By combining dual-enSERT single-cell transcriptomics, characterise gene expression cells where is normally ectopically active, revealing candidate pathways that may lead misregulation. Finally, demonstrate widespread utility by testing fifteen uncharacterised rare common neurodevelopmental disorders. In doing so identify reproducibly alter activity OTX2 MIR9-2 brain enhancers, implicating them autism. Dual-enSERT thus allows researchers go from identifying comparative embryos under

Язык: Английский

Процитировано

1
Mapping the regulatory effects of common and rare non-coding variants across cellular and developmental contexts in the brain and heart DOI Creative Commons
Andrew R. Marderstein, Soumya Kundu, Evin M. Padhi

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 19, 2025

Abstract Whole genome sequencing has identified over a billion non-coding variants in humans, while GWAS revealed the as significant contributor to disease. However, prioritizing causal common and rare human disease, understanding how selective pressures have shaped genome, remains challenge. Here, we predicted effects of 15 million with deep learning models trained on single-cell ATAC-seq across 132 cellular contexts adult fetal brain heart, producing nearly two context-specific predictions. Using these predictions, distinguish candidate underlying traits diseases their effects. While variant are more cell-type-specific, exert cell-type-shared regulatory effects, particularly targeting affecting neurons. To prioritize de novo mutations extreme developed FLARE, functional genomic model constraint. FLARE outperformed other methods case from autism-affected families near syndromic autism-associated genes; for example, identifying mutation outliers CNTNAP2 that would be missed by alternative approaches. Overall, our findings demonstrate potential integrating maps population genetics learning-based effect prediction elucidate mechanisms development disease–ultimately, supporting notion genetic contributions neurodevelopmental disorders predominantly rare.

Язык: Английский

Процитировано

1
A human-specific enhancer fine-tunes radial glia potency and corticogenesis DOI
Jing Liu, Federica Mosti, Hanzhi Zhao

и другие.

Nature, Год журнала: 2025, Номер unknown

Опубликована: Май 14, 2025

Язык: Английский

Процитировано

1
Identifying non-coding variant effects at scale via machine learning models of cis-regulatory reporter assays DOI Creative Commons
John C. Butts, Stephen Rong, Sager J. Gosai

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 18, 2025

Abstract The inability to interpret the functional impact of non-coding variants has been a major impediment in promise precision medicine. While high-throughput experimental approaches such as Massively Parallel Reporter Assays (MPRAs) have made progress identifying causal and their underlying molecular mechanisms, these tools cannot exhaustively measure variant effects genome-wide. Here we present MPAC, an ensemble machine-learning models trained on MPRA data that provides accurate scalable prediction cis-regulatory variants. Using MPAC predict allelic for 575M single nucleotide (SNVs) across diverse applications, including complex trait genetics, clinical tumor sequencing, evolutionary analyses, saturation mutagenesis. We find predictions match performance empirical MPRAs trait-associated alleles. demonstrate utility by applying it ClinVar, pathogenic variation with higher accuracy than other sequence-to-function models. also nominate 1,892 candidate cancer drivers predicting somatic SNVs COSMIC database. Next, evaluate population-level genetic all 514M gnomAD, quantifying relationship between regulatory function constraint. Finally, generate prospective maps using in-silico mutagenesis 18,658 human promoters, observing widespread selection against predicted disrupt promoter activity. Collectively, this study establishes value comprehensive, publicly available resource interpretation.

Язык: Английский

Процитировано

0
Massively parallel approaches for characterizing noncoding functional variation in human evolution DOI
Stephen Rong,

Elise Root,

Steven K. Reilly

и другие.

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 88, С. 102256 - 102256

Опубликована: Авг. 31, 2024

Язык: Английский

Процитировано

2
How our brains are built: emerging approaches to understand human-specific features DOI
Nicole D. Moss,

Davoneshia Lollis,

Debra L. Silver

и другие.

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 89, С. 102278 - 102278

Опубликована: Ноя. 15, 2024

Язык: Английский

Процитировано

2
Rare disease genomics and precision medicine DOI Creative Commons
Juhyeon Hong,

D. Lee,

A. Hwang

и другие.

Genomics & Informatics, Год журнала: 2024, Номер 22(1)

Опубликована: Дек. 3, 2024

Abstract Rare diseases, though individually uncommon, collectively affect millions worldwide. Genomic technologies and big data analytics have revolutionized diagnosing understanding these conditions. This review explores the role of genomics in rare disease research, impact large consortium initiatives, advancements extensive analysis, integration artificial intelligence (AI) machine learning (ML), therapeutic implications precision medicine. We also discuss challenges sharing privacy concerns, emphasizing need for collaborative efforts secure practices to advance research.

Язык: Английский

Процитировано

2
Evolutionary neurogenomics at single-cell resolution DOI
Emre Caglayan, Geneviève Konopka

Current Opinion in Genetics & Development, Год журнала: 2024, Номер 88, С. 102239 - 102239

Опубликована: Авг. 1, 2024

Язык: Английский

Процитировано

1
A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders DOI Creative Commons
Arthur S. Lee, Lauren J Ayers, Michael Kosicki

и другие.

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 27, 2024

Язык: Английский

Процитировано

1
Rapid and Quantitative Functional Interrogation of Human Enhancer Variant Activity in Live Mice DOI Creative Commons
Ethan W. Hollingsworth,

Taryn A. Liu,

Sandra Jacinto

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 10, 2023

Abstract Functional analysis of non-coding variants associated with human congenital disorders remains challenging due to the lack efficient in vivo models. Here we introduce dual-enSERT, a robust Cas9-based two-color fluorescent reporter system which enables rapid, quantitative comparison enhancer allele activities live mice any genetic background. We use this new technology examine and measure gain- loss-of-function effects linked limb polydactyly, autism, craniofacial malformation. By combining dual-enSERT single-cell transcriptomics, characterize variant alleles at cellular resolution, thereby implicating candidate molecular pathways pathogenic misregulation. further show that independent, polydactyly-linked lead ectopic expression same cell populations, indicating shared mechanisms underlying pathogenesis. Finally, streamline for F0 animals by placing both reporters on transgene separated synthetic insulator. Dual-enSERT allows researchers go from identifying comparative activity embryos under two weeks.

Язык: Английский

Процитировано

3