通过神经元反向追踪基因,发现阿尔茨海默病的潜在致病基因。
Unravelling Causal Genetic Biomarkers of Alzheimer's Disease via Neuron to Gene-token Backtracking in Neural Architecture: A Groundbreaking Reverse-Gene-Finder Approach
- 从高致病性神经元反向追溯到输入层基因,定位关键致病基因。
- 识别出多个与阿尔茨海默病强相关的候选基因,具备高置信度。
- 方法可解释性强,适用于其他复杂疾病基因发现。
阿尔茨海默病(AD)影响全球超过5500万人,但其关键遗传驱动因素仍不明确。基于基因组基础模型的最新进展,本文提出创新的逆向基因寻因技术(Reverse-Gene-Finder),一种在神经网络架构中实现从神经元到基因令牌的反向追踪方法,以揭示驱动AD发病的新因果遗传生物标志物。该技术包含三大创新:首先,假设最具致病性的基因(MCGs)应具有激活最具致病性神经元(MCNs)的最高概率;其次,在输入层使用基因令牌表示,使每个基因(已知或未知于AD)在输入空间中作为离散唯一实体存在;最后,不同于传统前向传播的神经网络结构,本研究开发了创新的反向追踪机制,从MCNs回溯至输入层,识别出最致病令牌(MCTs)及其对应基因。Reverse-Gene-Finder具有高度可解释性、泛化性和适应性,为其他疾病场景中的基因发现提供了有前景的路径。
原文摘要 · Abstract (English)
Alzheimer's Disease (AD) affects over 55 million people globally, yet the key genetic contributors remain poorly understood. Leveraging recent advancements in genomic foundation models, we present the innovative Reverse-Gene-Finder technology, a ground-breaking neuron-to-gene-token backtracking approach in a neural network architecture to elucidate the novel causal genetic biomarkers driving AD onset. Reverse-Gene-Finder comprises three key innovations. Firstly, we exploit the observation that genes with the highest probability of causing AD, defined as the most causal genes (MCGs), must have the highest probability of activating those neurons with the highest probability of causing AD, defined as the most causal neurons (MCNs). Secondly, we utilize a gene token representation at the input layer to allow each gene (known or novel to AD) to be represented as a discrete and unique entity in the input space. Lastly, in contrast to the existing neural network architectures, which track neuron activations from the input layer to the output layer in a feed-forward manner, we develop an innovative backtracking method to track backwards from the MCNs to the input layer, identifying the Most Causal Tokens (MCTs) and the corresponding MCGs. Reverse-Gene-Finder is highly interpretable, generalizable, and adaptable, providing a promising avenue for application in other disease scenarios.
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