Kwang Jeon is now a professor in the Department of Biochemistry in Tennessee and editor of the International Review of Cytology
. In 1966, when he was a postgraduate studying Amoeba proteus
at the State University of New York at Buffalo, his cultures of amoebae were invaded by a hitherto unknown bacterium (now labelled the x-bacterium). At first the plague seemed universally lethal. However, in the weeks that followed, a small minority of amoebae survived despite the presence of tens of thousands of bacteria permanently in their cytoplasm. Then, over the succeeding year of persistent infection, something very interesting was seen to develop. When Jeon used antibiotics to kill the cytoplasmic bacteria, the amoebae also died. If, on the other hand, he released the bacteria from their cytoplasmic confinement, the bacteria also failed to survive on culture media. The bacterium and amoeba had fused into a mutually interdependent new life form, now known as the x-amoeba.35
This union of two very different life forms is known as symbiosis. Over decades of study, Jeon has confirmed that the symbiotic union of x-bacterium and A. proteus
took place at genomic level.36
Jeon's observation shows how pandemic parasitism can 'cull' a host population (i.e. species gene pool) and then coevolve with the surviving residuum, to become a mutualism. It also shows us how the evolutionary force of symbiosis, known as symbiogenesis—gave rise to mitochondria and chloroplasts, making it possible for us to breathe oxygen and for plants to capture the energy of sunlight.37
Symbiogenesis is seen to begin with the random coming together of different life forms, bringing to the union very different pre-evolved abilities. Natural selection does not initiate the symbiotic union but it certainly influences the outcome. The evolutionary biologist John Maynard Smith saw a key difference between the way natural selection works in symbiogenesis and neo-Darwinian evolution. Rather than, or perhaps even in addition to, operating at individual (or single gene) level, in symbiogenesis selection acts at the level of the partnership, adapting it to a stable evolutionary strategy.38
This may help us to understand the nature of the interaction between human endogenous retroviruses and the rest of the human genome.
The integration of HERVs into the human genome was assumed to be irreversible. But in 2002 Medstrand and colleagues demonstrated that HERVs can in fact be removed, perhaps through chromosome deletions but more probably through sexual homologous recombination.3
The impressive accumulation of retroelements discovered on the Y chromosome supports the latter, since, as an unmatched chromosome, it is precluded from elimination of HERV elements through homologous allelic recombination. Why, then, have such vast numbers of HERVs and their fragments been retained? The explanation is likely to be multifactorial but mutualism might explain part of this enigma. In a mutualistic relationship, a virus that evolved in a detrimental way to its host would threaten the partnership, as would a host that changed in any way detrimental to the virus. Natural selection would select against these eventualities while selecting for changes that preserved and strengthened the relationship. The exogenous retrovirus that gave rise to the HERV-W endogenous family is believed to have entered the ancestral genome less than 40 million years ago. Bonnaud and his colleagues have tracked the action of natural selection on the HERV-W locus, ERVWE1 (whose env
gene codes for syncytin) in chimpanzee, gorilla, orangutan and gibbon, revealing a specific genetic signature crucial to the gene's fusogenic action that has been conserved by natural selection over the tens of millions of years of primate divergence.39
This is an important demonstration. It confirms Maynard Smith's prediction of natural selection working at the level of the partnership in a mutualistic symbiosis involving HERV-W and the human genome.
Symbiogenesis would also help explain several other observed features of HERVs, including the loss, over time, of their infectious independence. Natural selection would not be expected to preserve non-contributory genes in the HERV genomes. Our symbiotically derived human mitochondria have been whittled down, over two billion years of evolution, from an original complement of three thousand or so genes to thirty-seven in the mitochondria themselves and a few hundred that have moved to play a part in the nucleus.
