Posts Tagged ‘Genetics’

CRISPRs and bacterial pathogenesis

Friday, April 25th, 2014

CRISPRs have taken microbiology by storm in the last few years. If you haven’t caught up yet, there’s a short introductory primer here. CRISPRs (or CRISPR-Cas systems as they are now tending to be called) protect bacteria from infection by bacteriophages and other mobile genetic elements including plasmids. Because they are barriers to horizontal gene transfer, CRISPRs reduce the speed of eviolution of pathogens. but CRISPRs can increase also virulence by modulating gene expression. A recent short review discusses the “love-hate relationship between bacterial pathogens and their CRISPR-Cas systems“.

CRISPR-Cas system

Impact of CRISPR immunity on the emergence and virulence of bacterial pathogens. (2014) Current Opinion in Microbiology, 17, 82-90.
CRISPR-Cas systems protect prokaryotes from viruses and plasmids and function primarily as an adaptive immune system in these organisms. Recent discoveries, however, revealed unexpected roles for CRISPR loci as barriers to horizontal gene transfer and as modulators of gene expression. We review how both of these functions of CRISPR-Cas systems can affect the emergence and virulence of human bacterial pathogens.

 

 

Human telomeres carry an integrated copy of human herpesvirus 6

Friday, October 11th, 2013

Telomeres They may not know it, but up to half a million people in Britain today may carry a particular form of herpesvirus 6 inherited from a parent in their genetic material. Recent research led by Nicola Royle at the University of Leicester has identified a mechanism by which the inherited herpesvirus 6 can escape from the chromosome and may be able to reactivate under certain conditions.

This research may have important implications for transplantation, as those seeking transplants are often immunosuppressed, and are more susceptible to viral reactivation. The implications of the study suggested screening donors for this inherited form of HHV-6 could help doctors make more informed decisions about which donors to use.

 

Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome. Nucleic Acids Research, September 2013 doi: 10.1093/nar/gkt840
Linear chromosomes are stabilized by telomeres, but the presence of short dysfunctional telomeres triggers cellular senescence in human somatic tissues, thus contributing to ageing. Approximately 1% of the population inherits a chromosomally integrated copy of human herpesvirus 6 (CI-HHV-6), but the consequences of integration for the virus and for the telomere with the insertion are unknown. Here we show that the telomere on the distal end of the integrated virus is frequently the shortest measured in somatic cells but not the germline. The telomere carrying the CI-HHV-6 is also prone to truncations that result in the formation of a short telomere at a novel location within the viral genome. We detected extra-chromosomal circular HHV-6 molecules, some surprisingly comprising the entire viral genome with a single fully reconstituted direct repeat region (DR) with both terminal cleavage and packaging elements (PAC1 and PAC2). Truncated CI-HHV-6 and extra-chromosomal circular molecules are likely reciprocal products that arise through excision of a telomere-loop (t-loop) formed within the CI-HHV-6 genome. In summary, we show that the CI-HHV-6 genome disrupts stability of the associated telomere and this facilitates the release of viral sequences as circular molecules, some of which have the potential to become fully functioning viruses.

 

Burkholderia, evolution and chronic disease

Thursday, October 3rd, 2013

Burkholderia pseudomallei The Gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a serious infectious disease of humans and animals. Once considered an esoteric tropical disease confined to Southeast Asia and northern Australia, research on B. pseudomallei has recently gained global prominence due to its classification as a potential bioterrorism agent by countries such as the United States and also by increasing numbers of case reports from regions where it is not endemic.

An environmental bacterium typically found in soil and water, assessing the true global prevalence of melioidosis is challenged by the fact that clinical symptoms associated with B. pseudomallei infection are extremely varied and may be confused with diverse conditions such as lung cancer, tuberculosis, or Staphyloccocus aureus infection. These diagnostic challenges, coupled with lack of awareness among clinicians, have likely contributed to underdiagnosis and the high mortality rate of melioidosis, as initial treatment is often either inappropriate or delayed. Even after antibiotic treatment, relapses are frequent, and after resolution of acute symptoms, chronic melioidosis can also occur, and the symptoms can persist for months to years.

