New method to evaluate radiation effect by detecting structural variation

• Project/Area Number: 19K22913
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 63:Environmental analyses and evaluation and related fields
• Research Institution: Nagasaki University
• Principal Investigator: Yoshiura Koh-ichiro 長崎大学, 原爆後障害医療研究所, 教授 (00304931)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2020: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: DNA変異 / 一塩基変異 / 欠失 / 放射線 / 残存変異 / 不死化ヒト正常細胞 / 変異導入率 / ショートリードNGS / 不死化ヒト正常線維芽細胞 / DNA二本鎖切断 / ロングリードNGS / 定量的測定 / ショートリード次世代シークエンサー / ロングリード次世代シークエンサー / ゲノム / ロングリードシーケンサー / 構造異常

Outline of Research at the Start

欠失を主とした構造異常を数えることで放射線影響を測定しようとする研究である。放射線被ばくにより 50 ヶ所/グレイ照射（これまでの常識的推定値）の二本鎖切断が生じるのに対し，放射線誘発性の二本鎖切断はいくつ残るのか不明である。本研究では，この 50ヶ所/グレイ照射の修復エラー（＞比較的大きな欠失として細胞に刻印されると推察している）を検出したい，というのが基本構想である。培養による人工的構造異常導入が排除できるかが研究上の制約となる。
本研究により，構造異常を放射線被ばく指標と出来るか，実際に構造異常がどれくらいの率で惹起されるか・残るかを正確に把握しようとする研究である。

Outline of Final Research Achievements

The purpose of this study is to calculate how much DNA damage (DNA mutation) remains when cultured cells are irradiated with 1 Gray of radiation. It is believed that 1 gray irradiation causes double-strand breaks in 40 ~ 50 DNA in one cell whole genome, but those double-strand breaks are repaired by the cell's repair mechanism and the actual number of mutations retained in one cell is unknown.
In the single nucleotide variation number search, 2 cells in the 3 gray irradiated group and 3 cells in the non-irradiated group were compared, but there was no difference. Although the number of analyzed targets is small, it is unlikely that at least 10 or more single nucleotide variation will remain in one cell. The number of deletions, which is the most interested kind of mutation, is in the process of being analyzed.

Academic Significance and Societal Importance of the Research Achievements

本研究により放射線１グレイ当たりの細胞に残存する変異数が算出できれば，放射線照射を受けた際の，当該部位での腫瘍形成および次世代への影響（遺伝的影響）の確率が計算できるはずである。腫瘍形成においては幹細胞の数，遺伝的影響においては性腺での修復能など，さらなる考慮すべき点は残るものの確率計算のための基本値が取得できたことになる。
これまで，基本量と考えられる「放射線１グレイ当たりの細胞に残存する変異数」が不明なことが問題であり，本研究によって放射線の影響を定量的に議論できる基盤情報を提供することに意義がある。

