arXiv:2410.21345q-bio.GNcs.AI2024-10中稿 · NeurIPS

用混合方法生成更准确的基因组序列,突破单一模型局限。

Absorb & Escape: Overcoming Single Model Limitations in Generating Genomic Sequences

  • 先用扩散模型生成初稿,再用自回归模型迭代优化。
  • 在15个物种上测试,显著提升序列多样性和功能一致性。
  • 适合需要高保真基因序列设计的合成生物学研究者。

近期免疫学与合成生物学的发展推动了深度生成模型在DNA序列设计中的应用。当前主流方法包括自回归(AR)模型与扩散模型(DMs)。然而,基因组序列具有功能异质性,由多个相连区域(如启动子区、外显子、内含子)组成,各区域内元素服从相同分布,但整体序列非均匀。这种异质性使单一模型难以准确生成基因组序列。本文分析了AR模型与DMs在异质序列生成中的关键局限:(i) AR模型通过分解学习转移概率,但无法捕捉序列全局特性;(ii) DMs能恢复全局分布,却在碱基层面易出错。为此,我们提出后训练采样方法Absorb & Escape(A&E),实现从AR与DM中组合生成。该方法以扩散模型生成样本为起点,通过吸收与逃逸交替步骤,利用自回归模型逐步提升样本质量。我们在15个物种上对条件与无条件DNA生成进行大量实验,结果表明,在基序分布、多样性及基因组整合测试中,A&E显著优于现有先进AR模型与DMs。

原文摘要 · Abstract (English)

Abstract Recent advances in immunology and synthetic biology have accelerated the development of deep generative methods for DNA sequence design. Two dominant approaches in this field are AutoRegressive (AR) models and Diffusion Models (DMs). However, genomic sequences are functionally heterogeneous, consisting of multiple connected regions (e.g., Promoter Regions, Exons, and Introns) where elements within each region come from the same probability distribution, but the overall sequence is non-homogeneous. This heterogeneous nature presents challenges for a single model to accurately generate genomic sequences. In this paper, we analyze the properties of AR models and DMs in heterogeneous genomic sequence generation, pointing out crucial limitations in both methods: (i) AR models capture the underlying distribution of data by factorizing and learning the transition probability but fail to capture the global property of DNA sequences. (ii) DMs learn to recover the global distribution but tend to produce errors at the base pair level. To overcome the limitations of both approaches, we propose a post-training sampling method, termed Absorb & Escape (A&E) to perform compositional generation from AR models and DMs. This approach starts with samples generated by DMs and refines the sample quality using an AR model through the alternation of the Absorb and Escape steps. To assess the quality of generated sequences, we conduct extensive experiments on 15 species for conditional and unconditional DNA generation. The experiment results from motif distribution, diversity checks, and genome integration tests unequivocally show that A&E outperforms state-of-the-art AR models and DMs in genomic sequence generation.

基因组生成扩散模型自回归模型合成生物学

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