Retroviral integrations contribute to elevated host cancer rates during germline invasion

AbstractRepeated retroviral infections of vertebrate germlines have made endogenous retroviruses ubiquitous features of mammalian genomes. However, millions of years of evolution obscure many of the immediate repercussions of retroviral endogenisation on host health. Here we examine retroviral endogenisation during its earliest stages in the koala (Phascolarctos cinereus), a species undergoing germline invasion by koala retrovirus (KoRV) and affected by high cancer prevalence. We characterise KoRV integration sites (IS) in tumour and healthy tissues from 10 koalas, detecting 1002 unique IS, with hotspots of integration occurring in the vicinity of known cancer genes. We find that tumours accumulate novel IS, with proximate genes over-represented for cancer associations. We detect dysregulation of genes containing IS and identify a highly-expressed transduced oncogene. Our data provide insights into the tremendous mutational load suffered by the host during active retroviral germline invasion, a process repeatedly experienced and overcome during the evolution of vertebrate lineages.

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Molecular Diagnosis of Koala Retrovirus (KoRV) in South Australian Koalas (Phascolarctos cinereus)

Animals ◽

10.3390/ani11051477 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1477

Author(s):

Tamsyn Stephenson ◽

Natasha Speight ◽

Wai Yee Low ◽

Lucy Woolford ◽

Rick Tearle ◽

...

Keyword(s):

South Australia ◽

Rna Seq ◽

High Complexity ◽

Phascolarctos Cinereus ◽

Viral Loads ◽

Lymphoid Neoplasia ◽

Central Regions ◽

Almost All ◽

Retroviral Infections ◽

Koala Retrovirus

Koala retrovirus, a recent discovery in Australian koalas, is endogenised in 100% of northern koalas but has lower prevalence in southern populations, with lower proviral and viral loads, and an undetermined level of endogenisation. KoRV has been associated with lymphoid neoplasia, e.g., lymphoma. Recent studies have revealed high complexity in southern koala retroviral infections, with a need to clarify what constitutes positive and negative cases. This study aimed to define KoRV infection status in Mount Lofty Ranges koalas in South Australia using RNA-seq and proviral analysis (n = 216). The basis for positivity of KoRV was deemed the presence of central regions of the KoRV genome (gag 2, pol, env 1, and env 2) and based on this, 41% (89/216) koalas were positive, 57% (124/216) negative, and 2% inconclusive. These genes showed higher expression in lymph node tissue from KoRV positive koalas with lymphoma compared with other KoRV positive koalas, which showed lower, fragmented expression. Terminal regions (LTRs, partial gag, and partial env) were present in SA koalas regardless of KoRV status, with almost all (99.5%, 215/216) koalas positive for gag 1 by proviral PCR. Further investigation is needed to understand the differences in KoRV infection in southern koala populations.

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Tracking interspecies transmission and long-term evolution of an ancient retrovirus using the genomes of modern mammals

eLife ◽

10.7554/elife.12704 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 13

Author(s):

William E Diehl ◽

Nirali Patel ◽

Kate Halm ◽

Welkin E Johnson

Keyword(s):

Fossil Record ◽

Viral Infections ◽

Endogenous Retroviruses ◽

Interspecies Transmission ◽

Viral Spread ◽

Protein Functions ◽

History Of ◽

Mammalian Genomes ◽

Retroviral Infections

Mammalian genomes typically contain hundreds of thousands of endogenous retroviruses (ERVs), derived from ancient retroviral infections. Using this molecular 'fossil' record, we reconstructed the natural history of a specific retrovirus lineage (ERV-Fc) that disseminated widely between ~33 and ~15 million years ago, corresponding to the Oligocene and early Miocene epochs. Intercontinental viral spread, numerous instances of interspecies transmission and emergence in hosts representing at least 11 mammalian orders, and a significant role for recombination in diversification of this viral lineage were also revealed. By reconstructing the canonical retroviral genes, we identified patterns of adaptation consistent with selection to maintain essential viral protein functions. Our results demonstrate the unique potential of the ERV fossil record for studying the processes of viral spread and emergence as they play out across macro-evolutionary timescales, such that looking back in time may prove insightful for predicting the long-term consequences of newly emerging viral infections.

