Phase variation as a major mechanism of adaptation in
            <i>Mycobacterium tuberculosis</i>
            complex

Vargas, Roger; Luna, Michael J.; Freschi, Luca; Mg, Marin; Froom, Ruby; Murphy, Kenan C.; Campbell, Elizabeth A.; Ioerger, Thomas R.; Sassetti, Christopher M.; Mustafa, Farhat

doi:10.1073/pnas.2301394120

Cited by 8 publications

(3 citation statements)

References 70 publications

(112 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…274 of these genes could be aligned to H37Rv by miniprot and 90% of the aligned regions overlap with annotated CDS in RefSeq. We note that although overlapping genes in different open reading frames are rare in H37Rv (0.2% of coding regions), these genes may occur in other strains and may have functional implications ( Vargas et al 2023 , Snobre et al 2024 ). PPanGGOLiN’s preference to count such genes in the pangenome is not necessarily a weakness.…”

Section: Resultsmentioning

confidence: 87%

Exploring gene content with pangene graphs

Li,

Marin,

Farhat

2024

Bioinformatics

Self Cite

View full text Add to dashboard Cite

Motivation The gene content regulates the biology of an organism. It varies between species and between individuals of the same species. Although tools have been developed to identify gene content changes in bacterial genomes, none is applicable to collections of large eukaryotic genomes such as the human pangenome. Results We developed pangene, a computational tool to identify gene orientation, gene order and gene copy-number changes in a collection of genomes. Pangene aligns a set of input protein sequences to the genomes, resolves redundancies between protein sequences and constructs a gene graph with each genome represented as a walk in the graph. It additionally finds subgraphs, which we call bibubbles, that capture gene content changes. Applied to the human pangenome, pangene identifies known gene-level variations and reveals complex haplotypes that are not well studied before. Pangene also works with high-quality bacterial pangenome and reports similar numbers of core and accessory genes in comparison to existing tools. Availability and implementation Source code at https://github.com/lh3/pangene; pre-built pangene graphs can be downloaded from https://zenodo.org/records/8118576 and visualized at https://pangene.bioinweb.org.

show abstract

Section: Resultsmentioning

confidence: 87%

Exploring gene content with pangene graphs

Li,

Marin,

Farhat

2024

Bioinformatics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Given that indel events in the homopolymeric tract is mainly caused by strand slippage of replicative DNA polymerase 21 , these results indicate a role of mycobacterial dnaQ in DNA replication. Of note, recent studies showed that the indel events occurred in homopolymeric tract may have a strong impact on Mtb ’s pathogenesis and drug tolerance 22–24 .…”

Section: Resultsmentioning

confidence: 99%

Mycobacterial DnaQ is an Alternative Proofreader Ensuring DNA Replication Fidelity

Deng,

Liu,

Cui

et al. 2023

Preprint

View full text Add to dashboard Cite

Remove of mis-incorporated nucleotides ensures replicative fidelity. Although the ϵ-exonuclease DnaQ is a well-established proofreader in the model organismEscherichia coli, proofreading in mycobacteria relies on the polymerase and histidinol phosphatase (PHP) domain of replicative polymerase despite the presence of an alternative DnaQ homolog. Here, we show that depletion of DnaQ inMycolicibacterium smegmatisresults in increased mutation rate, leading to AT-biased mutagenesis and elevated insertions/deletions in homopolymer tract. We demonstrated that mycobacterial DnaQ binds to the β-clamp and functions synergistically with the PHP domain to correct replication errors. Further, we found that the mycobacterial DnaQ sustains replicative fidelity upon chromosome topological stress. Intriguingly, we showed that a naturally evolved DnaQ variant prevalent in clinicalMycobacterium tuberculosisisolates enables hypermutability and is associated with extensive drug resistance. These results collectively establish that the alternative DnaQ functions in proofreading, and thus reveal that mycobacteria deploy two proofreaders to maintain replicative fidelity.

show abstract

“…As such, pseudogenes sometimes comprise a substantial portion of the genome of obligate symbionts that no longer require functions provided by the host [ 2 ]. Bacteria also use pseudogenization as a means of regulation, wherein a subset of the population contains a frameshift that disables a protein’s function [ 3 ]. The number of pseudogenes can vary enormously in genomes from the same species, suggesting pseudogenization is a major mode of evolution.…”

Section: Introductionmentioning

confidence: 99%

Many purported pseudogenes in bacterial genomes are bona fide genes

Cooley,

Wright

2024

BMC Genomics

View full text Add to dashboard Cite

Background Microbial genomes are largely comprised of protein coding sequences, yet some genomes contain many pseudogenes caused by frameshifts or internal stop codons. These pseudogenes are believed to result from gene degradation during evolution but could also be technical artifacts of genome sequencing or assembly. Results Using a combination of observational and experimental data, we show that many putative pseudogenes are attributable to errors that are incorporated into genomes during assembly. Within 126,564 publicly available genomes, we observed that nearly identical genomes often substantially differed in pseudogene counts. Causal inference implicated assembler, sequencing platform, and coverage as likely causative factors. Reassembly of genomes from raw reads confirmed that each variable affects the number of putative pseudogenes in an assembly. Furthermore, simulated sequencing reads corroborated our observations that the quality and quantity of raw data can significantly impact the number of pseudogenes in an assembler dependent fashion. The number of unexpected pseudogenes due to internal stops was highly correlated (R2 = 0.96) with average nucleotide identity to the ground truth genome, implying relative pseudogene counts can be used as a proxy for overall assembly correctness. Applying our method to assemblies in RefSeq resulted in rejection of 3.6% of assemblies due to significantly elevated pseudogene counts. Reassembly from real reads obtained from high coverage genomes showed considerable variability in spurious pseudogenes beyond that observed with simulated reads, reinforcing the finding that high coverage is necessary to mitigate assembly errors. Conclusions Collectively, these results demonstrate that many pseudogenes in microbial genome assemblies are actually genes. Our results suggest that high read coverage is required for correct assembly and indicate an inflated number of pseudogenes due to internal stops is indicative of poor overall assembly quality.

show abstract

Phase variation as a major mechanism of adaptation in Mycobacterium tuberculosis complex

Cited by 8 publications

References 70 publications

Exploring gene content with pangene graphs

Exploring gene content with pangene graphs

Mycobacterial DnaQ is an Alternative Proofreader Ensuring DNA Replication Fidelity

Many purported pseudogenes in bacterial genomes are bona fide genes

Contact Info

Product

Resources

About