Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition
Abstract 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 diploidde novogenome 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, andRB1) 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..
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 30. Sept. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2023.09.26.559521 |
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| PPN (Katalog-ID): |
XBI040983641 |
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| 100 | 1 | |a Vollger, Mitchell R. |e verfasserin |0 (orcid)0000-0002-8651-1615 |4 aut | |
| 245 | 1 | 0 | |a Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition |
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| 520 | |a Abstract 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 diploidde novogenome 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, andRB1) 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. | ||
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| 700 | 1 | |a Underwood, Jason G. |4 aut | |
| 700 | 1 | |a Cheng, Yong-Han H. |0 (orcid)0000-0001-7686-0697 |4 aut | |
| 700 | 1 | |a Ranchalis, Jane |4 aut | |
| 700 | 1 | |a Mao, Yizi |0 (orcid)0000-0001-5743-6831 |4 aut | |
| 700 | 1 | |a Blue, Elizabeth E. |0 (orcid)0000-0002-0633-0305 |4 aut | |
| 700 | 1 | |a Schwarze, Ulrike |4 aut | |
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