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Article

Patterns of Coevolutionary Adaptations across Time and Space in Mouse Gammaretroviruses and Three Restrictive Host Factors

by
Guney Boso
1,†,
Oscar Lam
1,†,
Devinka Bamunusinghe
1,‡,
Andrew J. Oler
2,
Kurt Wollenberg
2,
Qingping Liu
1,
Esther Shaffer
1 and
Christine A. Kozak
1,*
1
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
2
Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA
*
Author to whom correspondence should be addressed.
†
Co-equal first authors.
‡
Current address: Qiagen, Germantown, MD 20874, USA.
Viruses 2021, 13(9), 1864; https://doi.org/10.3390/v13091864
Submission received: 1 July 2021 / Revised: 4 September 2021 / Accepted: 15 September 2021 / Published: 18 September 2021
(This article belongs to the Special Issue RNA Viruses: Structure, Adaptation, and Evolution)
Browse Figures
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Abstract

:
The classical laboratory mouse strains are genetic mosaics of three Mus musculus subspecies that occupy distinct regions of Eurasia. These strains and subspecies carry infectious and endogenous mouse leukemia viruses (MLVs) that can be pathogenic and mutagenic. MLVs evolved in concert with restrictive host factors with some under positive selection, including the XPR1 receptor for xenotropic/polytropic MLVs (X/P-MLVs) and the post-entry restriction factor Fv1. Since positive selection marks host-pathogen genetic conflicts, we examined MLVs for counter-adaptations at sites that interact with XPR1, Fv1, and the CAT1 receptor for ecotropic MLVs (E-MLVs). Results describe different co-adaptive evolutionary paths within the ranges occupied by these virus-infected subspecies. The interface of CAT1, and the otherwise variable E-MLV envelopes, is highly conserved; antiviral protection is afforded by the Fv4 restriction factor. XPR1 and X/P-MLVs variants show coordinate geographic distributions, with receptor critical sites in envelope, under positive selection but with little variation in envelope and XPR1 in mice carrying P-ERVs. The major Fv1 target in the viral capsid is under positive selection, and the distribution of Fv1 alleles is subspecies-correlated. These data document adaptive, spatial and temporal, co-evolutionary trajectories at the critical interfaces of MLVs and the host factors that restrict their replication.

1. Introduction

The classical inbred strains of laboratory mice carry mouse leukemia viruses (MLVs) of three host range groups: ecotropic, xenotropic, and polytropic (E-MLVs, X-MLVs, P-MLVs) [1,2,3]. These gammaretroviruses are found either as infectious retroviruses (XRVs) or as endogenous retroviruses (ERVs), which are viral DNA copies inserted into host chromosomes during past infections. These inbred strains are intersubspecific hybrids of three house mouse subspecies, Mus musculus musculus, M. m. castaneus, and M. m. domesticus [4]. All of these subspecies carry MLVs; polytropic ERVs (P-ERVs) are predominate in Western European and North African M. m. domesticus, while xenotropic and ecotropic XRVs and ERVs (X- and E-MLVs) are found in Eurasian M. m. castaneus and M. m. musculus [5]. These subspecies, and the viruses they carry, likely originated in the Indian subcontinent and the neighboring Iranian plateau [6] but followed humans engaged in migration or trade and now have a global distribution with largely nonoverlapping geographic ranges in Eurasia that can be separated by defined hybrid zones [7].
The various laboratory strains and wild mouse subspecies differ in their susceptibility to MLVs, and to virus-induced disease, due to host factors that can inhibit virus replication at different stages of the virus life cycle, including entry, reverse transcription, transport to the nucleus, transcription, and budding [8]. Some of these factors have no known function other than virus restriction, while others serve important host functions that also facilitate virus replication but can have restrictive polymorphic variants. These factors act to mitigate the consequences of exposure to infectious and endogenous MLVs that can be pathogenic and mutagenic. Polymorphisms in these host restriction factors can alter virus restriction patterns, and viruses can acquire adaptive mutations at sites that interact with these antiviral host factors. This evolutionary “arms race”, described by the Red Queen hypothesis [9], notes that both the host and pathogen have to change continuously to keep up with the newly acquired antagonistic adaptations in their adversaries. This process has produced adaptive changes in the post-entry restriction factor Fv1 and in the XPR1 receptor for X/P-MLVs [10,11]. Both genes are under positive selection, in rodents, that is centered on sites critical for virus restriction. These analyses, however, present a limited picture of this host-pathogen co-evolutionary history as they have largely focused on the host partner in these conflicts.
The divergence of M. musculus, into subspecies that are geographically separated, also provides a unique opportunity to describe any phylogeographic evolutionary patterns in these viruses and host restriction factors. Antagonistic host-pathogen interactions can drive evolutionary changes on spatial, as well as temporal, scales, generating genetic diversity in physically separated populations. Coevolution can thus proceed along different trajectories in separated populations, creating distinctive geographic mosaics as described by the Geographic Mosaic Theory of Evolution [12].
Here, we focused our attention on the divergence of MLVs and ERVs in M. musculus, examining the capsid target of Fv1 and the receptor binding domains (RBDs) of X/P- and E-MLV envs, which utilize the XPR1 and CAT1 receptors, respectively. We looked for positive or purifying selection at these protein interfaces and for any previously overlooked restriction factor variants. We describe the geographic distribution of MLV env variants and Fv1 alleles in natural house mouse populations. We show evidence of reciprocal positive selection at the MLV sites that interact with Fv1 and the XPR1 receptor, but we find a “cold spot” in European M. m. domesticus where there is no obvious sign of conflict between the MLVs they harbor and XPR1. We also report that, despite extensive sequence variation in the E-MLV RBD, these MLVs show no adaptive changes in the receptor binding pocket nor is there variation in the receptor critical region of the M. musculus CAT1 suggesting that other factors, such as the Fv4 restriction gene in some virus-infected populations, help mitigate the consequences of infection.

2. Materials and Methods

2.1. Sources of Mouse DNAs and RNAs

Sources of mice and DNAs are listed in Table S1. Some DNAs were isolated from mice maintained in our laboratory or obtained from M. Potter (NCI, Bethesda, MD, USA) and from S. Rasheed (University of Southern California, Los Angeles, CA, USA). Additional DNAs from wild-caught or wild-derived mice were purchased from The Jackson Laboratory (Bar Harbor, ME, USA) and from RIKEN BioResource Center (Tsukuba, Japan) with assistance from Drs. Toshihiko Shiroishi and Takehide Murata, or were obtained from R. Abe (Naval Medical Research Institute, Bethesda, MD, USA) and from S. Chattopadhyay and H. Morse III (NIAID, Bethesda, MD, USA).

