大型言語モデルを用いたCRISPR-Cas12aクラードの発見

Yuanyuan Feng¹, Junchao Shi¹, Zhanwei Li¹

¹Research Center for Life Sciences computing, Zhejiang Lab, Hangzhou, China.

Nature communications

|August 23, 2025

まとめ

この研究は,新しいCRISPR-Casタンパク質とその機能を発見するために言語モデルを使用し,新しい遺伝子編集と疾患検出戦略を可能にします.

科学分野:

ゲノミクス
分子生物学
バイオ情報学

背景:

CRISPR-Casシステムは生命科学の強力なツールですがメタゲノムには特徴づけられていない膨大な数の Cas タンパク質があります
Casタンパク質を識別する従来の方法は,配列の並べ替えに依存し,発見を制限しています.
新しい Cas タンパク質の機能を探求することは,遺伝子編集技術の進歩に不可欠です.

研究の目的:

進化的スケール言語モデル (ESM) を活用して,メタゲノムデータから未知のCasタンパク質を特定し,特徴づけること.
ESMと機械学習を統合することで,未定のCas12aタンパク質のトランス・クリア活性を予測する.
新しく発見されたCasタンパク質の構造的・機能的多様性を探求する.

主な方法:

CRISPR-Casデータで訓練された進化的スケール言語モデル (ESM) を使用して,アラインメントフリーCasタンパク質を識別します.
機械学習とESMを統合して,未分類のCas12aのトランスクリア活動を予測する.
タンパク質の構造とRNAの相互作用を調査するために,構造分析と冷凍電子顕微鏡 (CryoEM) を使用する.
遺伝子クラスタを分類して文書化されていない Cas タンパク質の機能を調べる

主要な成果:

配列調整に頼らずにESMを使用してCasタンパク質の正確な識別.
7つの未確認のCas12aサブタイプが発見され独特のCRISPRロキュアと3Dフォールドが発見されました
Cas1,Cas2,Cas4タンパク質の8つのサブタイプを特定した.
新しいCas12a亜型に対する広範囲のPAM認識による独特のRNA相互作用と独特のDNA分裂偏好を明らかにする.
新しいCas12a PAMを用いた腫瘍遺伝子のSNPの特定検出戦略の開発

結論:

進化的スケール言語モデルは,メタゲノムにおける未定のCasタンパク質を発見し,機能的に注釈するための強力なアプローチを提供します.
発見されたCas12aサブタイプは,独特の生化学的特性と構造的特徴を示し,CRISPRのツールキットを拡張しています.
この研究は,微生物の多様性とそのバイオテクノロジーの応用の研究を加速させるためのAI駆動の方法の可能性を示しています.
開発された検出戦略は,新しいCRISPR-Casシステムを用いた標的型疾患診断の可能性を強調しています.

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