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Mobilization of Endogenous Retroviruses in Mice after Infection with an Exogenous Retrovirus

Journal of Virology ◽

10.1128/jvi.01926-08 ◽

2008 ◽

Vol 83 (6) ◽

pp. 2429-2435 ◽

Cited By ~ 22

Author(s):

Leonard H. Evans ◽

A. S. M. Alamgir ◽

Nick Owens ◽

Nick Weber ◽

Kimmo Virtaneva ◽

...

Keyword(s):

Germ Line ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Gene Sequences ◽

Endogenous Viruses ◽

Mammalian Genomes ◽

Leukemia Viruses ◽

Retroviral Infections ◽

Ecotropic Virus ◽

Rna Transcript

ABSTRACT Mammalian genomes harbor a large number of retroviral elements acquired as germ line insertions during evolution. Although many of the endogenous retroviruses are defective, several contain one or more intact viral genes that are expressed under certain physiological or pathological conditions. This is true of the endogenous polytropic retroviruses that generate recombinant polytropic murine leukemia viruses (MuLVs). In these recombinants the env gene sequences of exogenous ecotropic MuLVs are replaced with env gene sequences from an endogenous polytropic retrovirus. Although replication-competent endogenous polytropic retroviruses have not been observed, the recombinant polytropic viruses are capable of replicating in numerous species. Recombination occurs during reverse transcription of a virion RNA heterodimer comprised of an RNA transcript from an endogenous polytropic virus and an RNA transcript from an exogenous ecotropic MuLV RNA. It is possible that homodimers corresponding to two full-length endogenous RNA genomes are also packaged. Thus, infection by an exogenous virus may result not only in recombination with endogenous sequences, but also in the mobilization of complete endogenous retrovirus genomes via pseudotyping within exogenous retroviral virions. We report that the infection of mice with an ecotropic virus results in pseudotyping of intact endogenous viruses that have not undergone recombination. The endogenous retroviruses infect and are integrated into target cell genomes and subsequently replicate and spread as pseudotyped viruses. The mobilization of endogenous retroviruses upon infection with an exogenous retrovirus may represent a major interaction of exogenous retroviruses with endogenous retroviruses and may have profound effects on the pathogenicity of retroviral infections.

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Origin and recent expansion of an endogenous gammaretroviral lineage in canids

10.1101/414607 ◽

2018 ◽

Author(s):

Julia V. Halo ◽

Amanda L. Pendleton ◽

Abigail S. Jarosz ◽

Robert J. Gifford ◽

Malika L. Day ◽

...

Keyword(s):

Canis Lupus ◽

Sequence Variation ◽

Sequence Data ◽

Endogenous Retroviruses ◽

Domestic Dog ◽

Whole Genome Sequence ◽

Canis Lupus Familiaris ◽

Origin And Evolution ◽

Mammalian Genomes ◽

Retroviral Infections

AbstractMammalian genomes contain a fossilized record of ancient retroviral infections in the form of endogenous retroviruses (ERVs). We used whole genome sequence data to assess the origin and evolution of the recently active ERV-Fc gammaretroviral lineage based on the record of past infections retained in the genome of the domestic dog,Canis lupus familiaris.We identified 165 loci, including 58 insertions absent from the dog reference assembly, and characterized element polymorphism across 332 canids from nine species. Insertions were found throughout the dog genome including within and near gene models. Analysis of 19 proviral sequences identified shared disruptive mutations indicating defective proviruses were spread via complementation. The patterns of ERV polymorphism and sequence variation indicate multiple circulating viruses infected canid ancestors within the last 20 million to within 1.6 million years with a recent bust of germline invasion in the lineage leading to wolves and dogs.