2.2. Primers, PCR, Cloning and Sequencing

Primers for PCR (Table S2) were designed to amplify the full-length or C-terminal half of Fv1, MLV subtype specific segments, and the full length CAT1 receptor or genomic CAT1 segments, including exons 3-5, which cover the receptor determining region. Selected PCR products were cloned into pCR2.1-TOPO (Thermo Fisher, Waltham, MA, USA) and sequenced (Datafile S1). Other sequences used for analysis included previously reported mouse ERVs and XRVs and genes for CAT1 and Fv1 from various Mus musculus subspecies and other rodents (Table S3) [13,14,15].

2.3. Identification of Variants in Fv1 and Slc7a1(CAT1) Genes in M. m. castaneus

Aligned sequence reads (BAM formatwere obtained for ten wild M. m. castaneus animals trapped in different locations in northwest India from Daniel Halligan and P. Keightley (University of Edinburgh) [16]. Reads were subset for the Fv1 and CAT1 genes using SAMtools (version 0.1.18) [17], coordinates chr4:147242588-147244967 or chr5:149138986-149211480 according to the mm9/NCBIM37 reference assembly. For Fv1, files for each strain were converted to FASTQ format with bam2fastx (from TopHat package [18]) and aligned to the reference using BWA MEM [19] (version 0.7.5a-r405) For both genes, duplicates were marked with MarkDuplicates (http://broadinstitute.github.io/, accessed on 22 December 2014; version 1.75), and variants were called using GATK (version 3.3) Best Practice methods [20,21,22], including indel realignment, single-sample calling with HaplotypeCaller and joint genotyping with GenotypeGVCFs. To further refine the indels at the C-terminus of Fv1, reads were assembled with SOAPdenovo2 [23] (version LINUX-generic-r240) with kmer setting ranging from 25 to 61 and resulting contigs with coverage > 1 were assembled using Lasergene SeqMan (DNASTAR, Inc, Madison, WI, USA). Variant effects were annotated using VEP [24] (archived tool at http://may2012.archive.ensembl.org/tools.html, accessed on 22 December 2014). Linkage/phasing of variants within a strain was determined by HaplotypeCaller or manual inspection of paired reads using IGV [25], SAMtools, and BLAT [26] at the UCSC Genome Browser (http://genome.ucsc.edu/, accessed on 22 December 2014) [27].

2.4. Identification of the Subspecies Origin of Fv1

We used the Mouse Phylogeny Viewer (MPV) at the University of North Carolina (http://msub.csbio.unc.edu, accessed on 14 March 2021) [28] to identify the subspecies of origin of Fv1 alleles using chromosome coordinates from the NCBI37/mm9 reference assembly. This browser uses a set of diagnostic single-nucleotide polymorphisms (SNPs) to define the local subspecific origin along each autosome and the X chromosome for a set of 100 classical laboratory strains and 98 wild-derived and wild-caught mice. MPV also identifies regions of haplotype identity for the inbred strains and the SNP variants that define those regions.

2.5. Phylogenetic and Positive Selection Analyses

The sequence of the Slc7a1 (CAT1) gene and segments of env and gag from E- and X/P-MLVs were aligned using MUSCLE as implemented in Geneious 10.0.9 using default settings [29,30]. Env genes were analyzed using a set of full-length genes as well as a larger set covering the RBDenv that includes newly sequenced wild mouse ERVs and previously published sequences [31]; the capsid analysis emphasized E-XRVs tested for Fv1 sensitivity. Phylogenetic trees were generated using the RaxML program with the GTR+G+I model and 500 bootstraps for branch support [32].
For maximum-likelihood analysis of codon evolution, we used codeml of PAML 4.9, in addition to four programs on the DataMonkey Web server: MEME, FUBAR, SLAC, and FEL [33,34]. Alignments for RBDenv of E-MLVs and the CAT1 genomic segments were trimmed to the shortest sequence and were manually inspected to exclude indels found in more than a few species, as recommended by the developers of PAML. Primer sequences used for amplification were excluded from the analysis. To calculate branch-specific dN/dS values, we utilized the free-ratio model in codeml of PAML, and to identify specific codons under positive selection, the F61 and F3x4 codon frequency models were used with different initial seed values of ω. Likelihood ratio tests were performed to compare two pairs of site-specific models: M1, a neutral model that does not allow positive selection, with M2, a model that allows positive selection; M7, another neutral model with beta distribution of dN/dS values, with M8, a positive-selection model with beta distribution. In each case, chi-square analysis was done, and a model that allowed positive selection was a significantly better fit to the data than the null (neutral) model (p < 0.05). Posterior probabilities of codons under positive selection were inferred using the BEB algorithm in the M8 model [35]. Alternative tests for positive-selection analyses used the MEME, FEL, SLAC, and FUBAR programs with recommended settings [36] and the positively selected residues with p < 0.1 were chosen.

