Analysis of Stop Codons within Prokaryotic Protein-Coding Genes Suggests Frequent Readthrough Events

Belinky, Frida; Ganguly, Ishan; Poliakov, Eugenia; Yurchenko, Vyacheslav; Rogozin, Igor B.

doi:10.3390/ijms22041876

Cited by 8 publications

(5 citation statements)

References 73 publications

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“…The comparison of pseudogenes with their functional homologs showed that most pseudogenes are truncated (480,349, 71%). Recent studies suggest that early stop codons in many truncated pseudogenes correspond to nonsense mutations (24), or transient alleles that may be reversed under purifying selection (25). Comparing the evolutionary rates of truncated and non-truncated pseudogenes we find that truncated pseudogenes are characterized by higher dN and dS, as well as higher dN/dS compared to non-truncated pseudogenes (Supplementary Figure S3), as is expected for DNA evolution following a relaxation of selection pressure (i.e., gene non-functionalization).…”

Section: Resultsmentioning

confidence: 99%

Pseudogenes in plasmid genomes reveal past transitions in plasmid mobility

Hanke,

Wang,

Dagan

2023

Preprint

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Evidence for gene non-functionalization due to mutational processes is found in genomes in the form of pseudogenes. Pseudogenes are known to be rare in prokaryote chromosomes, with the exception of lineages that underwent an extreme genome reduction (e.g., obligatory pathogens). Much less is known about the frequency of pseudogenes in prokaryotic plasmids; those are genetic elements that can transfer between cells and may encode beneficial traits for their host. Non-functionalization of plasmid-encoded genes may alter the plasmid characteristics, e.g., mobility, or their effect on the host. Analyzing 10,832 prokaryotic genomes, we find that plasmid genomes are characterized by threefold-higher pseudogene density compared to chromosomes. The majority of plasmid pseudogenes correspond to deteriorated transposable elements. A detailed analysis of enterobacterial plasmids furthermore reveals frequent gene non-functionalization events associated with the loss of plasmid self-transmissibility. Reconstructing the evolution of closely related plasmids revealed that non-functionalization of the conjugation machinery led to the emergence of non-mobilizable plasmid types. Examples are virulence plasmids inEscherichiaandSalmonella. Our study highlights non-functionalization of core plasmid mobility functions as one route for the evolution of domesticated plasmids. Pseudogenes in plasmids supply insights into past transitions in plasmid mobility that are akin to transitions in bacterial lifestyle.

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Section: Resultsmentioning

confidence: 99%

Pseudogenes in plasmid genomes reveal past transitions in plasmid mobility

Hanke,

Wang,

Dagan

2023

Preprint

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“…The mean half-life of pseudogenes in Buchnera , an endocellular bacterial symbiont found in insects, is approximately 24 million years ( 61 ). Moreover, the dN/dS values (ratios of substitution rates at non-synonymous and synonymous sites) of pseudogenes are significantly lower than 1 ( 62 ), indicative of a strong purifying selection on pseudogenes, namely pseudogenes are still functional to some extent.…”

Section: Discussionmentioning

confidence: 97%

“Pseudo-pseudogenes” in bacterial genomes: Proteogenomics reveals a wide but low protein expression of pseudogenes in Salmonella enterica

Feng

Wang

Chien³

et al. 2022

Nucleic Acids Research

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Pseudogenes (genes disrupted by frameshift or in-frame stop codons) are ubiquitously present in the bacterial genome and considered as nonfunctional fossil. Here, we used RNA-seq and mass-spectrometry technologies to measure the transcriptomes and proteomes of Salmonella enterica serovars Paratyphi A and Typhi. All pseudogenes’ mRNA sequences remained disrupted, and were present at comparable levels to their intact homologs. At the protein level, however, 101 out of 161 pseudogenes suggested successful translation, with their low expression regardless of growth conditions, genetic background and pseudogenization causes. The majority of frameshifting detected was compensatory for -1 frameshift mutations. Readthrough of in-frame stop codons primarily involved UAG; and cytosine was the most frequent base adjacent to the codon. Using a fluorescence reporter system, fifteen pseudogenes were confirmed to express successfully in vivo in Escherichia coli. Expression of the intact copy of the fifteen pseudogenes in S. Typhi affected bacterial pathogenesis as revealed in human macrophage and epithelial cell infection models. The above findings suggest the need to revisit the nonstandard translation mechanism as well as the biological role of pseudogenes in the bacterial genome.

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“…This is a conservative approach: after removal of this mutation, all probability values associated with ORF8b become even smaller. The reason why we did not remove the missense mutation is that although readthrough events are rare, they are still possible [ 40 ]. We also detected one tandem double substitution AGG -> GGT (Fig.…”

Section: Discussionmentioning

confidence: 99%

The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection

et al. 2023

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Background Accessory proteins have diverse roles in coronavirus pathobiology. One of them in SARS-CoV (the causative agent of the severe acute respiratory syndrome outbreak in 2002–2003) is encoded by the open reading frame 8 (ORF8). Among the most dramatic genomic changes observed in SARS-CoV isolated from patients during the peak of the pandemic in 2003 was the acquisition of a characteristic 29-nucleotide deletion in ORF8. This deletion cause splitting of ORF8 into two smaller ORFs, namely ORF8a and ORF8b. Functional consequences of this event are not entirely clear. Results Here, we performed evolutionary analyses of ORF8a and ORF8b genes and documented that in both cases the frequency of synonymous mutations was greater than that of nonsynonymous ones. These results suggest that ORF8a and ORF8b are under purifying selection, thus proteins translated from these ORFs are likely to be functionally important. Comparisons with several other SARS-CoV genes revealed that another accessory gene, ORF7a, has a similar ratio of nonsynonymous to synonymous mutations suggesting that ORF8a, ORF8b, and ORF7a are under similar selection pressure. Conclusions Our results for SARS-CoV echo the known excess of deletions in the ORF7a-ORF7b-ORF8 complex of accessory genes in SARS-CoV-2. A high frequency of deletions in this gene complex might reflect recurrent searches in “functional space” of various accessory protein combinations that may eventually produce more advantageous configurations of accessory proteins similar to the fixed deletion in the SARS-CoV ORF8 gene.

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Analysis of Stop Codons within Prokaryotic Protein-Coding Genes Suggests Frequent Readthrough Events

Cited by 8 publications

References 73 publications

Pseudogenes in plasmid genomes reveal past transitions in plasmid mobility

Pseudogenes in plasmid genomes reveal past transitions in plasmid mobility

“Pseudo-pseudogenes” in bacterial genomes: Proteogenomics reveals a wide but low protein expression of pseudogenes in Salmonella enterica

The 29-nucleotide deletion in SARS-CoV: truncated versions of ORF8 are under purifying selection

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