Figure 2.
Obelisks encode putatively well-folded proteins
a) Obelisk open reading frame 1 (Oblin-1) is predicted (total mean-pLDDT ± SD = 83.8 ± 13.4, see methods) to fold into a stereotyped N-terminal “globule” formed of a three alpha helix (orange) bundle partially wrapping around an orthogonal four helix bundle, capped with a beta sheet “clasp” (blue, globule mean-pLDDT = 90.1 ± 8.7), joined by an intervening region harbouring the conserved domain-A (magenta) with no predicted tertiary structure, to an arbitrarily placed C-terminal alpha helix. “Globule” emphasised on the right. b) a to-scale (secondary structure) topological representation of Oblin-1 with the “globule” shaded in grey, and the domain-A emphasised with this bit-score sequence logo (see methods). c) Obelisk Oblin-2 is confidently predicted (mean-pLDDT = 97.1 ± 4.6 ) to fold into an alpha helix which appears to be a leucine zipper. Sequence logo of an “i+7” leucine spacing emphasised in red, with hydrophobic “d” position residues emphasised in yellow (expanded in Supplementary Figure 4b). d) homo-multimer predictions of Obelisk-alpha Oblin-2. top: dimer (mean-pLDDT = 94.6 ± 0.6), bottom: trimer (mean-pLDDT = 93.6 ± 0.6). Side-on representations of homomultimers shown with numbers of inter-helix salt-bridges (see Supplementary Figure 5).
Obelisks encode putatively well-folded proteins
a) Obelisk open reading frame 1 (Oblin-1) is predicted (total mean-pLDDT ± SD = 83.8 ± 13.4, see methods) to fold into a stereotyped N-terminal “globule” formed of a three alpha helix (orange) bundle partially wrapping around an orthogonal four helix bundle, capped with a beta sheet “clasp” (blue, globule mean-pLDDT = 90.1 ± 8.7), joined by an intervening region harbouring the conserved domain-A (magenta) with no predicted tertiary structure, to an arbitrarily placed C-terminal alpha helix. “Globule” emphasised on the right. b) a to-scale (secondary structure) topological representation of Oblin-1 with the “globule” shaded in grey, and the domain-A emphasised with this bit-score sequence logo (see methods). c) Obelisk Oblin-2 is confidently predicted (mean-pLDDT = 97.1 ± 4.6 ) to fold into an alpha helix which appears to be a leucine zipper. Sequence logo of an “i+7” leucine spacing emphasised in red, with hydrophobic “d” position residues emphasised in yellow (expanded in Supplementary Figure 4b). d) homo-multimer predictions of Obelisk-alpha Oblin-2. top: dimer (mean-pLDDT = 94.6 ± 0.6), bottom: trimer (mean-pLDDT = 93.6 ± 0.6). Side-on representations of homomultimers shown with numbers of inter-helix salt-bridges (see Supplementary Figure 5).
At least with most of creationism's putative 'intelligent' designer, there is something that they appear to be for, other than simply reproducing themselves - even if it is, in the case of viruses and bacteria, increasing the suffering in the world by making other organisms sick.
But scientists have just discovered a small particle that seems to be in the edge of life, less so even than a virus, which doesn’t appear to do anything other than replicate, although it seems to need bacteria in which to do this. It’s not clear what harm it does to its bacterial host or even if it has some symbiotic function. But it appears to be almost everywhere, especially in our mouths and gut, where it appears to have speciated into several different forms. The team have named it 'obelisk' because it forms a rod-like shape.
It was discovered by a team of Stanford University researchers led by Andrew Z. Fire, a previous recipient of the 2006 Nobel Prize for Physiology or Medicine who have reported to have 'identified 29,959 Obelisks (clustered at 90% nucleotide identity), with examples from all seven continents and in diverse ecological niches'. Their report has been provided with free access ahead of peer-reviewed publication, in the preprint server, bioRxiv.
The question remains, what do these particles do exactly and are they potentially harmful, or are they beneficial in some way? At least one of their hosts in which they replicate is one of the bacteria responsible for the plaque on our teeth that is responsible for dental caries and gum disease that can result in lost teeth, Streptococcus sanguinis.
Like most viruses, obelisks are a single, circular strand of RNA, but unlike viruses, they don't have a protein coat. They have one and maybe two genes which code for proteins named 'oblins' which are unrelated to any other known proteins. In this respect they differ from other recently (1970) discovered free-living strands of RNA called viroids, which don't have any recognisable genes but are known to cause serious diseases in plants.
In the following article, reprinted from The Conversation under a Creative Commons license, Professor Ed Feil, Professor of Microbial Evolution at The Milner Centre for Evolution, University of Bath, explains the significance of this discovery. His article is reformatted for stylistic consistency:
A new virus-like entity has just been discovered – ‘obelisks’ explained
Ed Feil, University of Bath
Biological entities called obelisks have been hiding – in large numbers – inside the human mouth and gut. These microscopic entities, which were recently discovered by a team at Stanford University, are circular bits of genetic material that contain one or two genes and self-organise into a rod-like shape.