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Degradation and remobilization of endogenous retroviruses by recombination during the earliest stages of a germ-line invasion

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1807598115 ◽

2018 ◽

Vol 115 (34) ◽

pp. 8609-8614 ◽

Cited By ~ 15

Author(s):

Ulrike Löber ◽

Matthew Hobbs ◽

Anisha Dayaram ◽

Kyriakos Tsangaras ◽

Kiersten Jones ◽

...

Keyword(s):

Germ Line ◽

New South ◽

New South Wales ◽

Endogenous Retroviruses ◽

Phascolarctos Cinereus ◽

Recombinant Viruses ◽

South Wales ◽

Geographic Distributions ◽

Koala Retrovirus

Endogenous retroviruses (ERVs) are proviral sequences that result from colonization of the host germ line by exogenous retroviruses. The majority of ERVs represent defective retroviral copies. However, for most ERVs, endogenization occurred millions of years ago, obscuring the stages by which ERVs become defective and the changes in both virus and host important to the process. The koala retrovirus, KoRV, only recently began invading the germ line of the koala (Phascolarctos cinereus), permitting analysis of retroviral endogenization on a prospective basis. Here, we report that recombination with host genomic elements disrupts retroviruses during the earliest stages of germ-line invasion. One type of recombinant, designated recKoRV1, was formed by recombination of KoRV with an older degraded retroelement. Many genomic copies of recKoRV1 were detected across koalas. The prevalence of recKoRV1 was higher in northern than in southern Australian koalas, as is the case for KoRV, with differences in recKoRV1 prevalence, but not KoRV prevalence, between inland and coastal New South Wales. At least 15 additional different recombination events between KoRV and the older endogenous retroelement generated distinct recKoRVs with different geographic distributions. All of the identified recombinant viruses appear to have arisen independently and have highly disrupted ORFs, which suggests that recombination with existing degraded endogenous retroelements may be a means by which replication-competent ERVs that enter the germ line are degraded.

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Using non-invasive sampling methods to determine the prevalence and distribution of Chlamydia pecorum and koala retrovirus in a remnant koala population with conservation importance

Wildlife Research ◽

10.1071/wr17184 ◽

2018 ◽

Vol 45 (4) ◽

pp. 366 ◽

Cited By ~ 1

Author(s):

Faye Wedrowicz ◽

Jennifer Mosse ◽

Wendy Wright ◽

Fiona E. Hogan

Keyword(s):

Native Species ◽

Conservation Strategies ◽

The South ◽

Phascolarctos Cinereus ◽

Urogenital Infection ◽

Non Invasive ◽

Chlamydia Pecorum ◽

Genetic Sampling ◽

Pathogen Prevalence ◽

Koala Retrovirus

Context Pathogenic infections are an important consideration for the conservation of native species, but obtaining such data from wild populations can be expensive and difficult. Two pathogens have been implicated in the decline of some koala (Phascolarctos cinereus) populations: urogenital infection with Chlamydia pecorum and koala retrovirus subgroup A (KoRV-A). Pathogen data for a wild koala population of conservation importance in South Gippsland, Victoria are essentially absent. Aims This study uses non-invasive sampling of koala scats to provide prevalence and genotype data for C. pecorum and KoRV-A in the South Gippsland koala population, and compares pathogen prevalence between wild koalas and koalas in rescue shelters. Methods C. pecorum and KoRV-A provirus were detected by PCR of DNA isolated from scats collected in the field. Pathogen genetic variation was investigated using DNA sequencing of the C. pecorum ompA and KoRV-A env genes. Key results C. pecorum and KoRV-A were detected in 61% and 27% of wild South Gippsland individuals tested, respectively. KoRV-A infection tended to be higher in shelter koalas compared with wild koalas. In contrast with other Victorian koala populations sampled, greater pathogen diversity was present in South Gippsland. Conclusions In the South Gippsland koala population, C. pecorum is widespread and common whereas KoRV appears less prevalent than previously thought. Further work exploring the dynamics of these pathogens in South Gippsland koalas is warranted and may help inform future conservation strategies for this important population. Implications Non-invasive genetic sampling from scats is a powerful method for obtaining data regarding pathogen prevalence and diversity in wildlife. The use of non-invasive methods for the study of pathogens may help fill research gaps in a way that would be difficult or expensive to achieve using traditional methods.