Symbiogenesis needed to be clarified from a symbiological standpoint before it could be applied to HERVs. In my book, Darwin's Blind Spot, I redefined it as follows:
'Symbiogenesis is evolutionary change arising from the interaction of dissimilar life forms. It takes two major forms: endosymbiosis, when the interaction is at the level of the genomes, and exosymbiosis, when the interaction may be behavioural or involve the sharing of metabolites, including gene-coded products.'36
De Bary's original definition of symbiosis included parasitism—indeed mutualism commonly derives from parasitism. It is thus inevitable that all HERVs begin their evolutionary association with the human genome as parasitic symbionts. Most, if not all, have lost this parasitic potential, though a few, as we have seen, retain infectivity in a much attenuated fashion. A conundrum at present unanswerable is how many of the vast numbers of HERVs in the human genome have evolved to mutualism. The evolution of mutualistic symbiosis can be analysed on a cost–benefit basis, according to the contributing traits of the participating partners.40
What is cheap to produce for one partner is expensive or impossible for the other, and vice versa. This is what gives mutualistic symbiosis such powerful evolutionary potential. Our human cells, for example, cannot readily form syncytia. The retrovirus HERV-W joined the symbiotic partnership with the pre-evolved ability to offer this, and perhaps several other useful potentials. What then does the human genome offer the virus in return? The answer would appear to be immortality, though at a price. As we observed in the symbiogenetic creation of the x-amoeba, what began as independent interacting partners are honed by natural selection into a single genomic union in which the continuing interaction is no longer at the level of individual life-forms but their contributing individual genes or genetic derivatives: the HERVs in our genome have lost the ability to survive independently, but their removal from our genome would also make us extinct.
This mutualistic interpretation has received important confirmation from an independent series of investigations by Villarreal, who has concluded, from phylogenetic analysis of viral and host lineages, that 80% of viral genes have no counterparts in the eukaryotic genetic database. This contradicts an older view that retroviruses originated from eukaryotic genomes. Viruses are enormously creative in the manufacture of new genes, which they can contribute to their hosts in symbiotic unions. If Villarreal and his colleague DeFilippis are correct, one such viral contribution to the human lineage was a crucial group of DNA polymerases.41
Genomes have evolved several 'epigenetic' mechanisms to control gene expression. For example, methylation of genetic elements is one way in which a host genome can when necessary silence viral genes during development and normal metabolism. Over the past decade, a system known as RNA interference (RNAi) has emerged as another genomic mechanism for silencing unwanted gene expression—for example, of genes involved in cancer, AIDS and hepatitis. One such RNAi, which responds to the presence of double-stranded RNA genes, has been found to be important in controlling gene expression in humans as well as many other life forms and is likely to have arisen as a defence mechanism to combat invasion by double-stranded RNA viruses. In Villarreal's opinion, this shows such striking behavioural similarities to known viral systems that it may well have derived from another viral symbiosis—though its origin is far more ancient than that of human endogenous retroviruses. The American Society for Microbiology regards this subject of viral contribution to host evolution as so important that it has commissioned Villarreal to write a book to educate the next generation of scientists.42
Of course, many HERVs may not have evolved to mutualism. Moreover, even longstanding mutualistic symbioses can be damaged or disrupted. The bleaching of coral is an example of such a disruption to a hitherto evolutionary stable strategy. So too are the illnesses and genetic disorders linked to impaired function of human mitochondria.36
In 2001 Lee and colleagues found evidence that pre-eclampsia is accompanied by a substantial reduction in syncytin expression and its dislocation from its normal position in the syncytial tissues,43
observations that were confirmed by Knerr and colleagues.44
Since the expression and function of syncytin are reduced by hypoxia, the disturbance seen in pre-eclampsia might be secondary to poor placental perfusion;45
nevertheless, the same group suggests that pre-eclampsia may be viewed as an 'altered syncytin system'.46
That the link between syncytin and pre-eclampsia is still far from resolved reflects the very complex and dynamic nature of the mechanics involved in the single best understood HERV mutualism.
With the expansion of studies into the role of HERVs and their products in physiology and pathology, we can look forward to rapid progress in this extraordinary new chapter of biological and medical advance.