Although the study is still in preprint form, meaning that it has not been peer-reviewed, it has already been extensively written about, including in two heavyweight journals: Nature and Science.
Let’s delve deeper into the strange world of very tiny “lifeforms”.
In biology, as in physics, things can get weirder and the rules fuzzier as we move through smaller and smaller scales.
Viruses, being unable to replicate without the help of a host, can most generously be considered to be on the edge of what constitutes life. Yet the estimated 10 nonillion (one followed by 31 zeroes) individual viruses on the planet can be found in every conceivable habitat and, through infecting and manipulating their hosts, have probably affected the evolutionary trajectories of all life.
Peering even further down into the world of minuscule biological entities, are the viroids – tiny scraps of genetic material (DNA-like molecules known as RNA) that cannot make proteins and, unlike viruses, don’t have a protective shell to encase their genome.
Viroids are examples of ribozymes: RNA molecules that may be a distant echo of the very first self-replicating genetic elements from which cellular life emerged.
Viroids can self-cleave (chop up) and re-ligate (stick back together) their genome as part of the replication cycle. And, despite their simplicity, they can cause serious disease in flowering plants.
Between a virus and a viroid – perhaps
The new preprint describes “viroid-like colonists of human microbiomes”. If “viroid-like” sounds non-committal, that is entirely deliberate. The newly discovered biological entity falls somewhere between viruses and viroids.
In fact, the name obelisks was proposed not only because of their shape, but also to provide wiggle room in case they turn out to be more like RNA plasmids (a different type of genetic element that resides inside bacteria) than either viruses or viroids.
Like viroids, obelisks have a circular single-stranded RNA genome and no protein coat but, like viruses, their genomes contain genes that are predicted to code for proteins.
All obelisks so far described encode a single major protein known as obulin, and many encode a second, smaller obulin.
Obulins bear no evolutionary resemblance, or “homology”, to any other protein found, and there are few clues as to their function.
By analysing existing datasets taken from the gut and mouth of humans as well as other diverse sources, the Stanford team found almost 30,000 distinct obelisk types.
These obelisk genomes have been previously overlooked because they are so dissimilar to anything described previously. The Stanford team found them using a clever bespoke method for searching databases for single-stranded circular RNA molecules to fish out any viroid-like elements.
It is clear from their results that obelisks are not rare. The researchers found them in datasets spanning the globe and in diverse niches.
These elements were detected in around 7% of microbiome datasets from the human gut and 50% of datasets from the mouth. However, whether these datasets provide a true representation of the prevalence and distribution of obelisks is unclear.
Different obelisk types were found in different body sites and in different donors. Long-term data revealed that people can harbour a single obelisk type for around a year.
Obelisks probably rely on microbial host cells to replicate, including those that live inside humans to replicate. Bacteria or fungi are likely hosts, but it is not known which exact species harbour these elements.
However, the researchers provide a critical lead through the analysis by providing strong evidence that a common bacterial component of dental plaque, Streptococcus sanguinis, plays host to a specific obelisk type.
We might have to re-think the gut microbiome.
Friend or foe?
As S sanguinis is easy to grow and experiment on in the laboratory, this will provide a valuable model for understanding the fundamentals of obelisk biology.
This is critical, as nothing is known about the broader evolutionary and ecological significance of obelisks. They may be parasitic and harm host cells, or they may be beneficial.
Hosts may have evolved elaborate defence mechanisms against obelisks, or else actively recruit them to gain some unsuspected advantage. If obelisks change or upset the human microbiome, this may in turn have implications for human health – they may even have therapeutic potential.
Alternatively, obelisks may cause neither harm nor benefit to their microbial host, or to humans. Instead, they may simply exist as stealthy evolutionary passengers, silently and endlessly replicating, like the original “selfish gene”.
Ed Feil, Professor of Microbial Evolution at The Milner Centre for Evolution, University of Bath
This article is republished from The Conversation under a Creative Commons license. Read the original article.
AbstractIt's fascinating to think that these could be descendants of the first self-catalysing RNA replicators from which all life on Earth is thought to have evolved, but if it turns out they are beneficial to S. sanguinis, they are implicated in causing dental caries and the gum disease that can cause tooth loss, in which case, aficionados of creationism's malevolent designer won't be in the least surprised. They could also share a common ancestor with viruses.
Here, we describe the “Obelisks,” a previously unrecognised class of viroid-like elements that we first identified in human gut metatranscriptomic data. “Obelisks” share several properties: (i) apparently circular RNA ∼1kb genome assemblies, (ii) predicted rod-like secondary structures encompassing the entire genome, and (iii) open reading frames coding for a novel protein superfamily, which we call the “Oblins”. We find that Obelisks form their own distinct phylogenetic group with no detectable sequence or structural similarity to known biological agents. Further, Obelisks are prevalent in tested human microbiome metatranscriptomes with representatives detected in ∼7% of analysed stool metatranscriptomes (29/440) and in ∼50% of analysed oral metatranscriptomes (17/32). Obelisk compositions appear to differ between the anatomic sites and are capable of persisting in individuals, with continued presence over >300 days observed in one case. Large scale searches identified 29,959 Obelisks (clustered at 90% nucleotide identity), with examples from all seven continents and in diverse ecological niches. From this search, a subset of Obelisks are identified to code for Obelisk-specific variants of the hammerhead type-III self-cleaving ribozyme. Lastly, we identified one case of a bacterial species (Streptococcus sanguinis) in which a subset of defined laboratory strains harboured a specific Obelisk RNA population. As such, Obelisks comprise a class of diverse RNAs that have colonised, and gone unnoticed in, human, and global microbiomes.