3. Results and Discussion

3.1. E-MLVs and Their CAT1 Receptor

3.1.1. E-MLVs

E-MLVs infect cells of the mouse and some related rodents. Decades of studies identified three E-MLV env subtypes carried by laboratory and/or wild mice (AKV, Cas/Frg, HoMLV), and a fourth group consisting of the laboratory-derived FMR strains (Friend, Moloney, and Rauscher). E-MLV genomes appear to be recombinants with different E-MLV env genes embedded in non-ecotropic gag-pol backbones [15]. Despite their shared ecotropism, the surface (SU) domains of the env subtypes are only 66.4–77% identical, with similar identities in the RBD—the first 236 codons of the SU (Figure 1). While many of these subtype differences localize to the proline-rich region [15], most polymorphisms within RBD are concentrated in the VRA and VRB variable domains [37].
Here we typed a large panel of wild-caught and wild-derived mice (Table S1) by PCR to identify the presence and geographic distribution of AKV, Cas/Frg, and HoMLV ERVs. Primers were specific for the gag-pol and env regions of HoMLV, the env genes of AKV and Cas/Frg, and the virus-cell junction and empty insertion site of the Cas/Frg env, integrated at Fv4, a restriction factor that blocks E-MLV replication [38] (Table S2). Consistent with limited earlier analyses based on Southern blotting [5,39,40], E-ERV envs were restricted to some M. musculus subspecies indicating their recent acquisition (Figure 2). No mice carry HoMLV except the original source, the Eastern European mouse M. spicilegus, in which HoMLV did not endogenize [41], while the AKV, Cas/Frg, and Fv4 envs show broad, but distinctive, geographic distributions, although none are found in M. m. domesticus of Western Europe and North Africa (Figure 2). AKV E-ERVs, carried by many classical inbred strains [1,42], are found in M. m. musculus populations in southern China, Russia, and Korea, as well as Japan, where house mice are natural hybrids of M. m. musculus and M. m. castaneus and are often designated as a separate subspecies, M. m. molossinus [43]. Cas/FrgMLVs are found in Korea and SE China as well as the various countries of SE Asia (Figure 2).
The Cas/Frg-derived protective factor Fv4 is an expressed env gene carried by all mice from SE Asia, Eastern China, and Korea (Figure 2), indicating that this ERV was domesticated in M. m. castaneus. We also found this highly advantageous antiviral gene in about half of the mice sampled in Japan and in all seven of the mice trapped in Lake Casitas, CA. Fv4 is thus present where mice of two different subspecies were artificially introduced through commensalism: M. m. castaneus and M. m. musculus in Japan, and M. m. castaneus and M. m. domesticus in California [5,44]. Although effective against AKV MLVs in laboratory mice [45], Fv4 has not successfully crossed the hybrid zone separating M. m. castaneus and M. m. musculus in China, a barrier largely defined by the Yantgze River [46]. This suggests the possibility that AKV type E-MLVs are not a major survival threat in M. m. musculus, likely due to the fact that lymphomagenesis by E-MLVs requires recombination with P-ERVs [47], which are not carried by M. m. musculus [5]. The Cas/Frg E-MLVs present in California and M. m. castaneus can also induce neurological diseases without alteration by recombination [48], but they are subject to Fv4 restriction.
We sequenced env genes from various wild mice to screen for additional E-env variants. Sequence alignments and a phylogenetic tree of the env or RBD sequences show five clades with distinctive patterns of shared substitutions (Figure 3 and Figure S1); these clades correspond to the three known wild mouse subtypes and the FMR viruses, and they identify a novel AKV-related mouse subtype, AKCh E-MLV, found in mice trapped in regions occupied by M. m. castaneus in Wuhan, in the S. Central city of Lasa, near the western Chinese border and in Russia near the eastern Chinese border. In RBD, AKCh MLVs are 99% identical but 90% identical to AKV MLVs. The Cas/Frg env genes were found in M. m. castaneus and in mice trapped in S. California, and AKV MLV envs were identified in M. m. molossinus.
The N-terminal end of the MLV RBD containing VRA has been linked to receptor choice [37]. Virus entry into susceptible mouse cells is governed by seven RBD residues [49], three of which (S84, D86, W102) form a binding pocket for the CAT1 receptor [50]. Substitutions at six of these seven sites in FMR isolates can alter infectivity and/or induce cytopathic syncytia in some susceptible cells (Table 1).
Despite the extensive sequence variation in the E-MLV env genes, two of the three binding pocket residues, D86 and W102, are invariant in all naturally occurring env genes, while the third site shows the conservative substitution S84A in Cas/Frg E-MLVs; this substitution is also found in the FrMLV variant F-S MLV, where it modifies, but does not compromise, receptor use [51] (Table 1). The other sites that can influence virus entry show a few substitutions found in XRVs or that are lineage specific. S76 and/or S77 are deleted in MoMLV and HoMLV, and substitutions are found in the Cas E-MLVs (S76D, S77K). The only wild mouse virus substitution at E116 (E116G) is found in HoMLV, which is replication competent.
Two sets of env sequences, 11 full length and 28 segments of the RBDenv, were separately tested for evidence of diversifying/positive or purifying/negative selection, based on the ratio of the rate of nonsynonymous (dN) versus synonymous (dS) changes. Laboratory derived FMR strains were excluded from this analysis since their evolutionary path was likely different than the other groups. Using the maximum likelihood models in the codeml program of PAML4, and the MEME, FEL, FUBAR, and SLAC programs in the datamonkey webserver, we identified an excess of nonsynonymous mutations (dN/dS > 1, p < 0.1) at 26 sites scattered throughout the sequence, 15 of which were identified in the full env analysis, and 11 additional sites were found in the analysis based on RBD (Figure 4, Table S4). There are 14 of the 26 sites in the RBD, which includes VRA and VRB, with seven in VRA (Figure 4, Table S4), four of which form a patch surrounding the deletion, which alters MoMLV entry (Table 1), but none are at the residues that form the binding pocket. The various replacement mutations at all sites under positive selection are found in infectious E-MLVs.
These data show that the E-MLVs all use the CAT1 receptor but the extensive diversity among their env genes does not impact sites involved in virus entry. While it is possible the different env subtypes are independent acquisitions, it is more likely they derive from cumulative adaptations to their different mouse hosts, resulting in the emergence of three distinctive E-MLV envs in Eurasia and a fourth set of laboratory-derived FMR viruses. The limited historical record shows that FMR viruses were isolated from passaged tumors that probably arose in fancy mice carrying AKV E-MLVs; this virus was likely present in the fancy mouse progenitors of laboratory strains, which included the Japanese waltzer mouse [57]. These tumors had undergone forced passage through many mouse hosts for decades before virus isolation, the first report of which was by Gross in 1951 [58] who passed such tumors and tumor filtrates in mice as well as rats; this work inspired other investigators to attempt virus isolation from other transplantable tumors. MoMLV, for example, was isolated by John Moloney in 1960 [59] from Sarcoma 37, a tumor that had been passaged in mice since 1907 [60], before the development of inbred strains. Similarly, FrMLV was isolated by Charlotte Friend, in 1957, from an NIH Swiss mouse inoculated with Ehrlich ascites cells [61]. The env sequence variants in these FMR viruses were thus acquired over a short time frame. Similarly, in natural populations, the acquired changes in the Eurasian and FMR Env proteins differ from each other and from the Eastern European HoMLV. The evolutionary pressures responsible for the observed env variation are, therefore, unrelated to receptor interactions but may result from evasive changes in response to host immune defenses [62]. Env glycoproteins stud the outside of the virion and are thus vulnerable to host defenses, and the majority of sites under positive selection are in RBD, the most prominently exposed domain of the viral Env.

