The evolution of 5'UTR length was shaped by natural selection for its functional impact on gene expression

The 5'UTR of mRNA transcripts differs in length by three orders of magnitude among genes within a eukaryotic genome. Many genes also generate transcript isoforms with heterogeneous lengths of 5'UTR by transcription from distantly located transcription start sites (TSSs). A null model was proposed that the diversification of 5'UTR length is largely stochastic attributing to random gain or loss of TSS and 5'UTR length evolved neutrally by genetic drift ("the null model"). Yet, multiple studies reported observations that are inconsistent with the null model. We conducted integrative analyses of multi-omics data to revisit the functional significance and evolution of 5'UTR length. Our results reveal a strong negative correlation between transcripts' 5'UTR lengths and their expression levels. Regulatory and evolutionary changes of 5'UTR lengths are also negatively associated with changes in expression levels. We proposed that the fixation of a 5'UTR length variant has been shaped by nature selection to better meet different expression demands among genes due to a negative impact of long 5'UTR on translation efficiency. As the expression demands are highly diverse among genes and dynamic in response to environmental changes, different lengths of 5'UTR were favored by natural selection during evolution, creating a highly diverse landscape of 5'UTR lengths. Our model improves understanding of the evolution of gene structure in eukaryotes, and supports that ATU might facilitate fine-tuning of gene expression outcome by producing different lengths of 5'UTR to adjust translation efficiency. ### Competing Interest Statement The authors have declared no competing interest.