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Molecular fossils illuminate the evolution of retroviruses following a macroevolutionary transition from land to water

PLoS Pathogens ◽

10.1371/journal.ppat.1009730 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009730

Author(s):

Jialu Zheng ◽

Jianhua Wang ◽

Zhen Gong ◽

Guan-Zhu Han

Keyword(s):

Phylogenetic Analyses ◽

Endogenous Retroviruses ◽

Integration Time ◽

Aquatic Environments ◽

Ongoing Activity ◽

Aquatic Life ◽

Origin And Evolution ◽

Molecular Fossils ◽

Retroviral Infections

The ancestor of cetaceans underwent a macroevolutionary transition from land to water early in the Eocene Period >50 million years ago. However, little is known about how diverse retroviruses evolved during this shift from terrestrial to aquatic environments. Did retroviruses transition into water accompanying their hosts? Did retroviruses infect cetaceans through cross-species transmission after cetaceans invaded the aquatic environments? Endogenous retroviruses (ERVs) provide important molecular fossils for tracing the evolution of retroviruses during this macroevolutionary transition. Here, we use a phylogenomic approach to study the origin and evolution of ERVs in cetaceans. We identify a total of 8,724 ERVs within the genomes of 25 cetaceans, and phylogenetic analyses suggest these ERVs cluster into 315 independent lineages, each of which represents one or more independent endogenization events. We find that cetacean ERVs originated through two possible routes. 298 ERV lineages may derive from retrovirus endogenization that occurred before or during the transition from land to water of cetaceans, and most of these cetacean ERVs were reaching evolutionary dead-ends. 17 ERV lineages are likely to arise from independent retrovirus endogenization events that occurred after the split of mysticetes and odontocetes, indicating that diverse retroviruses infected cetaceans through cross-species transmission from non-cetacean mammals after the transition to aquatic life of cetaceans. Both integration time and synteny analyses support the recent or ongoing activity of multiple retroviral lineages in cetaceans, some of which proliferated into hundreds of copies within the host genomes. Although ERVs only recorded a proportion of past retroviral infections, our findings illuminate the complex evolution of retroviruses during one of the most marked macroevolutionary transitions in vertebrate history.

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MysTR: an Endogenous Retrovirus Family in Mammals That Is Undergoing Recent Amplifications to Unprecedented Copy Numbers

Journal of Virology ◽

10.1128/jvi.79.23.14698-14707.2005 ◽

2005 ◽

Vol 79 (23) ◽

pp. 14698-14707 ◽

Cited By ~ 15

Author(s):

Michael A. Cantrell ◽

Martina M. Ederer ◽

Issac K. Erickson ◽

Vicki J. Swier ◽

Robert J. Baker ◽

...

Keyword(s):

Repetitive Sequences ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

South American ◽

Coding Regions ◽

Copy Numbers ◽

Species Analysis ◽

Outgroup Species ◽

Mammalian Genomes ◽

Oryzomys Palustris

ABSTRACT A large percentage of the repetitive elements in mammalian genomes are retroelements, which have been moved primarily by LINE-1 retrotransposons and endogenous retroviruses. Although LINE-1 elements have remained active throughout the mammalian radiation, specific groups of endogenous retroviruses generally remain active for comparatively shorter periods of time. Identification of an unusual extinction of LINE-1 activity in a group of South American rodents has opened a window for examination of the interplay in mammalian genomes between these ubiquitous retroelements. In the course of a search for any type of repetitive sequences whose copy numbers have substantially changed in Oryzomys palustris, a species that has lost LINE-1 activity, versus Sigmodon hispidus, a closely related species retaining LINE-1 activity, we have identified an endogenous retrovirus family differentially amplified in these two species. Analysis of three full-length, recently transposed copies, called mysTR elements, revealed gag, pro, and pol coding regions containing stop codons which may have accumulated either before or after retrotransposition. Isolation of related sequences in S. hispidus and the LINE-1 active outgroup species, Peromyscus maniculatus, by PCR of a pro-pol region has allowed determination of copy numbers in each species. Unusually high copy numbers of approximately 10,000 in O. palustris versus 1,000 in S. hispidus and 4,500 in the more distantly related P.maniculatus leave open the question of whether there is a connection between endogenous retrovirus activity and LINE-1 inactivity. Nevertheless, these independent expansions of mysTR represent recent amplifications of this endogenous retrovirus family to unprecedented levels.