3.1.2. CAT1 Receptor

All E-XRVs use the CAT1 receptor, encoded by Slc7a1, and the active receptor sites have previously been localized to a patch of critical residues (232NVKYGE237) in the third of its seven extra cellular loops (ECL3) [63] (Figure 4). CAT1 is an amino acid transporter that functions as an E-XRV receptor only in Mus species and some other rodents, including rats and hamsters, where virus entry can be restricted by glycosylation [64,65]. The receptor critical region of CAT1 varies extensively between E-MLV susceptible and resistant species, as well as among susceptible rodent species, none of which has any obvious effect on transport function [66]. Two variants of the laboratory mouse receptor, mCAT1, have been found in wild mice. The M. dunni receptor, dCAT1, has an added residue in the receptor critical region (NVKYGGE) and its restriction of MoMLV is regulated by glycosylation [67]. A second variant, found in the African pygmy mouse M. minutoides, has a V233L replacement that has no effect on AKV MLV entry [68], although V233 has been assigned a role in virus entry and gp70 binding [69,70]. These two CAT1 variants are carried by mice that have had no known exposure to E-MLVs.
Few CAT1 genes carried by M. musculus had been characterized [49], so we examined CAT1 sequences from M. musculus subspecies, selected from widely separated geographic locations, including mice with and without E-ERVs. We identified no new variants in the CAT1 ECL3. Ten additional CAT1 genes, mined from the genomes of individually trapped M. m. castaneus mice, revealed that four are heterozygous for the V233L polymorphism (H12, H25, H24, H28) and two are homozygotes (H14, H26).
Evaluation of the rodent CAT1 for positive selection included sequences from various Mus species and other rodents (Table S3). The phylogenetic tree generated for this analysis showed strong bootstrap support in the vast majority of branches and revealed clustering of CAT1 sequences from the genus Mus and the subfamily Murinae, with a clear separation of the species in the different rodent suborders (Figure S2). This screen identified 14 sites under positive selection, including a cluster at the C-terminus of ECL3 with two sites, V233 and E237, which are within the patch implicated in virus entry (Figure 4, Table S4). Limiting the analysis to mice and hamsters, which are generally susceptible to E-MLV infection, identifies only five sites under positive selection, none of which is in ECL3. Thus, while two sites within the receptor critical region are under positive selection in the broader set of rodent species, sites important for E-XRV entry have remained unchanged in taxa exposed to virus challenge.
This analysis of E-MLVs and their CAT1 receptor in wild mice shows that, although E-MLVs are recently acquired and show substantial variation in env, their acquisition, spread, and rapid diversification has not altered the receptor interface in M. musculus. While this near absence of CAT1 polymorphism, in response to virus challenge, may reflect a relatively short evolutionary timeframe, a comparable time period produced multiple functional variants of the receptor used by the X/P-MLVs carried by these same mice (see below). One possible explanation for the failure of CAT1 to evolve in response to potentially lethal virus challenge is the presence of the Fv4 restriction factor in many E-MLV infected mouse populations (Figure 2). The Cas/Frg env inserted at this gene produces an Env glycoprotein, originally proposed to block exogenous infection by interference [38], and also has a fusion defect, so its incorporation into virions in virus-infected Fv4-positive mice results in entry defective virions [71]. The presence of this dispersed and highly effective Fv4 antiviral gene, in E-MLV infected wild mice, would thus decrease virus-directed selection pressure on CAT1. This also supports the suggestion that the extensive E-MLV env variation is unrelated to receptor interactions.

3.2. X/P-MLVs and Their XPR1 Receptor

The XPR1-dependent X/P-XRVs were initially distinguished as two host range groups: broad host range xenotropic XRVs (X-XRVs), otherwise unable to infect cells of most laboratory mice [72], and polytropic XRVs (P-XRVs) able to infect mice and other species [73]. These host range differences are due to polymorphisms in the viral env RBD and corresponding changes in the receptor determining regions of XPR1 [11].

3.2.1. XPR1

The functional variants and adaptive evolution of XPR1 have been described previously. To summarize: The X/P-XRVs use the XPR1 receptor to infect cells of M. musculus subspecies as well as all but a few other mammals [74]. XPR1 is a ubiquitously expressed phosphate exporter, and sequence variations in phylogenetically distinct species maintain exporter function [75]. Mus taxa carry six distinctive functional variants of Xpr1 [11], one of which, Xpr1sxv, is permissive, while the rest restrict different subsets of XPR1-dependent viruses. The permissive receptor, Xpr1sxv, predates the divergence of the house mouse subspecies and their acquisition of MLVs, and is retained exclusively by one subspecies, M. m. domesticus [11]. The five restrictive XPR1 receptor variants show a taxon-delimited distribution in Eurasian subspecies: M. m. musculus (Xpr1m), M. m. castaneus (Xpr1c, Xpr1c2), and M. m. molossinus (Xpr1m, Xpr1n) [76]. These variants are marked by alterations in two of the four putative XPR1 ECLs and include replacement mutations as well as three different but overlapping deletions [11,77]. Additional sequence variants found in M. tenellus, and in Iranian M. musculus, have not been tested for receptor function [11,14]. Phylogenetic analysis of the rodent Xpr1 showed it to be under positive selection, affecting key residues implicated in receptor function in ECL3 and ECL4 [11] (Figure 4).

