Endogenous retroviruses in primates

Abstract

Numerous endogenous retroviruses\r(ERVs) are found in all mammalian genomes, for \rexample, they are the source of approximately 8% of\rall\rhuman and chimpanzee \rgenetic material. These insertions represent retroviruses which have, by chance, \rintegrated into the germline and so are transmitte\rd vertically from parents to \roffspring.\rThe human genome is rich in ERVs, which have been characterised in some \rdetail.\rHowever, \rin many non\r-\rhuman primates these insertions have not been well\r-\rstudied. \rERVs are subject to the mutation rate of the\rir\rhost, r\rather than the\rfaster retro\rvirus\rmutation rate\r, so they change much more slowly than exogenous retroviruses.\rThis \rmeans ERVs provide a snapshot of the retroviruses a host has been exposed to during \rits evolutionary history, including retroviruses which are\rno longer circulating and for \rwhich sequence information would otherwise be lost.\rERVs have many effects on their \rhosts; they can be co\r-\ropted for functional roles, they provide regions of sequence \rsimilarity where mispairing can occur, their insertion can\rdisrupt genes and they \rprovide regulatory elements for existing genes.\rAccurate annotation and \rcharacterisation of these regions is an important step in interpreting the huge amount \rof genetic information available for increasing numbers of organisms.\rThis project represents an extensive study into the diversity of ERVs in the genomes of \rprimates and related ERVs in rodents. Lagomorphs (rabbits and hares) and tree \rshrews are also analysed, as the closest relatives of primates and rodents. The focus is \ro\rn groups of ERVs for which previous analyses are patchy or outdated, particularly in \rterms of their evolutionary history and possible transmission routes. A pipeline has \rbeen developed to comprehensively and rapidly screen genomes for ERVs and \rphylogenetic\ranalysis has been performed in order to characterise these ERVs.\rAlmost 200,000 ERV fragments, many of which have not previously been \rcharacterised, were identified using this pipeline, distributed across six retroviral \rgenera and 33 vertebrate genomes.\rT\rhese fragments were used to investigate several \rareas of interest: the potential origin of primate ERVs, in rodents or other hosts; the \rERV content of the less well\r-\rstudied primates; the endogenous lentiviruses; \rmammalian endogenous epsilonretroviruses and\rthe origin of pathogenic gibbon ape \rii\rleukaemia virus.\rLaboratory study was used to complement the bioinformatics \ranalysis where appropriate.\rThis analysis had several interesting outcomes.\rFirst, a novel endogenous member of \rthe lentivirus genus of retrov\riruses, which are rarely found in an endogenous form, \rwas identified in the bushbaby \rGalago moholi\r.\rThis ERV may represent an ancient \rancestor of modern \rhuman immunodeficiency virus (\rHIV\r)\r, as it is the oldest member \rof the lentivirus genus (the genus which\rHIV belongs to) that has been identified in a \rprimate living on the African mainland, alongside the primate hosts where the HIV \rpandemic originated.\rThis ERV appears to have been transmitted between \rG. moholi \rand two species of Malagasy primate in the las\rt five million years, many millions of \ryears after these species have had any contact, suggesting that the virus has been \rtransmitted from one host to another via a third, vector species.\r(Hart et al., 1996)\rGibbon ape leukaemia virus was responsible for l\reukaemia and lymphoma in several \rgibbon\rcolonies \rduring the 1970s and has since then been thought of as a \rcirculating \rpathogen in this species. Using a combination of techniques we have \restablished \rthat \rthis virus\ris not a common pathogen of \rmodern gibbons\rand identified a route through \rwhich a single cross species transmission event from a rodent may have resulted in all \rknown cases of this disease worldwide.\rWe have also identified endogenous epsilonretroviruses, usually considered to be \rviruses of fish a\rnd amphibians, in all screened species of primates.\rBased on these \rresults, there is an ancient evolutionary relationship between epsilonretroviruses and \rprimates. As these viruses \ronce had\rthe potential to infect primates\rand\rare currently\rwidespread in f\rish, this result raises questions about the pathogenic potential of these \rviruses.\rMany other ERVs were identified\rin\rprimates, rodents and related species and we \rpropose a classification scheme for these viruses and use this scheme as a basis to \rexplore the ERV content of these hosts.\rUsing this technique, previously unknown \rERVs which are recombinant and which have the\rpotential to produce active viral \rparticles have been identified.