用度量学习重构细胞谱系树,仅需少量数据就能准确推断分化路径。
Reconstructing Cell Lineage Trees from Phenotypic Features with Metric Learning
- 基于Transformer的度量学习方法,将谱系推断转化为几何结构优化问题。
- 在合成数据和真实单细胞测序数据上均实现高精度谱系重建,最小化监督需求。
- 适用于难以基因标记的生物模型,为发育生物学提供新计算工具。
受精卵如何发育成多种特化细胞是生物学核心问题。细胞通过分裂与分化形成复杂组织,但其分子机制尚不明确。研究发育过程的关键是推断细胞谱系树,揭示复制与分化中的分子决策。尽管基因工程谱系追踪技术取得进展,但在许多生物中不可行或存在伦理限制。相比之下,现代单细胞技术可在广泛生物系统中测量高维分子特征(如转录组)。本文提出CellTreeQM,一种基于Transformer架构的深度学习方法,通过构建具备树图几何特性的嵌入空间,实现谱系推断。我们将谱系重建建模为树度量学习任务,系统评估了有监督、弱监督和无监督训练设置,并建立谱系重建基准以全面评估方法性能。在两类数据上验证:(1) 基于布朗运动与独立噪声及伪信号的合成数据;(2) 分辨谱系的单细胞RNA测序数据集。实验表明,CellTreeQM在极少监督与有限数据下即可恢复谱系结构,提供可扩展的框架,用于探索复杂动物模型中的细胞谱系关系。据我们所知,这是首个将细胞谱系推断显式建模为度量学习任务的方法,为未来揭示细胞谱系分子动态的计算模型铺平道路。
原文摘要 · Abstract (English)
How a single fertilized cell gives rise to a complex array of specialized cell types in development is a central question in biology. The cells grow, divide, and acquire differentiated characteristics through poorly understood molecular processes. A key approach to studying developmental processes is to infer the tree graph of cell lineage division and differentiation histories, providing an analytical framework for dissecting individual cells' molecular decisions during replication and differentiation. Although genetically engineered lineage-tracing methods have advanced the field, they are either infeasible or ethically constrained in many organisms. In contrast, modern single-cell technologies can measure high-content molecular profiles (e.g., transcriptomes) in a wide range of biological systems. Here, we introduce CellTreeQM, a novel deep learning method based on transformer architectures that learns an embedding space with geometric properties optimized for tree-graph inference. By formulating lineage reconstruction as a tree-metric learning problem, we have systematically explored supervised, weakly supervised, and unsupervised training settings and present a Lineage Reconstruction Benchmark to facilitate comprehensive evaluation of our learning method. We benchmarked the method on (1) synthetic data modeled via Brownian motion with independent noise and spurious signals and (2) lineage-resolved single-cell RNA sequencing datasets. Experimental results show that CellTreeQM recovers lineage structures with minimal supervision and limited data, offering a scalable framework for uncovering cell lineage relationships in challenging animal models. To our knowledge, this is the first method to cast cell lineage inference explicitly as a metric learning task, paving the way for future computational models aimed at uncovering the molecular dynamics of cell lineage.
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