Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition
Resolving the molecular basis of a Mendelian condition (MC) remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome, and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion, and structural variant calling and diploid de novo genome assembly, and permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility, and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network (UDN) participant with a chromosome X;13 balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA, PDK3, MAB21L1, and RB1) previously associated with single-gene MCs. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four 'omes' to resolve. These included nonsense-mediated decay, fusion transcript formation, enhancer adoption, transcriptional readthrough silencing, and inappropriate X chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 27. Sept. |
| Sprache: |
Englisch |
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| Links: |
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| Anmerkungen: |
Date Revised 10.02.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.09.26.559521 |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Vollger, Mitchell R |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition |
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| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Resolving the molecular basis of a Mendelian condition (MC) remains challenging owing to the diverse mechanisms by which genetic variants cause disease. To address this, we developed a synchronized long-read genome, methylome, epigenome, and transcriptome sequencing approach, which enables accurate single-nucleotide, insertion-deletion, and structural variant calling and diploid de novo genome assembly, and permits the simultaneous elucidation of haplotype-resolved CpG methylation, chromatin accessibility, and full-length transcript information in a single long-read sequencing run. Application of this approach to an Undiagnosed Diseases Network (UDN) participant with a chromosome X;13 balanced translocation of uncertain significance revealed that this translocation disrupted the functioning of four separate genes (NBEA, PDK3, MAB21L1, and RB1) previously associated with single-gene MCs. Notably, the function of each gene was disrupted via a distinct mechanism that required integration of the four 'omes' to resolve. These included nonsense-mediated decay, fusion transcript formation, enhancer adoption, transcriptional readthrough silencing, and inappropriate X chromosome inactivation of autosomal genes. Overall, this highlights the utility of synchronized long-read multi-omic profiling for mechanistically resolving complex phenotypes | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Korlach, Jonas |e verfasserin |4 aut | |
| 700 | 1 | |a Eldred, Kiara C |e verfasserin |4 aut | |
| 700 | 1 | |a Swanson, Elliott |e verfasserin |4 aut | |
| 700 | 1 | |a Underwood, Jason G |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Yong-Han H |e verfasserin |4 aut | |
| 700 | 1 | |a Ranchalis, Jane |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Yizi |e verfasserin |4 aut | |
| 700 | 1 | |a Blue, Elizabeth E |e verfasserin |4 aut | |
| 700 | 1 | |a Schwarze, Ulrike |e verfasserin |4 aut | |
| 700 | 1 | |a Munson, Katherine M |e verfasserin |4 aut | |
| 700 | 1 | |a Saunders, Christopher T |e verfasserin |4 aut | |
| 700 | 1 | |a Wenger, Aaron M |e verfasserin |4 aut | |
| 700 | 1 | |a Allworth, Aimee |e verfasserin |4 aut | |
| 700 | 1 | |a Chanprasert, Sirisak |e verfasserin |4 aut | |
| 700 | 1 | |a Duerden, Brittney L |e verfasserin |4 aut | |
| 700 | 1 | |a Glass, Ian |e verfasserin |4 aut | |
| 700 | 1 | |a Horike-Pyne, Martha |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Leppig, Kathleen A |e verfasserin |4 aut | |
| 700 | 1 | |a McLaughlin, Ian J |e verfasserin |4 aut | |
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