arXiv:2511.09512cs.LG2025-11

从基因序列直接预测敲除后多种表型异常,且可解释机制。

GenePheno: Interpretable Gene Knockout-Induced Phenotype Abnormality Prediction from Gene Sequences

  • 基于对比多标签学习与功能瓶颈层,捕捉表型关联与生物一致性。
  • 在4个数据集上达当前最优基因级F_max与表型级AUC。
  • 输出可解释的功能概念,适合生物机制研究者使用。

解析基因序列如何决定表型是生物学的基础挑战,也是实现可扩展、假设驱动实验的关键。该任务因序列与表型间巨大的模态差异以及基因的多效性而复杂。现有方法多聚焦特定基因变异对有限表型的影响,而通用的基因敲除表型预测则严重依赖人工标注的遗传信息,限制了可扩展性与泛化能力。因此,仅从基因序列直接预测多种表型异常仍鲜有探索。我们提出GenePheno,首个可解释的多标签预测框架,直接从基因序列预测敲除引发的多种表型异常。GenePheno采用对比多标签学习目标以捕捉表型间相关性,并引入独占正则化以保证生物学一致性。其进一步集成基因功能瓶颈层,输出人类可读的功能概念,反映表型形成的机制。为推动该领域发展,我们构建了4个数据集,以标准基因序列为输入,多标签表型异常为目标。在这些数据集上,GenePheno在基因级$F_{\text{max}}$与表型级AUC上均达到当前最优,案例研究证实其揭示基因功能机制的能力。

原文摘要 · Abstract (English)

Exploring how genetic sequences shape phenotypes is a fundamental challenge in biology and a key step toward scalable, hypothesis-driven experimentation. The task is complicated by the large modality gap between sequences and phenotypes, as well as the pleiotropic nature of gene-phenotype relationships. Existing sequence-based efforts focus on the degree to which variants of specific genes alter a limited set of phenotypes, while general gene knockout induced phenotype abnormality prediction methods heavily rely on curated genetic information as inputs, which limits scalability and generalizability. As a result, the task of broadly predicting the presence of multiple phenotype abnormalities under gene knockout directly from gene sequences remains underexplored. We introduce GenePheno, the first interpretable multi-label prediction framework that predicts knockout induced phenotypic abnormalities from gene sequences. GenePheno employs a contrastive multi-label learning objective that captures inter-phenotype correlations, complemented by an exclusive regularization that enforces biological consistency. It further incorporates a gene function bottleneck layer, offering human interpretable concepts that reflect functional mechanisms behind phenotype formation. To support progress in this area, we curate four datasets with canonical gene sequences as input and multi-label phenotypic abnormalities induced by gene knockouts as targets. Across these datasets, GenePheno achieves state-of-the-art gene-centric $F_{\text{max}}$ and phenotype-centric AUC, and case studies demonstrate its ability to reveal gene functional mechanisms.

基因预测可解释性多标签学习生物机制

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