Determinants of genome-wide distribution and evolution of uORFs in eukaryotes

Hong Zhang,Jian Lu,Changcheng Wu,Yirong Wang,Yirong Wang,Xinkai Wu,Xiaolu Tang

doi:10.1038/s41467-021-21394-y

Hong Zhang, Jian Lu + Show 5 more

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https://doi.org/10.1038/s41467-021-21394-y

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Journal: Nature Communications	Publication Date: Feb 17, 2021
Citations: 46	License type: open-access

Affiliation: Peking University, Hunan University

Abstract

Upstream open reading frames (uORFs) play widespread regulatory functions in modulating mRNA translation in eukaryotes, but the principles underlying the genomic distribution and evolution of uORFs remain poorly understood. Here, we analyze ~17 million putative canonical uORFs in 478 eukaryotic species that span most of the extant taxa of eukaryotes. We demonstrate how positive and purifying selection, coupled with differences in effective population size (Ne), has shaped the contents of uORFs in eukaryotes. Besides, gene expression level is important in influencing uORF occurrences across genes in a species. Our analyses suggest that most uORFs might play regulatory roles rather than encode functional peptides. We also show that the Kozak sequence context of uORFs has evolved across eukaryotic clades, and that noncanonical uORFs tend to have weaker suppressive effects than canonical uORFs in translation regulation. This study provides insights into the driving forces underlying uORF evolution in eukaryotes.

Highlights

Upstream open reading frames play widespread regulatory functions in modulating mRNA translation in eukaryotes, but the principles underlying the genomic distribution and evolution of uORFs remain poorly understood
As most species surveyed in this study currently have no ribosome profiling data, and it is very challenging to predict the noncanonical uORFs in silico reliably, we only focused on the putative canonical uORFs that start with the AUG start codon
The uORFs analyzed in this study are restricted to the putative canonical uORFs unless explicitly stated otherwise

Summary

Introduction

Upstream open reading frames (uORFs) play widespread regulatory functions in modulating mRNA translation in eukaryotes, but the principles underlying the genomic distribution and evolution of uORFs remain poorly understood. Our recent study indicated that many uAUGs recently fixed in Drosophila melanogaster were driven by positive Darwinian selection[32], which suggests that some uORFs and NTEs might be adaptive Despite these exciting progress, the principles underlying the genomic distribution and evolution of uORFs and NTEs are poorly understood. We compare the conservation patterns of start codons versus coding regions of the canonical uORFs in different clades, disentangled the relationship between the Kozak sequence context and the translational efficiency of uORFs, and explore the evolution of Kozak contextual characteristics across eukaryotes. Our analyses present a broad overview of the interspecies variability of uAUGs in eukaryotes and provide insights into the general principles underlying the distribution and sequence evolution of uORFs and NTEs in eukaryotes

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