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Ancestral Mutations Acquired in Refrex-1, a Restriction Factor against Feline Retroviruses, during its Cooption and Domestication

Journal of Virology ◽

10.1128/jvi.01904-15 ◽

2015 ◽

Vol 90 (3) ◽

pp. 1470-1485 ◽

Cited By ~ 7

Author(s):

Jumpei Ito ◽

Takuya Baba ◽

Junna Kawasaki ◽

Kazuo Nishigaki

Keyword(s):

Field Model ◽

Leukemia Virus ◽

Endogenous Retroviruses ◽

Chimeric Virus ◽

Feline Leukemia Virus ◽

Domestic Cats ◽

Terminal Domain ◽

Viral Particles ◽

Triangular Relationships ◽

Retroviral Infections

ABSTRACTEndogenous retroviruses (ERVs) are remnants of ancestral retroviral infections of germ cells. Retroviral endogenization is an adaptation process for the host genome, and ERVs are gradually attenuated or inactivated by mutation. However, some ERVs that have been “domesticated” by their hosts eventually gain physiological functions, such as placentation or viral resistance. We previously reported the discovery of Refrex-1, a soluble antiretroviral factor in domestic cats that specifically inhibits infection by feline leukemia virus subgroup D (FeLV-D), a chimeric virus of FeLV, and a feline ERV, ERV-DC. Refrex-1 is a truncated envelope protein (Env) encoded by both ERV-DC7 and ERV-DC16 proviral loci. Here, we reconstituted ancestral and functional Env from ERV-DC7 and ERV-DC16 envelope genes (env) by inducing reverse mutations. Unexpectedly, ERV-DC7 and ERV-DC16 full-length Env (ERV-DC7 fl and ERV-DC16 fl), reconstructed by removing stop codons, did not produce infectious viral particles. ERV-DC7 fl and ERV-DC16 fl were highly expressed in cells but were not cleaved into surface subunits (SU) and transmembrane subunits, nor were they incorporated into virions. G407R/N427I-A429T and Y431D substitutions within the SU C-terminal domain of ERV-DC7 fl and ERV-DC16 fl, respectively, caused these dysfunctions. The residues glycine 407 and tyrosine 431 are relatively conserved among infectious gammaretroviruses, and their substitution causes the same dysfunctions as the tested retroviruses. Our results reveal that specific mutations within the SU C-terminal domain suppressed Env cleavage and incorporation into virions and indicate that these mutations contributed to the domestication of Refrex-1 through multistep events that occurred in the postintegration period.IMPORTANCEDomestic cats are colonized with various exogenous retroviruses (exRVs), such as feline leukemia virus (FeLV), and their genomes contain numerous ERVs, some of which are replication-competent proviruses. The feline hosts, exRVs, and ERVs have complicated genetic interactions and provide an interesting field model for triangular relationships: recombination between FeLV and ERV-DC, which is a feline ERV, generated FeLV-D, a chimeric virus, and FeLV-D is restricted by Refrex-1, an antiretroviral factor corresponding to truncated Env of ERV-DC7 and ERV-DC16. Here, we reconstructed ancestral, functional Env from ERV-DC7 and ERV-DC16envby inducing reverse mutations to elucidate how Refrex-1 was generated from its ancestor. Our results reveal that they were repeatedly inactivated by mutations preventing Env maturation. Our results provide insights into how ERVs were “domesticated” by their hosts and identify the mutations that mediated these evolutions. Notably, experiments that restore inactivated ERVs might uncover previously unrecognized features or properties of retroviruses.

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