3.2.2. X/P-MLVs

Compared to the E-MLVs, X/P-MLVs show considerably less overall sequence divergence in SU and RBD (>89.5%) (Figure 5a), but at least six X-XRV isolates have been described that differ in their ability to use the restrictive XPR1 variants [78]. While the critical Env residues involved in XPR1 receptor interactions have not been identified, receptor choice has been mapped to the VRA variable domain in the RBD [37]. The VRA differs in sequence and size among infectious X/P-XRVs; relative to P-XRVs, the X-XRV RBDenv is larger, with three distinct indels (insertions/deletions) involving nine codons at the 5′ end of VRA (Figure 5b). Infectious X/P-XRVs with different VRA indel patterns show different XPR1 receptor preferences, suggesting these indels may contribute to receptor specificity [49,78].
Southern blotting previously showed that, unlike E-ERVs, X/P-ERVs are carried by all M. musculus subspecies, indicating that X/P-ERVs were acquired by this species earlier than the E-ERVs [5]. Sequenced X/P-ERVs from geographically separated Mus taxa identified P-MLV-like VRA indel patterns and overall sequence homologies in Western Europe (M. m. domesticus) and in M. spretus, which is sympatric with M. m. domesticus in Spain and Morocco; these species are partially interfertile, explaining the acquisition of P-MLV ERVs by M. spretus. X-ERVs are not detected in M. m. domesticus but predominate in the three Eurasian subspecies. The geographic distribution of subspecific Xpr1 variants coincides with subspecies ranges and with the X/P-MLV env subtypes they carry, as previously shown [11].
In addition to their differences in geographic distribution, the P-MLV VRAs show more limited sequence variation compared to the X-MLVs (Figure 5c,d). In contrast to the P-MLVs, the X-MLV VRAs are marked by many more replacement mutations and some indels. This indicates that the conserved receptor/virus interface involving P-MLVs and their permissive XPR1 receptor does not show evidence of genetic conflicts, whereas there is substantial and coordinated sequence and functional variation at the interacting interface of the X-MLVs and their XPR1 receptors in Eurasian subspecies. These different patterns define geographically separated coevolutionary “hotspots” experiencing mutual antagonistic selection and “coldspots” with no evidence of selective adaptations. The existence of such “hotspots” and “coldspots” is one of the key predictions of Thompson’s Geographic Mosaic Theory of Coevolution [12].
The absence of adaptive changes at this interface in M. m. domesticus is likely due to the fact that P-ERVs do not produce infectious virus or transmit without the assistance of replication competent XRVs, which this subspecies does not harbor [5]. Infectious P-XRVs result from recombination [79], and transcribed products of P-ERVs can co-package into E-XRV virions [80,81]. These P-ERVs therefore pose less of a risk to their hosts than the ERVs carried by Eurasian mice, which can produce infectious X-, as well as E-XRVs [82,83].
Newly sequenced X/P-MLV env genes from geographically separated Mus taxa were aligned with known X/P-MLVs to construct phylogenetic trees using the full length env and a set of RBD sequences. Both trees showed strong bootstrap support at the majority of branches and a clear separation of X-MLVs and P-MLVs was observed (Figures S3 and S4). These sequences were evaluated for evidence of positive selection and together revealed 18 such sites in the RBD (Table S4). The one site identified by all five programs in both DNA sets is 217T, which maps near the C-terminus of the RBD and is one of two adjacent sites with a key role in mediating X/P-XRV entry into human and mink cells [84]. Six positively selected sites were mapped to the VRA and form a patch overlapping the six adjacent residues involved in the various deletions associated with the different entry phenotypes (Figure 4 and Table S4). Three additional sites under positive selection map to the second major variable region in RBD, VRB, which has a secondary role in virus entry [37].
Just as the domesticated Fv4 E-ERV env blocks replication of E-XRVs, there is evidence of comparable X/P-ERV env genes that serve protective functions. The first of these, Rmcf, has only been found in DBA/2 and related inbred strains [85,86], but M. m. castaneus carries at least one similar gene, Rmcf2, and possibly others [74,87]. While the CAT1 receptor may have been protected by Fv4 from selective pressures exerted by E-MLV infection, the distribution of Rmcf-like genes in wild mice has not been determined, but it is clearly not significant enough to obviate the co-adaptive changes that have altered XPR1 and X/P-MLVs.

3.3. Fv1 and Its Capsid Target

3.3.1. Fv1

The first antiretroviral host factor to be discovered was Fv1 [88]. Fv1 is a rodent-specific restriction factor that was identified for its post-entry restriction of different subgroups of mouse-tropic MLVs [89], but it can also restrict other retroviruses [90]. Fv1 is a co-opted retrovirus-related capsid sequence derived from the ERV-L family [91,92], and while it was originally thought to have originated in Mus, it was subsequently identified in other rodents [93,94]. The Fv1n allele, first identified in NIH Swiss cells, limits the replication of B-tropic E-XRVs, and the b allele, found in BALB/c mice, restricts N-tropic E-XRVs [95]. Laboratory strains carry two other restriction variants (Fv1nr, Fv1d) [96,97], and there are additional sequence and functional variants in wild mice [10]. These restriction variants are distinguished from one another at four residues in the C-terminal half of the gene, and by variations in length and sequence at the C-terminus, all of which influence the restriction phenotype [98]. The Mus Fv1 shows positive selection that is centered on six codons including three of the seven residues known to govern restriction (261, 268, 270, 349, 352, 358, 399) [90,98] (Figure 4). Additional residues under positive selection were identified in the expanded set of rodents carrying Fv1 [93,94].
The inbred strains represent different mosaics of the M. musculus subspecies [99]. The Mouse Phylogeny Viewer (MPV) is an online tool that identifies the subspecies of origin of segments along each chromosome for 98 inbred strains [4]. Here, we typed 35 mouse strains in the MPV dataset for Fv1 [42], and Figure 6a shows that the Fv1b allele originated in Japanese M. m. musculus, while the Fv1n,nr,d alleles are embedded in segments derived from M. m. domesticus. These three M. m. domesticus derived Fv1 alleles, however, are not found in shared haplotype segments defined by common flanking SNPs, suggesting their independent derivation or acquisition through mutation or recombination.
Fv1b and Fv1n,nr,d are distinguishable by a 1.3 kb indel at the Fv1 3′ terminus that extends Fv1b by 22 residues [92]. Our PCR analysis of Eurasian mouse DNAs found the Fv1b-like extension in 19/20 Japanese mice, in mice from SE Asia, and in Iranian mice, identified as M. bactrianus (Figure 6b). Mice from northern China, Russia, Eastern and Western Europe all produced the smaller Fv1n-like segment.
Fv1 sequences from selected house mice were determined by direct sequencing or were extracted from the genomes of ten M. m. castaneus mice. Of the 34 genes, 22 had an Fv1b extension, one of which included a 4 bp insert (Table 2). The residues that distinguish these genes are at positions 270, 352, 358, and 399; these sites are all functionally relevant, and three are under positive selection in Mus (Figure 4) [10]. The K358E substitution, found in Fv1b laboratory strains, was identified in only one of these genes—in a Japanese mouse. All 12 genes with short C-termini have residue combinations corresponding to three of the inbred strain alleles. Eight of the 22 genes with the longer extension have unusual residue combinations, suggesting these mice might face viral antagonists.
An Fv1 ORF is present in most other species in the Mus genus [10,100], and these have large C-terminal insertions [10], suggesting that this configuration is the ancestral form. Thus, the shorter Fv1n-like versions of this gene were likely generated by deletion and then acquired mutations at key sites. The retention of Fv1b-like genes is most prevalent in mice harboring Cas/Frg E-ERVs, which have B-tropic capsid genes that are therefore not restricted by Fv1b, a clear adaptive advantage for these MLVs.

