Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition

生物 表观基因组 遗传学 基因组 基因 计算生物学 表观遗传学 染色质 DNA甲基化 转录组 基因表达
作者
Mitchell R. Vollger,Jonas Korlach,Kiara C. Eldred,Elliott Swanson,Jason G. Underwood,Yong-Han Hank Cheng,Jane Ranchalis,Yizi Mao,Elizabeth Blue,Ulrike Schwarze,Katherine M. Munson,Christopher T. Saunders,Aaron M. Wenger,Aimee Allworth,Sirisak Chanprasert,Brittney L. Duerden,Ian A. Glass,Martha Horike‐Pyne,Michelle Kim,Kathleen A. Leppig,Ian McLaughlin,Jessica Ogawa,Elisabeth A. Rosenthal,Sam Sheppeard,Stephanie M. Sherman,Samuel Strohbehn,Amy Lawson Yuen,Thomas A. Reh,Peter H. Byers,Michael J. Bamshad,Fuki M. Hisama,Gail P. Jarvik,Yasemin Sancak,Katrina M. Dipple,Andrew B. Stergachis
标识
DOI:10.1101/2023.09.26.559521
摘要

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 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.
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