Research Products

• [Journal Article] Brothers with novel compound heterozygous mutations in COL27A1 causing dental and genital abnormalities (2021)
  • Author(s): Satoh Chisei、Kondoh Tatsuro、Shimizu Hitomi、Kinoshita Akira、Mishima Hiroyuki、Nishimura Gen、Miyazaki Mutsuko、Okano Kunihiko、Kumai Yoshihiko、Yoshiura Koh-ichiro
  • Journal Title: European Journal of Medical Genetics Volume: 64 Issue: 2 Pages: 104125-104125
  • DOI: 10.1016/j.ejmg.2020.104125
  • Peer Reviewed
• [Journal Article] A unique missense variant in the E1A-binding protein P400 gene is implicated in schizophrenia by whole-exome sequencing and mutant mouse models (2021)
  • Author(s): Yoshiro Morimoto, Shinji Ono, Shintaro Yoshida, Hiroyuki Mishima, Akira Kinoshita, Takeshi Tanaka, Yoshihiro Komohara, Naohiro Kurotaki, Tatsuya Kishino, Yuji Okazaki, Hiroki Ozawa, Koh-ichiro Yoshiura, Akira Imamura
  • Journal Title: Translational Psychiatry Volume: 11 Issue: 1 Pages: 132-132
  • DOI: 10.1038/s41398-021-01258-1
  • NAID: 120007000270
  • Peer Reviewed / Open Access
• [Journal Article] Expression of unfolded protein response markers in the pheochromocytoma with Waardenburg syndrome: a case report (2020)
  • Author(s): Morita Shuhei、Takeshima Ken、Ariyasu Hiroyuki、Furukawa Yasushi、Kishimoto Shohei、Tsuji Tomoya、Uraki Shinsuke、Mishima Hiroyuki、Kinoshita Akira、Takahashi Yuichi、Inaba Hidefumi、Iwakura Hiroshi、Furuta Hiroto、Nishi Masahiro、Doi Asako、Murata Shin-ichi、Yoshiura Koh-ichiro、Akamizu Takashi
  • Journal Title: BMC Endocrine Disorders Volume: 20 Issue: 1 Pages: 90-90
  • DOI: 10.1186/s12902-020-00574-9
  • Peer Reviewed / Open Access
• [Journal Article] Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib. (2020)
  • Author(s): Yamashita Y, Morita S, Hosoi H, Kobata H, Kishimoto S, Ishibashi T, Mishima H, Kinoshita A, Backes BJ, Yoshiura KI, Papa FR, Sonoki T, Tamura S
  • Journal Title: Int J Mol Sci. Volume: Aug 31;21(17) Issue: 17 Pages: 6314-6314
  • DOI: 10.3390/ijms21176314
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EEC-LM-ADULT syndrome caused by R319H mutation in TP63 with ectrodactyly, syndactyly, and teeth anomaly (2020)
  • Author(s): Otsuki Yuki、Ueda Koichi、Nuri Takashi、Satoh Chisei、Maekawa Ryuta、Yoshiura Koh-ichiro
  • Journal Title: Medicine Volume: 99 Issue: 44 Pages: e22816-e22816
  • DOI: 10.1097/md.0000000000022816
  • Peer Reviewed / Open Access
• [Journal Article] Possible mitochondrial dysfunction in a patient with deafness, dystonia, and cerebral hypomyelination (DDCH) due to BCAP31 Mutation. (2020)
  • Author(s): Shimizu K, Oba D, Nambu R, Tanaka M, Oguma E, Murayama K, Ohtake A, Yoshiura KI, Ohashi H.
  • Journal Title: Molecular Genetics and Genomic Medicine Volume: 17 Issue: 3
  • DOI: 10.1002/mgg3.1129
  • Peer Reviewed / Open Access
• [Journal Article] A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency (2019)
  • Author(s): Sumito Dateki, Satoshi Watanabe, Hiroyuki Mishima, Toshihiko Shirakawa, Minoru Morikawa, Eiichi Kinoshita, Koh-ichiro Yoshiura, and Hiroyuki Moriuchi
  • Journal Title: J Hum Genet Volume: 64 Issue: 4 Pages: 341-346
  • DOI: 10.1038/s10038-019-0566-8
  • NAID: 120006987778
  • Peer Reviewed
• [Journal Article] Identification of a homozygous frameshift variant in RFLNA in a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome (2019)
  • Author(s): Shimizu H, Watanabe S, Kinoshita A, Mishima H, Nishimura G, Moriuchi H, Yoshiura K, Dateki S
  • Journal Title: J Hum Genet Volume: 64 Issue: 5 Pages: 467-471
  • DOI: 10.1038/s10038-019-0581-9
  • NAID: 120006987791
  • Peer Reviewed
• [Journal Article] Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities (2019)
