Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition
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.
Blue Elizabeth E.、Korlach Jonas、Underwood Jason G.、Munson Katherine M.、Saunders Christopher T.、Allworth Aimee、Chanprasert Sirisak、Duerden Brittney L.、Leppig Kathleen A.、McLaughlin Ian J.、Rosenthal Elisabeth A.、Byers Peter H.、Jarvik Gail P.、Dipple Katrina M.、Ogawa Jessica、Strohbehn Samuel、Cheng Yong-Han H.、Bamshad Michael J.、Eldred Kiara C.、Kim Michelle、Horike-Pyne Martha、Stergachis Andrew B.、Sherman Stephanie M.、Swanson Elliott、Sancak Yasemin、Ranchalis Jane、Yuen Amy L.、Hisama Fuki M.、Vollger Mitchell R.、Reh Thomas A.、Wenger Aaron M.、Mao Yizi、Glass Ian、Sheppeard Sam、Schwarze Ulrike
基础医学遗传学分子生物学
Blue Elizabeth E.,Korlach Jonas,Underwood Jason G.,Munson Katherine M.,Saunders Christopher T.,Allworth Aimee,Chanprasert Sirisak,Duerden Brittney L.,Leppig Kathleen A.,McLaughlin Ian J.,Rosenthal Elisabeth A.,Byers Peter H.,Jarvik Gail P.,Dipple Katrina M.,Ogawa Jessica,Strohbehn Samuel,Cheng Yong-Han H.,Bamshad Michael J.,Eldred Kiara C.,Kim Michelle,Horike-Pyne Martha,Stergachis Andrew B.,Sherman Stephanie M.,Swanson Elliott,Sancak Yasemin,Ranchalis Jane,Yuen Amy L.,Hisama Fuki M.,Vollger Mitchell R.,Reh Thomas A.,Wenger Aaron M.,Mao Yizi,Glass Ian,Sheppeard Sam,Schwarze Ulrike.Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/2023.09.26.559521.点此复制
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