3.3.2. Viral Capsid Target of Fv1

Fv1 restriction targets the capsid of the viral gag gene [101,102]. Sequence comparisons and mutagenesis determined that the site determinative for N/B tropism is 110 [97], and residue replacements at other capsid sites can contribute to alternative restriction patterns defined as NR-tropic [96,103], D-tropic [97], or NB-tropic (viruses insensitive to both Fv1n and Fv1b) [104,105] (Figure 4). Virtually all laboratory mouse E-ERVs are N-tropic and carry R110. B-tropic E-MLVs, which carry E110, can be isolated from aging mice of Fv1b strains [106], and some Fv1b mice have acquired B-tropic E-MLV ERVs [107]. The C57BL/6 mouse reference genome carries Fv1b and has one E-ERV, Emv2, which is N-tropic and 36 X/P-ERVs with gag ORFs, of which 34 have the residue associated with B-tropism, E110.
We used these capsid gene sequences to construct a phylogeny. As shown in Figure S5, this phylogenetic tree showed strong bootstrap support at the majority of the nodes. Nine sites were determined to be under positive selection (Table S4). All programs identified positive selection at position 110, which determines N/B tropism, but at no other site implicated in Fv1-determined tropisms; no replacement mutations were found at positions 114 and 117, and the variations found at 92-95 did not show selection. These findings establish that the antagonistic interaction between Fv1 and its viral target has resulted in coevolutionary adaptive changes at the sites of interaction of both participants in this arms race.

4. Conclusions

The mouse gammaretroviruses co-evolved with their host species, and while the recently acquired MLV ERVs can retain the ability to produce viral proteins and infectious viruses, there are many host antiviral restriction genes that interfere with these processes. These interacting agents are subject to bidirectional selective pressures, resulting in a cyclical process that produces viruses that evade host restrictions and counter-adaptive changes to the restriction factors. Another component in this process is the geographic segregation of virus-infected M. musculus subspecies resulting in mosaic patterns of adaptations that generate distinctive MLV and restriction factor variants that can be taxon as well as locality specific.
The three virus/host pairings examined here provide examples of different co-evolutionary patterns. Our previous work showed that Fv1 and the XPR1 receptor are under positive selection in rodents [11,93] and that XPR1 has distinctive functional variants in house mouse subspecies [10,11]. Here, we show that Fv1 alleles also show defined geographic distributions as well as novel variants in house mouse populations. We also show that the variations in the Fv1 and XPR1 sites, critical for restriction, correlate with mutations in their viral targets that are also under positive selection.
There are two examples of coevolutionary “cold spots” with no significant selection at the interacting sites. First, the E-MLVs and their CAT1 receptor in M. musculus are not polymorphic at their interfaces in any of the three subspecies carrying E-MLVs. While that means these mice should be vulnerable to infection, their survival in the face of virus challenge is at least partly ensured by the presence of the Fv4 E-ERV in some of these populations. The second example, with no obvious virus-host conflict, is found in M. m. domesticus mice that retain the ancestral and fully permissive Xpr1sxv receptor. These mice carry P-ERVs, not known to produce virus except by recombination with XRVs of other host range groups [79]; P-ERVs can spread but this is XPR1-independent [108]. Thus, there is no ongoing conflict, as Xpr1 is under no pressure to adapt to ERVs that do not produce infectious virus, and variation in the P-ERV VRAs is much more limited than in their X-ERV counterparts.
Adaptations that provide a clear survival advantage to their hosts can spread rapidly through populations and into neighboring populations. Fv1 and Fv4 are both ERVs that have been coopted for antiviral functions; Fv1 is the gag capsid gene of the ancient MuERV-L family, while Fv4 is a Cas/Frg env. We show that Fv4 likely arose in SE Asia, but it is now fairly widespread in Japan and is also found in pockets of California [5]. For Fv1, b-like variants predominate in Japan and are present in about half the M. m. castaneus population in SE Asia and through southern Asia to Iran, which is the ancestral home of M. musculus [6]. Fv1b-like genes are also found in basal species in the genus Mus [10] suggesting that Fv1b is the ancestral form, and the Fv1n alleles were generated by deletion. Most wild mouse ERV gag genes carry the B-tropic determinant and are therefore not restricted by the Fv1b gene prevalent in these mice.
ERVs are stable components of the mammalian genome that can alter host gene function and that can induce a variety of pathologies. Analysis of these antagonistic pairings of restrictive genes and viruses has enhanced our understanding of their origins, spread, and diversification. These entities co-evolve on a temporal scale, as evidenced by positive selection at their interacting interfaces that produces functional variants, but their evolution can also be understood on a spatial scale with distinctive sets of virus/host combinations in different locations, as predicted by the Geographic Mosaic Theory of Evolution [12].

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/v13091864/s1, Datafile S1: Additional sequences, Figure S1: Phylogeny of E-MLV env sequences, Figure S2: Phylogeny of CAT1/Slc7a1 in rodents, Figure S3. Phylogeny of X/P-MLV env RBD sequences, Figure S4. Phylogeny of X/P-MLV env sequences, Figure S5. Phylogeny of X/P and E-MLV capsid sequences, Table S1. Sources of wild-caught and wild-derived mice and mouse DNAs, Table S2. Primer sequences used for PCR, Table S3. Accession numbers for MLV XRVs and ERVs and for CAT1 and Fv1 gene sequences, Table S4. Residues under positive selection as identified by separate programs.

Author Contributions

Conceptualization, C.A.K.; methodology, G.B., A.J.O. and K.W.; validation, G.B. and C.A.K.; formal analysis, G.B., O.L., A.J.O. and K.W.; investigation, O.L., D.B., E.S., G.B., Q.L. and C.A.K.; resources, C.A.K.; data curation, E.S., G.B. and C.A.K.; writing—original draft preparation, C.A.K.; writing—review and editing, G.B., A.J.O., K.W. and C.A.K.; supervision, C.A.K.; project administration, C.A.K.; funding acquisition, C.A.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases under grant number AI000300-38 to C.K.

Institutional Review Board Statement

Ethical review and approval were waived for this study, due to the fact that DNA and RNA isolation from animal tissues was done prior to the establishment of the Institute animal care and use protocol system.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article or supplementary material.

