Viral Dark Matter: We Do Not Know Anything
“The more I learn, the more I realize how much I don’t know”
When we think about viruses, we usually associate them with disease, but viruses are more than that. They are the most abundant entities on earth, with an estimated 10³¹ particles playing powerful roles in genome evolution and biogeochemical cycles, critical functions in the evolution and sustenance of life (Figure 1).
Edited from: Santiago-Rodriguez TM, Hollister EB. Unraveling the viral dark matter through viral metagenomics. Frontiers in Immunology. 2022;13:1005107. https://doi.org/10.3389/fimmu.2022.1005107
Furthermore, viruses have their own special place within the realm of Microbial Dark Matter, which is denominated Viral Dark Matter (see video for more information).
Viral dark matter is due to the fact that most viral sequences detected in nature cannot be linked to any known virus by eluding identification, cultivation, or classification. As of now, we have just scratched the surface of this vast realm, and understanding this hidden diversity promises to unveil insights into environmental stability, human health, and the evolutionary history of life.
Before the era of high-throughput sequencing, virology relied on traditional laboratory practices like culture techniques, electron microscopy, and serological assays, which set the foundation for most known and described viruses. However, millions of viruses still elude these classic methods, leaving us unaware of their existence. Furthermore, metagenomics approaches revealed that up to 99% of viral reads in some samples have no similarity to known viral genomes.
Figure 2. Quick Review of Metagenomics
Edited from: https://innovativegenomics.org/news/metagenomics-101-spencer-diamond/
Currently, pioneering studies are combining metagenomics with metaproteomics and transforming Viral Dark Matter data into meaningful biological data, like microbial host interactions and ecosystem dynamics. For example, studies like the one conducted by Brum et al. (2016) combined metagenomics with proteomic profiling to identify structural proteins from uncultivated marine viruses, discovering unknown viral proteins which helped to connect orphan genes to actual viral structures and infection mechanisms. Furthermore, other breakthroughs fueled by metagenomics, shedding light on Viral Dark Matter, have been able to identify human gut viruses like crAssphage, giant viruses like Mimivirus with genomes almost the size of bacteria, challenging the line between viral and cellular life, and have also been able to identify viral signatures almost everywhere on the planet. Referencing the opening quote of this blog, these findings show that the more we sequence, the more we realize how little we know about viruses, making this an exciting frontier to explore so we can learn more about life itself, since viruses hold secrets between cellular and acellular life.
However, as the amount of viromic data grows at a rate we cannot fully grasp, hope to decode these mysteries is not lost since we are in the era of artificial intelligence (AI) and deep learning tools, and these novel tools have shown prominent efficiency in decoding viromic data. For example, programs like DeepVirFinder and VIBRANT can accurately identify viral sequences from metagenomic datasets, even without close relatives in reference databases. They transform large amounts of data into meaningful biological information, enabling scientists to discover new viruses, predict host-virus interactions, and detect potential zoonotic threats before they arise.
Understanding Viral Dark Matter is more than just academic research since the implications of every discovery can reshape what we think we know about life, ecosystem dynamics, and evolution. This has been evident in human health, where many conditions may be influenced by undescribed viral communities of the human virome, as observed in inflammatory bowel disease (IBD), and the discovery of marine viruses and the role they play in climate change and biogeochemical cycles via viral shunting (Figure 3).
Figure 3: Viral Shunting
Edited from: 1. Marine Viruses: Submerged Players of Climate Change. ASM.org. https://asm.org:443/Articles/2023/June/Marine-Viruses-Submerged-Players-of-Climate-Chang
The exploration of Viral Dark Matter has just begun, and it is already reshaping the perception and knowledge we have of life, across every niche of the world, from the depths of the oceans to the human gut. As sequencing technologies and AI advance, our analysis tools improve, and we start to finally scratch the surface of this infinite realm, and understand that the most powerful forces acting to shape life on earth act unseen, waiting for us to discover them. Overall, unraveling Viral Dark Matter opens the doors to an infinite number of applications within every branch of the biological sciences and offers the opportunity to see viruses not only as pathogens but as ecological and genetic engineers that shape our world, redefining the future of biology.