Development of information system for functional annotation of genomic sequence alterations by using protein 3D structures

• Project/Area Number: 18K06194
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43060:System genome science-related
• Research Institution: Tohoku University
• Principal Investigator: Shirota Matsuyuki 東北大学, 医学系研究科, 講師 (00549462)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: タンパク質立体構造 / ゲノムバリアント / データベース / 機能欠失変異 / 蛋白質構造 / ゲノム配列変化 / 蛋白質機能 / 非同義置換 / 機能解析 / 蛋白質立体構造 / ゲノム / 塩基配列変化

Outline of Final Research Achievements

In this study, we developed an annotation system of nonsynonymous variants in the human genome to select those variants that can affect protein structure and function by evaluating various atomic interactions including hydrophobic interactions, protein-protein interactions, disulfide bonds, hydrogen bonds, and interactions with DNA, RNA, ions and other small ligands in the three-dimensional protein structures in Protein Data Bank. We applied this annotation system to known single nucleotide variants to facilitate interpretation of their functional roles and provided a web system that can annotate the variants of user's interest.

Academic Significance and Societal Importance of the Research Achievements

ヒトが持つゲノム配列の違いは、個人の体質や病気へのかかりやすさの違いに関係していることが知られているが、どのような配列がどのような特徴に関係しているかはよくわかっていない。この研究ではゲノム配列がコードするタンパク質の立体構造に注目し、原子レベルの相互作用をよく解析することで、タンパク質の機能を大きく変えるようなゲノム配列変化を調べることを可能にした。この研究によってゲノム配列の違いによって病気になりやすくなる分子レベルのメカニズムの解明につながることが期待できる。

Research Products

• [Presentation] Comprehensive and Up-to-date Annotation of Nonsynonymous Single Nucleotide Variants of Human Genome with Protein Structure Information (2020)
  • Author(s): Matsuyuki Shirota
  • Organizer: 第20回日本蛋白質科学会年会
• [Presentation] Analysis on nonsynonymous variations with possible structural and functional impact on loss-of-function intolerant proteins (2019)
  • Author(s): Matsuyuki Shirota
  • Organizer: ISMB 2019
  • Int'l Joint Research
• [Presentation] Development of a genome annotation system based on protein three-dimensional structures (2018)
  • Author(s): Matsuyuki Shirota
  • Organizer: ISMB2018
  • Int'l Joint Research
• [Presentation] 蛋白質立体構造と機能に影響しうるゲノムバリアントの選択と解析 (2018)
  • Author(s): 城田松之
  • Organizer: 日本生物物理学会第56回年会
• [Presentation] Development of genome variant annotation system with protein 3D structures and applications to variants in Japanese population (2018)
  • Author(s): Matsuyuki Shirota
  • Organizer: 第 7 回生命医薬情報学連合大会
• [Presentation] 蛋白質立体構造を用いたゲノムバリアントのアノテーション法の開発と日本人集団バリアントへの応用 (2018)
  • Author(s): 城田松之
  • Organizer: 第41回日本分子生物学会年会