arXiv:2602.10156q-bio.GNcs.LG2026-02被引 3

用基因组序列预测基因扰动对细胞的影响,实现零样本推理。

STRAND: Sequence-Conditioned Transport for Single-Cell Perturbations

  • 以调控序列条件化生成模型,编码扰动位点信息
  • 在低样本下提升33%判别性能,覆盖95%基因组区域
  • 适合研究基因调控机制或需要泛化能力的生物学家

预测基因扰动如何改变细胞状态是构建可控制基因调控模型的核心问题。针对同一基因的扰动可能因基因组位置不同(如转录起始位点、调控元件)产生不同的转录响应,而传统基因级模型将这些干预统一表示,丢失了差异。我们提出STRAND,一种基于调控DNA序列条件化的生成模型,通过编码扰动位点的序列来参数化从对照到扰动细胞状态的条件传输过程。相比固定基因标识符,序列表征支持在训练未见位点上的零样本推理,将推断时基因组覆盖率从基因级单细胞基础模型的约1.5%提升至约95%。我们在K562、Jurkat和RPE1细胞的CRISPR扰动数据集上评估STRAND,结果显示其在低样本条件下判别分数提升最高达33%,在未见基因扰动基准上取得最佳平均排序,且在新细胞系间迁移时皮尔逊相关系数提升最高达0.14。消融实验验证了序列条件化与传输机制的贡献,案例研究显示STRAND能识别出基因级模型遗漏的功能性替代转录起始位点。

原文摘要 · Abstract (English)

Predicting how genetic perturbations change cellular state is a core problem for building controllable models of gene regulation. Perturbations targeting the same gene can produce different transcriptional responses depending on their genomic locus, including different transcription start sites and regulatory elements. Gene-level perturbation models collapse these distinct interventions into the same representation. We introduce STRAND, a generative model that predicts single-cell transcriptional responses by conditioning on regulatory DNA sequence. STRAND represents a perturbation by encoding the sequence at its genomic locus and uses this representation to parameterize a conditional transport process from control to perturbed cell states. Representing perturbations by sequence, rather than by a fixed set of gene identifiers, supports zero-shot inference at loci not seen during training and expands inference-time genomic coverage from ~1.5% for gene-level single-cell foundation models to ~95% of the genome. We evaluate STRAND on CRISPR perturbation datasets in K562, Jurkat, and RPE1 cells. STRAND improves discrimination scores by up to 33% in low-sample regimes, achieves the best average rank on unseen gene perturbation benchmarks, and improves transfer to novel cell lines by up to 0.14 in Pearson correlation. Ablations isolate the gains to sequence conditioning and transport, and case studies show that STRAND resolves functionally alternative transcription start sites missed by gene-level models.

基因调控单细胞生成模型序列条件

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