The genetic and biochemical determinants of mRNA degradation rates in mammals

Abstract

ABSTRACTBackgroundDegradation rate is a fundamental aspect of mRNA metabolism, and the factors governing it remain poorly characterized. Understanding the genetic and biochemical determinants of mRNA half-life would enable a more precise identification of variants that perturb gene expression through post-transcriptional gene regulatory mechanisms.ResultsHere, we establish a compendium of 54 human and 27 mouse transcriptome-wide mRNA decay rate datasets. A meta-analysis of these data identified a prevalence of technical noise and measurement bias, induced partially by the underlying experimental strategy. Correcting for these biases allowed us to derive more precise, consensus measurements of half-life which exhibit enhanced consistency between species. We trained substantially improved statistical models based upon genetic and biochemical features to better predict half-life and characterize the factors molding it. Our state-of-the-art model, Saluki, is a hybrid convolutional and recurrent deep neural network which relies only upon an mRNA sequence annotated with coding frame and splice sites to predict half-life (r=0.77). Saluki predicts the impact of RNA sequences and genetic mutations therein on mRNA stability, in agreement with functional measurements derived from massively parallel reporter assays.ConclusionsOur work produces a more robust “ground truth” with regards to transcriptome-wide mRNA half-lives in mammalian cells. Using these consolidated measurements, we trained a model that is over 50% more accurate in predicting half-life from sequence than existing models. Our best model, Saluki, succinctly captures many of the known determinants of mRNA half-life and can be rapidly deployed to predict the functional consequences of arbitrary mutations in the transcriptome.