In a recent article, Price et al. demonstrate how comparative genomic sequencing can reveal the repertoire of genetic changes incurred by B. pseudomallei during chronic human infection. Their results have significant clinical ramifications and highlight B. pseudomallei’s ability to survive in a wide range of potential niches within hosts, through the acquisition of genetic adaptations that optimize fitness and resource utilization. These studies demonstrate B. pseudomallei’s remarkable ability to evolve genetically even within the same human host.

Less Is More: Burkholderia pseudomallei and Chronic Melioidosis. (2013) MBio. doi: 10.1128/mBio.00709-13

 

Smaller fleas upon their back to bite them

Wednesday, June 19th, 2013

Sputnik Rapid advances of genomics and metagenomics lead not only to the rapid growth of sequence databases but to discovery of fundamentally novel types of genetic elements. The discovery and characterization of giant viruses that infect unicellular eukaryotes, in particular members of the family Mimiviridae infecting amoeba, over the last decade revealed a remarkable new class of agents that are typical viruses by structure and reproduction strategy but exceed many parasitic bacteria in size and genomic complexity. Like bacteria, the giant viruses (sometimes called giruses) possess their own parasites and their own mobilomes, i.e. communities of associated mobile genetic elements.

The first virus infecting a giant virus, the Sputnik virophage, was isolated from a mimivirus-infected acanthamoeba and shown to replicate within the mimivirus factories and partially inhibit the reproduction of the host mimivirus. The second virophage, named Mavirus, is a parasite of the Cafeteria roenbergensis virus (CroV), a distant relative of the mimiviruses. The third virophage genome was isolated from the Antarctic Organic Lake (hence OLV, Organic Lake Virophage) where it apparently controls the reproduction of its virus host classified as a phycodnavirus. The three well-characterized virophages possess small isocahedral virions and genomes of 20 to 25 kilobase encoding 21 to 26 proteins each. Although the virophages are similar in genome size and structure and are generally construed as related, only a minority of the virophage genes are homologous.

Analysis of the Mavirus genome resulted in the discovery that this virophage shared 5 homologous genes with the large, self-replicating eukaryotic transposable elements of the Maverick/Polinton class (hereinafter Polintons). The Polintons that are scattered among genome of diverse eukaryotes and reach high abundance in some protists, such as Trichomonas vaginalis, have long been considered ‘virus-like’ transposons because of their large size (20 kb and larger) and the presence of several genes that are common in viruses but not in other transposable elements. The Mavirus shows by far the closest affinity with the Polintons among the currently known viruses, and accordingly, it has been proposed that the Polintons evolved from the virophages.

In addition to the virophages, the giant viruses host several other groups of mobile elements. These include self-splicing introns, inteins, putative bacterial-type transposons and the most recently discovered novel linear plasmids named transpovirons. The transpovirons are highly abundant genetic elements associated with several giant viruses of the Mimiviridae family that contain only 6 to 8 genes two of which are homologous to genes of the Sputnik virophage, indicating multiple gene exchanges within the giant virus mobilome.

 

Virophages, polintons, and transpovirons: a complex evolutionary network of diverse selfish genetic elements with different reproduction strategies. (2013) Virology Journal, 10:158 doi: 10.1186/1743-422X-10-158
Recent advances of genomics and metagenomics reveal remarkable diversity of viruses and other selfish genetic elements. In particular, giant viruses have been shown to possess their own mobilomes that include virophages, small viruses that parasitize on giant viruses of the Mimiviridae family, and transpovirons, distinct linear plasmids. One of the virophages known as the Mavirus, a parasite of the giant Cafeteria roenbergensis virus, shares several genes with large eukaryotic self-replicating transposon of the Polinton (Maverick) family, and it has been proposed that the polintons evolved from a Mavirus-like ancestor. We performed a comprehensive phylogenomic analysis of the available genomes of virophages and traced the evolutionary connections between the virophages and other selfish genetic elements. The comparison of the gene composition and genome organization of the virophages reveals 6 conserved, core genes that are organized in partially conserved arrays. Phylogenetic analysis of those core virophage genes, for which a sufficient diversity of homologs outside the virophages was detected, including the maturation protease and the packaging ATPase, supports the monophyly of the virophages. The results of this analysis appear incompatible with the origin of polintons from a Mavirus-like agent but rather suggest that Mavirus evolved through recombination between a polinton and an unknownvirus. Altogether, virophages, polintons, a distinct Tetrahymena transposable element Tlr1, transpovirons, adenoviruses, and some bacteriophages form a network of evolutionary relationships that is held together by overlapping sets of shared genes and appears to represent a distinct module in the vast total network of viruses and mobile elements. The results of the phylogenomic analysis of the virophages and related genetic elements are compatible with the concept of network-like evolution of the virus world and emphasize multiple evolutionary connections between bona fide viruses and other classes of capsid-less mobile elements.