  • Author(s): Morimoto Y, Yoshida S, Kinoshita A, Satoh C, Mishima H, Yamaguchi N, Matsuda K, Sakaguchi M, Tanaka T, Komohara Y, Imamura A, Ozawa H, Nakashima M, Kurotaki N, Kishino T, Yoshiura K, Ono S
  • Journal Title: Neurology Volume: 92 Issue: 20
  • DOI: 10.1212/wnl.0000000000007505
  • NAID: 120006987711
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel CCDC22 mutation in a patient with severe Epstein?Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia (2019)
  • Author(s): Yamashita Y, Nishikawa A, Iwahashi Y, Fujimoto M, Sasaki I, Mishima H, Kinoshita A, Hemmi H, Kanazawa N, Ohshima K, Imadome KI, Murata SI、Yoshiura KI, Kaisho T, Sonoki T, Tamura S
  • Journal Title: International Journal of Hematology Volume: 印刷中 Issue: 6 Pages: 744-750
  • DOI: 10.1007/s12185-019-02595-0
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Face2Gene using facial images of patients with congenital dysmorphic syndromes recruited in Japan (2019)
  • Author(s): Mishima Hiroyuki、Suzuki Hisato、Doi Michiko、Miyazaki Mutsuko、Watanabe Satoshi、Matsumoto Tadashi、Morifuji Kanako、Moriuchi Hiroyuki、Yoshiura Koh-ichiro、Kondoh Tatsuro、Kosaki Kenjiro
  • Journal Title: Journal of Human Genetics Volume: 64 Issue: 8 Pages: 789-794
  • DOI: 10.1038/s10038-019-0619-z
  • Peer Reviewed / Open Access
• [Journal Article] Cystic biliary atresia with paucity of bile ducts and gene mutation in KDM6A: a case report. (2019)
  • Author(s): Masui D, Fukahori S, Mizuochi T, Watanabe Y, Fukui K, Ishii S, Saikusa N, Hashizume N, Higashidate N, Sakamoto S, Takato A, Yoshiura KI, Tanaka Y, Yagi M.
  • Journal Title: Surgical Case Reports Volume: 5(1) Issue: 1 Pages: 132-132
  • DOI: 10.1186/s40792-019-0688-4
  • Peer Reviewed / Open Access
• [Journal Article] TERT mRNA Expression as a Novel Prognostic Marker in Papillary Thyroid Carcinomas (2019)
  • Author(s): Tanaka Aya、Matsuse Michiko、Saenko Vladimir、Nakao Tomoe、Yamanouchi Kosho、Sakimura Chika、Yano Hiroshi、Nishihara Eijun、Hirokawa Mitsuyoshi、Suzuki Keiji、Miyauchi Akira、Eguchi Susumu、Yoshiura Ko-ichiro、Yamashita Shunichi、Nagayasu Takeshi、Mitsutake Norisato
  • Journal Title: Thyroid Volume: 29 Issue: 8 Pages: 1105-1114
  • DOI: 10.1089/thy.2018.0695
  • NAID: 120006988431
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Atypical phenotype without fever in a Japanese family with an autosomal dominant transmission of familial Mediterranean fever due to heterozygous MEFV Thr577Asn mutations. (2019)
  • Author(s): Endo Y, Koga T, Nakashima M, Mishima H, Yoshiura KI, Kawakami A.
  • Journal Title: Clinical and Experimental Rheumatology Volume: 37 Suppl 121(6) Pages: 161-162
  • Peer Reviewed
• [Journal Article] Target Capture/Next-Generation Sequencing for Nonsyndromic Cleft Lip and Palate in the Japanese Population (2019)
  • Author(s): Shibano Masayasu、Watanabe Akira、Takano Nobuo、Mishima Hiroyuki、Kinoshita Akira、Yoshiura Koh-ichiro、Shibahara Takahiko
  • Journal Title: The Cleft Palate-Craniofacial Journal Volume: 57 Issue: 1 Pages: 80-87
  • DOI: 10.1177/1055665619857650
  • Peer Reviewed
• [Journal Article] KAT6B-related disorder in a patient with a novel frameshift variant (c.3925dup) (2019)
  • Author(s): Hamaguchi Yo、Aoki Mikihiro、Watanabe Satoshi、Mishima Hiroyuki、Yoshiura Koh-ichiro、Moriuchi Hiroyuki、Dateki Sumito
  • Journal Title: Human Genome Variation Volume: 6 Issue: 1 Pages: 54-54
  • DOI: 10.1038/s41439-019-0085-3
  • NAID: 120006988337
  • Peer Reviewed / Open Access
• [Journal Article] Genome analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki (2019)
