Our Viral Inheritance
Damien Marsic
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Source: http://www.sciencemag.org/content/340/6134/820.full
Vol. 340 no. 6134 pp. 820-821
DOI: 10.1126/science.1235148
Our Viral Inheritance
+ Author Affiliations
- 1Division of Infection and Immunity, University College London, Gower Street, London WC1E 6BT, UK.
- 2Division of Virology, MRC National Institute of Medical Research, The Ridgeway, London NW7 1AA, UK.
- E-mail: rwe...@ucl.ac.uk; jst...@nimr.mrc.ac.uk
The enormous scale of the invasion of vertebrate genomes by viral sequences has become apparent through analyses of complete genomes. Sequences derived from many kinds of RNA (1) and DNA (2) viruses have found a convenient resting place in host genomes during evolution, and the process is ongoing. Retroviral genomes, the major and best understood viral insertions (3), alone account for 6 to 14% of the genomes analyzed to date, including ∼8% of human DNA. These endogenous retroviruses (ERVs) comprise more genomic DNA than that encoding the host proteome. The functionality or otherwise of this "junk" DNA has become the focus of an intense debate (4, 5). Here we consider a number of consequences of ERV acquisition (see the figure).
How do ERVs affect the host species in which they reside? In theory, the consequences of ERV acquisition may be neutral, detrimental, or beneficial depending on the particular ERV and its integration site. Endogenous retroviruses can serve as a long-lasting viral reservoir and provide evidence for coexistence between retroviruses, in essentially modern form, and their hosts going back many millions of years (6). ERV expression is tightly regulated (7). Even though most ERVs are defective, some maintain their replicative capacity and can reemerge as infectious agents many generations later. Defective ERVs can also recombine to generate an infectious virus (8).
In the coevolutionary interplay between virus and host, the host has developed various strategies to dampen down the efficient replication of activated ERV. These include intracellular restriction factors (3) and mutation of host cell surface receptors (9) so that any reactivated virus can only infect other species, a phenomenon called xenotropism. Examples are retroviruses of gibbons and koalas that are derived from a rodent ERV and which cause leukemia in their new hosts. Moreover, the koala virus is currently colonizing the germ line as a new ERV (10). Thus, a virus embedded in the chromosomes of one host species without causing apparent harm can trigger a potentially devastating epidemic in another.
When the proviral DNA of a retrovirus integrates into germ-line DNA of the host, it becomes inherited alongside all host DNA sequences. The provirus may remain dormant or may be expressed in the ways indicated.
Retroviral insertion adds DNA to the host genome and may affect the control of host RNA transcription, splicing, or stability through viral signals. Insertion into essential genes may be deleterious but is unlikely to be important on an evolutionary time scale, with affected individuals rapidly lost by selection.
The inserted promoter and enhancer sequences in the long terminal repeat regions of ERV genomes may affect the expression of adjacent host genes. This is a well-known mechanism of activation of cellular genes in retroviral oncogenesis. It may also be important for generating novel patterns of gene expression through introduction of viral promoters or other regulatory sequences (1). For example, the tissue-specific expression of human salivary amylase is controlled by an ERV insertion (11) that may have helped our forebears to switch from a mainly fruit-based diet to one containing starch. Further, tight coexpression of the human endogenous retrovirus H (HERV-H) family with transcription factors for pluripotent human embryonic stem cells indicates that HERV-H may contribute to pluripotency (12).
Perhaps the most intriguing example of a useful ERV comes with the expression of ERV envelope glycoproteins in the placenta (13, 14), where cell fusion occurs in the trophoblast layer. The function of glycoproteins of enveloped viruses is to bind to target cells and effect fusion of the viral envelope with the host cell membrane. The fusion mechanism of ERV glycoproteins has been purloined on independent occasions by various orders of placental mammals to form the syncytiotrophoblast, and these viral glycoproteins are therefore called syncytins. Studies of knockout mice reveal that these genes are essential for placenta formation. As well as inducing cell-to-cell fusion, syncytins may locally suppress immune recognition at the maternal-fetal interface, implying a possible mechanism by which a mother is tolerant to the fetus(es) she carries (14).
The studies of syncytin show that big science and small science have complementary benefits. Mining the ever-expanding sequence and expression databases to identify ERVs that play interesting biological roles will continue to be of great importance as different ERVs can be deleterious or useful to the host. However, targeted studies of specific ERVs, like the ones encoding syncytins (15), will be required for testing the hypotheses generated by systems biology. There may well be other functions to be discovered, as well as further examples of gene regulation controlled by ERVs.
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