Assessing the efficacy of target adaptive sampling long-read sequencing through hereditary cancer patient genomes

Author:

Nakamura Wataru,Hirata Makoto,Oda Satoyo,Chiba Kenichi,Okada Ai,Mateos Raúl Nicolás,Sugawa Masahiro,Iida Naoko,Ushiama Mineko,Tanabe NorikoORCID,Sakamoto Hiromi,Sekine Shigeki,Hirasawa Akira,Kawai YosukeORCID,Tokunaga KatsushiORCID, ,Ishibashi-Ueda Hatsue,Tomita Tsutomu,Noguchi Michio,Takahashi Ayako,Goto Yu-ichi,Yoshida Sumiko,Hattori Kotaro,Matsumura Ryo,Iida Aritoshi,Maruoka Yutaka,Gatanaga Hiroyuki,Sugiyama Masaya,Suzuki Satoshi,Miyo Kengo,Matsubara Yoichi,Umezawa Akihiro,Hata Kenichiro,Kaname Tadashi,Ozaki Kouichi,Tokuda Haruhiko,Watanabe Hiroshi,Niida Shumpei,Noiri Eisei,Kitajima Koji,Omae Yosuke,Miyahara Reiko,Shimanuki Hideyuki,Tsujimoto Shin-ichiORCID,Shiba Norio,Ito ShuichiORCID,Yoshida Teruhiko,Shiraishi Yuichi

Abstract

AbstractInnovations in sequencing technology have led to the discovery of novel mutations that cause inherited diseases. However, many patients with suspected genetic diseases remain undiagnosed. Long-read sequencing technologies are expected to significantly improve the diagnostic rate by overcoming the limitations of short-read sequencing. In addition, Oxford Nanopore Technologies (ONT) offers adaptive sampling and computationally driven target enrichment technology. This enables more affordable intensive analysis of target gene regions compared to standard non-selective long-read sequencing. In this study, we developed an efficient computational workflow for target adaptive sampling long-read sequencing (TAS-LRS) and evaluated it through application to 33 genomes collected from suspected hereditary cancer patients. Our workflow can identify single nucleotide variants with nearly the same accuracy as the short-read platform and elucidate complex forms of structural variations. We also newly identified several SINE-R/VNTR/Alu (SVA) elements affecting the APC gene in two patients with familial adenomatous polyposis, as well as their sites of origin. In addition, we demonstrated that off-target reads from adaptive sampling, which is typically discarded, can be effectively used to accurately genotype common single-nucleotide polymorphisms (SNPs) across the entire genome, enabling the calculation of a polygenic risk score. Furthermore, we identified allele-specific MLH1 promoter hypermethylation in a Lynch syndrome patient. In summary, our workflow with TAS-LRS can simultaneously capture monogenic risk variants including complex structural variations, polygenic background as well as epigenetic alterations, and will be an efficient platform for genetic disease research and diagnosis.

Funder

Japan Agency for Medical Research and Development

Publisher

Springer Science and Business Media LLC

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