  • Author(s): Taguchi M, Mishima H, Shiozawa Y, Hayashida C, Kinoshita A, Nannya Y, Makishima H, Horai M, Matsuo M, Sato S, Itonaga H, Kato T, Taniguchi H, Imanishi D, Imaizumi Y, Hata T, Takenaka M, Moriuchi Y, Shiraishi Y, Miyano S, Ogawa S, Yoshiura K-i, Miyazaki Y
  • Journal Title: Haematologica Volume: 105 Issue: 2 Pages: 358-365
  • DOI: 10.3324/haematol.2019.219386
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of a variant associated with early-onset diabetes in the intron of the insulin gene with exome sequencing (2018)
  • Author(s): Matsuno, S., Furuta, H., Kosaka, K., Doi, A., Yorifuji, T., Fukuda, T., Senmaru, T., Uraki, S., Matsutani, N., Furuta, M., Mishima, H., Iwakura, H., Nishi, M., Yoshiura, K., Fukui, M. and Akamizu, T.
  • Journal Title: J Diabetes Investig Volume: Epub ahead of print Issue: 4 Pages: 947-950
  • DOI: 10.1111/jdi.12974
  • Peer Reviewed / Open Access
• [Presentation] 新しいゲノム解析技術 ~メチル化解析~ (2020)
  • Author(s): 吉浦孝一郎
  • Organizer: 第44回日本遺伝カウンセリング学会学術集会
  • Invited
• [Presentation] A case of COL4A1-related disorder diagnosed by exome sequencing at adult period. (2020)
  • Author(s): 中尾理沙，里 龍晴，林田 拓也，西口奈菜子，渡辺 聡，吉浦孝一郎，森内浩幸
  • Organizer: 第62回 日本小児神経学会学術集会
• [Presentation] PatakaraPlus: The project for individuals with Down Syndrome to develop oral and physical training and evaluation. (2020)
  • Author(s): Hiroyuki Mishima, Tetsuro Kitahara, Koh-Ichiro Yoshiura, Tomoko Komatsu, Masaichi Lee, Tatsuro Kondoh
  • Organizer: 日本人類遺伝学会第65回大会
  • Invited
• [Presentation] 重度の成長障害，精神運動発達遅滞を認めたOgden症候群の女児例． (2020)
  • Author(s): 川野奈々江，福島直喜，吉浦孝一郎，井原健二．
  • Organizer: 第42回小児遺伝学会学術集会 （コロナウイルス禍により開催中止）
• [Presentation] A case of CREBBP exon 31 de novo missense mutation presented with insomnia and intellectual disability without Rubinstein-Taybi syndrome phonotype. (2020)
  • Author(s): Yoriko Watanabe, Kaori Fukui K, Koichiro Yoshiura, Yushiro Yamashita.
  • Organizer: 2020 American College of Medical Genetics and Genomics (ACMG) Annual Clinical Genetics Meeting （コロナウイルス禍により開催中止）
  • Int'l Joint Research
• [Presentation] ヒト正常圧水頭症の原因遺伝子 (2019)
  • Author(s): 吉浦 孝一郎，森本芳郎，吉田真太朗，菰原義弘，松田勝也，中島正洋，三嶋博之，木下晃，小野慎治．
  • Organizer: 第4回 放射線災害・医科学研究拠点カンファランス
• [Presentation] Genome Sequence for diagnosis and successive research of genetic disorders． (2019)
  • Author(s): 吉浦孝一郎
  • Organizer: The 13th World Congress of The International Cleft Lip and Palate Foundation，第59回 日本先天異常学会学術集会
  • Int'l Joint Research / Invited
• [Presentation] 当院のIRUD の実績と遺伝カウンセリングの実際． (2019)
  • Author(s): 高尾真未，宮田海香子，松本 正，三嶋博之，三浦清徳，吉浦孝一郎．
  • Organizer: 第26回 出生前から小児期にわたるゲノム医療フォーラム
  • Invited
• [Presentation] IRUDによって原因遺伝子が確定した家族の出生前検査に対する思い． (2019)
  • Author(s): 宮田海香子，松本 正，高尾真未，三嶋博之，三浦清徳，吉浦孝一郎．
  • Organizer: 第26回 出生前から小児期にわたるゲノム医療フォーラム
  • Invited
• [Presentation] 周産期領域における遺伝カウンセリング． (2019)
  • Author(s): 長谷川ゆり，宮田海香子，三浦生子，吉浦孝一郎，三浦清徳．
  • Organizer: 第64回 日本人類遺伝学会
  • Invited
• [Presentation] 乳がん患者における血漿遊離DNA (cfDNA) 濃度と血漿循環腫瘍DNA (ctDNA) の解析． (2019)
  • Author(s): 及川将弘，瀬戸口優美香，榎本康子，久松和史，濱田哲夫，大坪竜太，松本 恵，矢野 洋，永安 武，三嶋博之，木下 晃，吉浦孝一郎．
  • Organizer: 第64回 日本人類遺伝学会
• [Presentation] 次世代シーケンサーを用いた日本全域の家族性地中海熱患者におけるMEFV遺伝子の包括的解析． (2019)
  • Author(s): 古賀智裕，三嶋博之，宮田海香子，三浦清徳，吉浦孝一郎，川上 純．
  • Organizer: 第64回 日本人類遺伝学会
• [Presentation] LARP7遺伝子複合ヘテロ接合体変異によるAlazami症候群の２症例． (2019)
  • Author(s): 伊達木澄人，里 龍晴，渡辺 聡，宮田海香子，近藤達郎，松本 正，吉浦孝一郎，森内浩幸．
  • Organizer: 第64回 日本人類遺伝学会
• [Presentation] 本邦における先天性形態以上症候群患者の顔貌画像を用い他診断補助システムFace2Geneの評価． (2019)
  • Author(s): 三嶋博之，鈴木寿人，近藤達郎，吉浦孝一郎，小崎健次郎．
  • Organizer: 第64回 日本人類遺伝学会
• [Book] 遺伝医学への招待（改訂第6版） (2020)
  • Author(s): （監修）新川詔夫、（著者）太田 亨，吉浦孝一郎，三宅紀子
  • Total Pages: 196
  • Publisher: 南江堂
  • ISBN: 9784524249312