Acknowledgments

We thank Portion King and Alicia Buckler-White for DNA sequencing, Hidetoshi Ikeda for valuable information and Toshihiko Shiroishi and Takehide Murata at the RIKEN BioResource Research Center, Tsukuka, Japan for assistance in obtaining a set of DNAs from wild-trapped mice for this study.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Jenkins, N.A.; Copeland, N.G.; Taylor, B.A.; Lee, B.K. Organization, distribution, and stability of endogenous ecotropic murine leukemia virus DNA sequences in chromosomes of Mus musculus. J. Virol. 1982, 43, 26–36. [Google Scholar] [CrossRef] [Green Version]
  2. O’Neill, R.R.; Khan, A.S.; Hoggan, M.D.; Hartley, J.W.; Martin, M.A.; Repaske, R. Specific hybridization probes demonstrate fewer xenotropic than mink cell focus-forming murine leukemia virus env-related sequences in DNAs from inbred laboratory mice. J. Virol. 1986, 58, 359–366. [Google Scholar] [CrossRef] [Green Version]
  3. Frankel, W.N.; Stoye, J.P.; Taylor, B.A.; Coffin, J.M. A linkage map of endogenous murine leukemia proviruses. Genetics 1990, 124, 221–236. [Google Scholar] [CrossRef]
  4. Yang, H.; Wang, J.R.; Didion, J.P.; Buus, R.J.; Bell, T.A.; Welsh, C.E.; Bonhomme, F.; Yu, A.H.; Nachman, M.W.; Pialek, J.; et al. Subspecific origin and haplotype diversity in the laboratory mouse. Nat. Genet. 2011, 43, 648–655. [Google Scholar] [CrossRef] [Green Version]
  5. Kozak, C.A.; O’Neill, R.R. Diverse wild mouse origins of xenotropic, mink cell focus-forming, and two types of ecotropic proviral genes. J. Virol. 1987, 61, 3082–3088. [Google Scholar] [CrossRef] [Green Version]
  6. Cucchi, T.; Papayianni, K.; Cersoy, S.; Aznar-Cormano, L.; Zazzo, A.; Debruyne, R.; Berthon, R.; Balasescu, A.; Simmons, A.; Valla, F.; et al. Tracking the Near Eastern origins and European dispersal of the western house mouse. Sci. Rep. 2020, 10, 8276. [Google Scholar] [CrossRef]
  7. Macholan, M.; Munclinger, P.; Sugerkova, M.; Dufkova, P.; Bimova, B.; Bozikova, E.; Zima, J.; Pialek, J. Genetic analysis of autosomal and X-linked markers across a mouse hybrid zone. Evolution 2007, 61, 746–771. [Google Scholar] [CrossRef] [PubMed]
  8. Boso, G.; Kozak, C.A. Retroviral Restriction Factors and Their Viral Targets: Restriction Strategies and Evolutionary Adaptations. Microorganisms 2020, 8, 1965. [Google Scholar] [CrossRef] [PubMed]
  9. Van Valen, L. A new evolutionary law. Evol. Theory 1973, 1, 1–30. [Google Scholar]
  10. Yan, Y.; Buckler-White, A.; Wollenberg, K.; Kozak, C.A. Origin, antiviral function and evidence for positive selection of the gammaretrovirus restriction gene Fv1 in the genus Mus. Proc. Natl. Acad. Sci. USA 2009, 106, 3259–3263. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  11. Yan, Y.; Liu, Q.; Wollenberg, K.; Martin, C.; Buckler-White, A.; Kozak, C.A. Evolution of functional and sequence variants of the mammalian XPR1 receptor for mouse xenotropic gammaretroviruses and the human-derived XMRV. J. Virol. 2010, 84, 11970–11980. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Thompson, J.N. The Geographic Mosaic of Coevolution; University of Chicago Press: Chicago, IL, USA, 2005. [Google Scholar]
  13. Jern, P.; Stoye, J.P.; Coffin, J.M. Role of APOBEC3 in genetic diversity among endogenous murine leukemia viruses. PLoS Genet. 2007, 3, e183. [Google Scholar] [CrossRef] [Green Version]
  14. Hasenkamp, N.; Solomon, T.; Tautz, D. Selective sweeps versus introgression–population genetic dynamics of the murine leukemia virus receptor Xpr1 in wild populations of the house mouse (Mus musculus). BMC Evol. Biol. 2015, 15, 248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Bamunusinghe, D.; Naghashfar, Z.; Buckler-White, A.; Plishka, R.; Baliji, S.; Liu, Q.; Kassner, J.; Oler, A.; Hartley, J.; Kozak, C.A. Sequence diversity, intersubgroup relationships, and origins of the mouse leukemia gammaretroviruses of laboratory and wild mice. J. Virol. 2016, 90, 4186–4198. [Google Scholar] [CrossRef] [Green Version]
  16. Halligan, D.L.; Kousathanas, A.; Ness, R.W.; Harr, B.; Eory, L.; Keane, T.M.; Adams, D.J.; Keightley, P.D. Contributions of protein-coding and regulatory change to adaptive molecular evolution in murid rodents. PLoS Genet. 2013, 9, e1003995. [Google Scholar] [CrossRef] [Green Version]
  17. Li, H.; Handsaker, B.; Wysoker, A.; Fennell, T.; Ruan, J.; Homer, N.; Marth, G.; Abecasis, G.; Durbin, R.; Subgroup, G.P.D.P. The Sequence Alignment/Map format and SAMtools. Bioinformatics 2009, 25, 2078–2079. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Trapnell, C.; Pachter, L.; Salzberg, S.L. TopHat: Discovering splice junctions with RNA-Seq. Bioinformatics 2009, 25, 1105–1111. [Google Scholar] [CrossRef] [PubMed]
  19. Li, H. Toward better understanding of artifacts in variant calling from high-coverage samples. Bioinformatics 2014, 30, 2843–2851. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  20. McKenna, A.; Hanna, M.; Banks, E.; Sivachenko, A.; Cibulskis, K.; Kernytsky, A.; Garimella, K.; Altshuler, D.; Gabriel, S.; Daly, M.; et al. The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010, 20, 1297–1303. [Google Scholar] [CrossRef] [Green Version]