 

No bacterium is an island

Friday, February 15th, 2013

Streptococcus pneumoniae A new paper in PLOS Pathogens demonstrates that the human pathogen Streptococcus pneumoniae (one of the causes of bacterial pneumonia) possesses an unusual enzyme that protects foreign DNA taken up during transformation, allowing exchange of pathogenicity islands donated from other pathogenic bacteria.

Exchange of pathogenicity islands is crucial for pneumococcal virulence, as illustrated by the impressive variability in the polysaccharide capsule, which is usually targeted by current vaccines. Acquisition of different capsule loci, by relying on this genetic transformation, thus allows for vaccine evasion. Natural genetic transformation is thought of as the bacterial equivalent of sexual reproduction, allowing intra- and inter-species genetic exchange. This process, involving uptake of foreign DNA as single-strands (ss) that leads to chromosomal integration, is transient in S. pneumoniae.
Restriction-modification (R-M) systems classically include a restrictase, which protects the host bacteria from attack by bacteriophage via the degradation of only the foreign double-stranded (ds) DNA, and a dsDNA methylase that methylates the host genome, providing self-immunity against this restrictase. Since they degrade only foreign DNA, R-M systems are proposed to antagonize transformation by DNA from other bacteria. The DpnII R-M system investigated in this study is present in around half of pneumococcal isolates tested and also possesses an unusual methylase of ssDNA, DpnA, which is specifically induced during the brief genetic transformation time window.

This study shows that DpnA gene is crucial for the exchange of pathogenicity islands when the foreign DNA is unmethylated (i.e., from a non-DpnII modified DNA donor). By methylating the internalized foreign ssDNA, DpnA protects the chromosome of those transformants that incorporate the foreign pathogenicity islands, such as the capsule locus. In the absence of this unique methylation, the novel transformant chromosomes would be degraded by the DpnII restrictase, thus forbidding the acceptance of the foreign DNA sequences. The researchers found that the role of DpnA is to protect foreign DNA, allowing pathogenicity island exchange between bacteria.

 

Programmed Protection of Foreign DNA from Restriction Allows Pathogenicity IslandExchange during Pneumococcal Transformation. (2013) PLoS Pathog 9(2): e1003178. doi:10.1371/journal.ppat.1003178
Natural genetic transformation can compensate for the absence of sexual reproduction in bacteria, allowing genetic diversification by recombination. It proceeds through the internalization of single stranded (ss) DNA fragments created from an exogenous double stranded (ds) DNA substrate, which are incorporated into the genome by homology. On the other hand, restriction- modification (R-M) systems, which protect bacteria from bacteriophage attack by degrading invading foreign DNA, potentially antagonize transformation. About half of the strains of the naturally transformable species and human pathogen Streptococcus pneumoniae possess an R-M system, DpnII, restricting unmethylated dsDNA. DpnII strains possess DpnA which is unusual in that it methylates ssDNA. Here we show that DpnA plays a crucial role in the protection of internalized heterologous transforming ssDNA, preventing the post-replicative destruction by DpnII of transformants produced by chromosomal inte- gration of heterogolous DNA by virtue of flanking homology. This protective role of DpnA is of particular importance for acquisition of pathogenicity islands, such as capsule loci, from non-DpnII origin by DpnII strains, likely contributing to pneumococcal virulence via escape from capsule-based vaccines. More generally, this finding is the first evidence for a mechanism that actively promotes genetic diversity of S. pneumoniae through active protection and incorporation of foreign DNA.

