On version control

I was thinking about booting up a PC that I haven’t used, since, oh, 2003 or so. I was wondering what would happen. Rather than just finding out (and potentially losing all my files), I asked several of my computer science / hacker friends whether the ‘ancient’ operating system would essentially protect me from all the new-fangled viruses out there. Their answer: an emphatic ‘no.’ Apparently there is enough similarity between operating systems for many of the viruses and worms and malware in general to still take advantage of a machine whose virus protection software is itself now woefully out of date. One of my friends said I’d have to go back to at least DOS 5 to get any protection. So, the PC remains in my closet for the moment.

But this got me to thinking: what about our operating systems and the viruses that attack them? Is the co-evolution of organisms and their pathogens / parasites such that old versions of either are no longer capable of infecting the newer versions, or vice versa? For example, could a really old plague still do harm to the human population, a topic I have speculated wildly on elsewhere (http://ellingtonlab.org/blog/2011/03/09/on-paleovirology/).

But this raises the interesting question of version control: do new version viruses infect old version wetware? And how would you even install the old version wetware? It’s not like we do alot of genetic engineering of humans, sigh. It then occurred to me that we are different degrees of ‘old.’ We retain the genes of antiquity to varying degrees, even within a population that has largely at this point equilibrated. This has been most forcefully brought out by the idea that we are all to some degrees Neandertals, and that we have different percentages and types of Neandertal genes between us (http://www.livescience.com/42933-humans-carry-20-percent-neanderthal-genes.html). This might be the biggest version control jump of all: could a H. sapiens virus infect a Neandertal, and vice versa? Would there be an inherent genetic barrier, and might we still contain such a barrier?

I went to the literature on a lark, assuming that no one could have published anything relevant to this arcane speculation. However, as is usually the case when I doubt PubMed, that glorious gift of the NCBI to humankind, I was wrong.

“… we analyzed individual sequence reads used to assemble the published Neandertal and Denisovan genomes for insertions of Human Endogenous Retrovirus K (HERV-K) DNA. Virus-host junctions were identified that defined 14 proviruses where modern humans contain the corresponding, empty, preintegration site. Thus, HERV-K reinfected germ lineage cells of Neandertals and Denisovans multiple times, and these events occurred around the time or or subsequent to the divergence of the archaic hominin lineages from that leading to modern humans.” (Agoni et al., Current Biology (2012), 22:R437; http://www.ncbi.nlm.nih.gov/pubmed/22677281).

So, cool! Version control is not enough. At least one retrovirus was hopping and bopping around the genome before and after the divergence.

Or maybe it is, sometimes?

“… one provirus (HERV-K-Ne1 = HERV-K-De6) was detected in both Neandertals and Denisovans and not in modern humans ….”

Or maybe we just don’t know enough, as a follow-up paper by Marchi et al. (Current Biology (2013), 23:R994; http://www.ncbi.nlm.nih.gov/pubmed/24262833) suggests:

“… while searching many new genome sequences of modern humans for ERVs [endogenous retroviruses], we have found most of these loci. For example, of the eight Denisovan loci for which Agoni et al. were able to give precise genome coordinates, at least seven exist in modern humans.”

The ultimate explanation for these discrepancies may be that ERVs are far from fixed in the human population, and rise and fall due to population dynamics (“… many loci will have persisted at fluctuating frequencies in all three lineages [human, Neandertal, Denisovan].”).

So, ancient viruses are still likely infecting modern hosts, although this does not suggest that *an* actually ancient (reconstructed) virus *would* of necessity infect a modern host.

What about the converse? Could an old human be infected by a modern virus? This is a bit more difficult to get at, but once again there is a marvel of literature that suggests that “… Most simian immunoviruses (SIVs), including the direct precursor of HIV, use their Nef protein to antagonize BST2 of their respective host species. Human BST2m, however, contains a five amino acid deletion in its cytoplasmic domain that confers resistance to Nef …. Here, we show that this protective deletion has already been present in Neandertal and Denisovan BST2 …. This ancient origin helps to explain why effectively spreading zoonotic transmissions of SIVs to humans have been rare, although SIVs are widespread in African non-human primates and humans must have been exposed to these viruses many times.” (Suater et al., Human Mutation (2011), 32:1243; http://www.ncbi.nlm.nih.gov/pubmed/21796732).

This is impressive. With a tip ‘o the hat to some ancient hominid that survived a sweep (or was just bottlenecked otherwise), we get to live free of HIV-1 from 800,000 years ago to roughly 1959. This is all the more remarkable to me because of my great respect for viral evolution. Viruses create quasispecies that are constantly testing our defenses; viruses evolve way, way faster than we do. And yet we are able, for the most part, to hold them at bay, with some rare and intermittent exceptions (http://ellingtonlab.org/blog/2010/10/05/on-predicting-evolution/). This speaks to the power of complex systems. We may evolve slowly, but we have multiple layers of defenses that can be subtly altered to place us out of reach of the sleek-but-limited pathogens that are competing for our ATP. It’s like we have deep combination locks and viruses can only count to 10, quickly, over and over again. Sara Sawyer taught me that, but I don’t listen to her enough.

Still, as we continue to be challenged by the geovirome (I just made that word up … I think … ha, yes, even Google does not know this word) it might be useful to use the Neandertal / Denisovan portions of our genomes as convenient references for the relative susceptibility of individuals and populations. Just in case the viruses, like Spinal Tap, learn to count to 11.


- originally posted on Tuesday, September 30th, 2014