Extrapolating Heterogeneous Time-Series Gene Expression Data using Sagittarius

Abstract

AbstractUnderstanding the temporal dynamics of gene expression is crucial for developmental biology, tumor biology, and biogerontology. However, some timepoints remain challenging to measure in the lab, particularly during very early or very late stages of a biological process. Here we propose Sagittarius, a transformer-based model that can accurately simulate gene expression profiles at timepoints outside of the range of times measured in the lab. The key idea behind Sagittarius is to learn a shared reference space for time series measurements, thereby explicitly modeling unaligned timepoints and conditional batch effects between time series, and making the model widely applicable to diverse biological settings. We show Sagittarius’s promising performance when extrapolating mammalian developmental gene expression, simulating drug-induced expression at unmeasured dose and treatment times, and augmenting datasets to accurately predict drug sensitivity. We also used Sagittarius to extrapolate mutation profiles for early-stage cancer patients, which enabled us to discover a gene set connected to the Hedgehog signaling pathway that may be related to tumorigenesis in sarcoma patients, includingPTCH1,ARID2, andMYCBP2. By augmenting experimental temporal datasets with crucial but difficult-to-measure extrapolated datapoints, Sagittarius enables deeper insights into the temporal dynamics of heterogeneous transcriptomic processes and can be broadly applied to biological time series extrapolation.