 

It’s not all down to the virus

Monday, February 4th, 2013

DNA When we think about virus pathogensis, we tend to get hung up on genetic variation and new “virulent” strains of virus appearing. The recent example of the Sydney 2012 strain of norovirus is a good example of this.

But we also know that around 20% of Europeans are highly resistant to symptomatic infections by noroviruses (Mendelian resistance to human norovirus infections. (2006) Seminars in immunology 18(6): 375-386).

Likewise, host variation in the IL28B gene is responsible for the outcome of hepatitis C virus (HCV) infection (Genetic Variation in the Interleukin-28B Gene Is Associated with Spontaneous Clearance and Progression of Hepatitis C Virus in Moroccan Patients. (2013) PLoS ONE 8(1): e54793).

So when you get sick, make sure you take your fair share of the responsibility!

 

E. coli spontaneous mutations

Thursday, December 27th, 2012

Mutation Knowledge of the rate and nature of spontaneous mutation is fundamental to understanding evolutionary and molecular processes. This report analyzes spontaneous mutations accumulated over thousands of generations by wild-type Escherichia coli and a derivative defective in mismatch repair (MMR), the primary pathway for correcting replication errors. Comparing results from the wild-type and repair-defective strains may lead to a deeper understanding of factors that determine mutation rates and spectra, how these factors may differ among organisms, and how they may be shaped by environmental conditions.

 

Rate and molecular spectrum of spontaneous mutations in the bacterium Escherichia coli as determined by whole-genome sequencing. PNAS USA 18 September 2012, doi: 10.1073/pnas.1210309109

The Epigenetics of Host–Pathogen Interactions

Wednesday, December 5th, 2012

A growing body of evidence points towards epigenetic mechanisms being responsible for a wide range of biological phenomena, from the plasticity of plant growth and development to the nutritional control of caste determination in honeybees and the etiology of human disease (e.g. cancer). With the (partial) elucidation of the molecular basis of epigenetic variation and the heritability of certain of these changes, the field of evolutionary epigenetics is flourishing.

Despite this, the role of epigenetics in shaping host–pathogen interactions has received comparatively little attention. Yet there is plenty of evidence supporting the implication of epigenetic mechanisms in the modulation of the biological interaction between hosts and pathogens. The phenotypic plasticity of many key parasite life-history traits appears to be under epigenetic control. Pathogen-induced effects in host phenotype may have transgenerational consequences, and the bases of these changes and their heritability probably have an epigenetic component. The significance of epigenetic modifications may go beyond providing a mechanistic basis for host and pathogen plasticity.

Epigenetic modifications

Epigenetic epidemiology has recently emerged as a promising area for future research on infectious diseases. In addition, the incorporation of epigenetic inheritance and epigenetic plasticity mechanisms to evolutionary models and empirical studies of host–pathogen interactions will provide new insights into the evolution and coevolution of these associations. This article reviews the evidence available for the role epigenetics on host–pathogen interactions, and the use of the epigenetic technologies available that can be cross-applied to host–pathogen studies, including recommendations and directions for future research on the burgeoning field of epigenetics as applied to host–pathogen interactions.

 

Epigenetics of Host–Pathogen Interactions: (2012) The Road Ahead and the Road Behind. PLoS Pathog 8(11): e1003007. doi:10.1371/journal.ppat.1003007

The cuddly giant panda – brought to you by bacteria 

Thursday, November 29th, 2012

The giant panda is one of the most endangered animals in the world, with only 2,500 to 3,000 individuals found in western China. Approximately 7 million years ago, the ancient giant panda was omnivorous, but it shifted from being an omnivore to a herbivore after 4.6 million years to 5 million years of evolution, with soft bamboo shoots, stems, and leaves comprising 99% of its diet. The modern giant panda retains a gastrointestinal tract typical of its carnivorous ancestry. Analysis of the giant panda genome revealed that it encodes all the enzymes necessary for a carnivorous digestive system but lacks those for digesting lignocellulose, the principal component of its bamboo diet. Microbes in the giant panda intestines help it digest cellulose and hemicellulose. So do they also help it digest lignin? Why, yes they do.

(2012) Evidence for Lignin Oxidation by the Giant Panda Fecal Microbiome. PLoS ONE 7(11): e50312. doi:10.1371/journal.pone.0050312 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0050312

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