Genome-wide evolution analysis reveals low CpG contents of fast-evolving genes and identifies antiviral microRNAs

Noncoding RNAs(ncRNAs) play important roles in many biological processes and provide materials for evolutionary adaptations beyond protein-coding genes, such as in the arms race between the host and pathogen. However, currently, a comprehensive high-resolution analysis of primate genomes that includes the latest annotated ncRNAs is not available. Here, we developed a computational pipeline to estimate the selections that act on noncoding regions based on comparisons with a large number of reference sequences in introns adjacent to the interested regions. Our method yields result comparable with those of the established codon-based method and phyloP method for coding genes;thus, it provides a holistic framework for estimating the selection on the entire genome. We further showed that fastevolving protein-coding genes and their corresponding 50 UTRs have a significantly lower frequency of the CpG dinucleotides than those evolving at an average pace, and these fast-evolving genes are enriched in the process of immunity and host defense. We also identified fast-evolving miRNAs with antiviral functions in cells. Our results provide a resource for high-resolution evolution analysis of the primate genomes.

SARS-CoV-2 helicase NSP13 hijacks the host protein EWSR1 to promote viral replication by enhancing RNA unwinding activity

Background:Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)emerged in December 2019 and has led to a global coronavirus disease 2019(COVID-19)pandemic.Currently,incomplete understanding of how SARS-CoV-2 arrogates the host cell to establish its life cycle has led to slow progress in the development of effective drugs.Results:In this study,we found that SARS-CoV-2 hijacks the host protein EWSR1(Ewing Sarcoma breakpoint region 1/EWS RNA binding protein 1)to promote the activity of its helicase NSP13 to facilitate viral propagation.NSP13 is highly conserved among coronaviruses and is crucial for virus replication,providing chemical energy to unwind viral RNA replication intermediates.Treatment with different SARS-CoV-2 NSP13 inhibitors in multi-ple cell lines infected with SARS-CoV-2 effectively suppressed SARS-CoV-2 infection.Using affinity-purification mass spectrometry,the RNA binding protein EWSR1 was then identified as a potent host factor that physically associated with NSP13.Furthermore,silencing EWSR1 dramatically reduced virus replication at both viral RNA and protein levels.Mechanistically,EWSR1 was found to bind to the NTPase domain of NSP13 and potentially enhance its dsRNA unwinding ability.Conclusions:Our results pinpoint EWSR1 as a novel host factor for NSP13 that could potentially be used for drug repurposing as a therapeutic target for COVID-19.