Introduction
RNA viruses (Riboviria) are in part defined by their encoding of their own replicative polymerases, a feature that can be leveraged for homology-based viral discovery 1–5. By contrast, viroids 6,7 and Hepatitis Delta-like viral (HDV) ‘satellites’ 8 (Supplementary Figure 1) co-opt eukaryotic host RNA polymerases for their replication, resulting in some of biology’s smallest known genomes (viroids: ∼350 nt; Delta: ∼1.7 kb). These streamlined genomes define the working limits of biological information transfer 9,10, and their simplicity raises the question of why, compared to Riboviria, there are so few known examples of viroids and similar agents. Recently, enquiries based on protein similarity have uncovered new Delta-like agents 2,11. Likewise, viroids, which lack any protein-coding capacity, are beginning to be surveyed at a larger scale based in part on circular genome maps and the presence of ribozyme-like features. These searches have led to an expanded family of known viroid-like RNAs and a revision of earlier models that their distribution is limited to plants 12–14. As such, these studies have already shifted virological paradigms, leaving open the possibility that an even broader category of viroid-like elements are present in living systems that might have been overlooked due to a lack of detectable similarity to known viroids and HDV family members.
The human gut microbiome (hGMB) is experimentally attractive for discovery of novel genetic agents. Indeed, metagenomic and metatranscriptomic 15 profiling of the hGMB has yielded new insights into prokaryotic, viral 16–18, and plasmid 19 ecology. To this end, we developed a reference-free bioinformatic approach (VNom) to identify novel viroid-like elements. We initially applied VNom to published Integrative Human Microbiome Project (iHMP) data 20 resulting in the identification of a new class of hGMB-colonising RNA agents, which we term ‘Obelisks’. Obelisks form a distinct phylogenetic group restricted to RNA datasets and lack any evident homology to characterised genomes or viromes. Obelisk RNA reads assemble into ∼1000 nt circles, which are predicted to fold into rod-like RNA secondary structures and code for at least one member of a novel “Oblin” protein superfamily. We further found that a subset of Obelisks harbour Obelisk-specific hammerhead ribozyme motifs. Querying 5.4 million public sequencing datasets, we identified 29,959 distinct Obelisks (90 % ID threshold) present across ∼220,000 datasets representing diverse ecosystems beyond the hGMB. Amongst the datasets with clear Obelisk representatives, we identified a definitive Obelisk-Host pair, with Streptococcus sanguinis acting as a replicative host. Lastly, we surveyed Obelisks in five published human oral and gut microbiome studies from 472 donors, finding an estimated ∼9.7 % donor prevalence within these datasets, with an apparent anatomy-specific Obelisk distribution.
Figure 4.
Obelisks form a self-consistent set
Predicted Obelisk secondary structures depicted as “jupiter” plots where chords represent predicted basepairs (coloured by basepair probability from 0, grey, to 1, red, see methods) with predicted open reading frames (ORFs, preceded by predicted Shine-Delgarno sequences, purple) depicted: Oblin-1 (green), Oblin-2 (yellow, based on blastp hits against the Oblin-2 consensus), and “2ndORF” (orange). Obelisk-ɣ’s suggested CRISPR spacer match illustrated in light blue. ColabFold predictions of Oblin-1 tertiary “globule” structures built with ad hoc multiple sequence alignment (MSA) construction (coloured cartoons) superimposed over the RDVA-derived MSA prediction for Obelisk-α where possible (black line, Figure 2a, see methods). Prediction confidence (pLDDT) shown as cartoon colouring as in Supplementary Figure 3. Greek letter key: α : alpha, β : beta, γ : gamma, δ : delta, ε : epsilon, ζ : zeta, η : eta, θ : theta, ι : iota, κ : kappa, λ : lambda, μ : mu, ν : nu, and ξ : xi.
Ivan N. Zheludev, Robert C. Edgar, Maria Jose Lopez-Galiano, Marcos de la Peña, Artem Babaian, Ami S. Bhatt, Andrew Z. Fire
Viroid-like colonists of human microbiomes
bioRxiv 2024.01.20.576352; doi: https://doi.org/10.1101/2024.01.20.576352
Copyright: © 2024 The authors.
Published by BioRxiv. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
For creationists, who dogma dictates that they can't attribute to evolution but must credit their assumed supernatural deity for creating them, there remains the problem of explaining the intelligence behind creating something that appears to do nothing, other than produce copies of itself - which of course is ultimately true of all forms of life.
The Unintelligent Designer: Refuting The Intelligent Design Hoax
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
Available in Hardcover, Paperback or ebook for Kindle
The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
Illustrated by Catherine Webber-Hounslow.
Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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