  21. Van der Auwera, G.A.; Carneiro, M.O.; Hartl, C.; Poplin, R.; Del Angel, G.; Levy-Moonshine, A.; Jordan, T.; Shakir, K.; Roazen, D.; Thibault, J.; et al. From FastQ data to high confidence variant calls: The Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinform. 2013, 11, 111011–111033. [Google Scholar] [CrossRef]
  22. DePristo, M.A.; Banks, E.; Poplin, R.; Garimella, K.V.; Maguire, J.R.; Hartl, C.; Philippakis, A.A.; del Angel, G.; Rivas, M.A.; Hanna, M.; et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 2011, 43, 491–498. [Google Scholar] [CrossRef] [PubMed]
  23. Luo, R.; Liu, B.; Xie, Y.; Li, Z.; Huang, W.; Yuan, J.; He, G.; Chen, Y.; Pan, Q.; Liu, Y.; et al. SOAPdenovo2: An empirically improved memory-efficient short-read de novo assembler. Gigascience 2012, 1, 18. [Google Scholar] [CrossRef]
  24. McLaren, W.; Pritchard, B.; Rios, D.; Chen, Y.; Flicek, P.; Cunningham, F. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 2010, 26, 2069–2070. [Google Scholar] [CrossRef] [PubMed]
  25. Thorvaldsdottir, H.; Robinson, J.T.; Mesirov, J.P. Integrative Genomics Viewer (IGV): High-performance genomics data visualization and exploration. Briefings Bioinform. 2013, 14, 178–192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Kent, W.J. BLAT--the BLAST-like alignment tool. Genome Res. 2002, 12, 656–664. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Kent, W.J.; Sugnet, C.W.; Furey, T.S.; Roskin, K.M.; Pringle, T.H.; Zahler, A.M.; Haussler, D. The human genome browser at UCSC. Genome Res. 2002, 12, 996–1006. [Google Scholar] [CrossRef] [Green Version]
  28. Wang, J.R.; de Villena, F.P.; McMillan, L. Comparative analysis and visualization of multiple collinear genomes. BMC Bioinform. 2012, 13 (Suppl. 3), S13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Edgar, R.C. MUSCLE: Multiple sequence alignment with high accuracy and high throughput. Nuc. Acids Res. 2004, 32, 1792–1797. [Google Scholar] [CrossRef] [Green Version]
  30. Kearse, M.; Moir, R.; Wilson, A.; Stones-Havas, S.; Cheung, M.; Sturrock, S.; Buxton, S.; Cooper, A.; Markowitz, S.; Duran, C.; et al. Geneious Basic: An integrated and extendable desktop software platform for the organization and analysis of sequence data. Bioinformatics 2012, 28, 1647–1649. [Google Scholar] [CrossRef]
  31. Alamgir, A.S.; Owens, N.; Lavignon, M.; Malik, F.; Evans, L.H. Precise identification of endogenous proviruses of NFS/N mice participating in recombination with Moloney ecotropic murine leukemia virus (MuLV) to generate polytropic MuLVs. J. Virol. 2005, 79, 4664–4671. [Google Scholar] [CrossRef] [Green Version]
  32. Stamatakis, A. RAxML version 8: A tool for phylogenetic analysis and post-analysis of large phylogenies. Bioinformatics 2014, 30, 1312–1313. [Google Scholar] [CrossRef]
  33. Weaver, S.; Shank, S.D.; Spielman, S.J.; Li, M.; Muse, S.V.; Kosakovsky Pond, S.L. Datamonkey 2.0: A modern web application for characterizing selective and other evolutionary processes. Mol. Biol. Evol. 2018, 35, 773–777. [Google Scholar] [CrossRef] [Green Version]
  34. Yang, Z. PAML 4: Phylogenetic analysis by maximum likelihood. Mol. Biol. Evol. 2007, 24, 1586–1591. [Google Scholar] [CrossRef] [Green Version]
  35. Yang, Z.; Wong, W.S.; Nielsen, R. Bayes empirical bayes inference of amino acid sites under positive selection. Mol. Biol. Evol. 2005, 22, 1107–1118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Delport, W.; Poon, A.F.; Frost, S.D.; Kosakovsky Pond, S.L. Datamonkey 2010: A suite of phylogenetic analysis tools for evolutionary biology. Bioinformatics 2010, 26, 2455–2457. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Battini, J.L.; Heard, J.M.; Danos, O. Receptor choice determinants in the envelope glycoproteins of amphotropic, xenotropic, and polytropic murine leukemia viruses. J. Virol. 1992, 66, 1468–1475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Ikeda, H.; Laigret, F.; Martin, M.A.; Repaske, R. Characterization of a molecularly cloned retroviral sequence associated with Fv-4 resistance. J. Virol. 1985, 55, 768–777. [Google Scholar] [CrossRef] [Green Version]
  39. Steffen, D.L.; Bird, S.; Weinberg, R.A. Evidence for the Asiatic origin of endogenous AKR-type murine leukemia proviruses. J. Virol. 1980, 35, 824–835. [Google Scholar] [CrossRef] [Green Version]
  40. Inaguma, Y.; Miyashita, N.; Moriwaki, K.; Huai, W.C.; Jin, M.L.; He, X.Q.; Ikeda, H. Acquisition of two endogenous ecotropic murine leukemia viruses in distinct Asian wild mouse populations. J. Virol. 1991, 65, 1796–1802. [Google Scholar] [CrossRef] [Green Version]
  41. Voytek, P.; Kozak, C.A. Nucleotide sequence and mode of transmission of the wild mouse ecotropic virus, HoMuLV. Virology 1989, 173, 58–67. [Google Scholar] [CrossRef]
  42. Skorski, M.; Bamunusinghe, D.; Liu, Q.; Shaffer, E.; Kozak, C.A. Distribution of endogenous gammaretroviruses and variants of the Fv1 restriction gene in individual mouse strains and strain subgroups. PLoS ONE 2019, 14, e0219576. [Google Scholar] [CrossRef] [Green Version]
  43. Yonekawa, H.; Moriwaki, K.; Gotoh, O.; Miyashita, N.; Matsushima, Y.; Shi, L.; Cho, W.; Zhen, X.; Tagashira, Y. Hybrid origin of Japanese mice “Mus musculus molossinus”: Evidence from restriction analysis of mitochondrial DNA. Mol. Biol. Evol. 1988, 5, 63–78. [Google Scholar] [PubMed]
  44. Gardner, M.B. Type C viruses of wild mice: Characterization and natural history of amphotropic, ecotropic, and xenotropic MuLV. Curr. Top. Microbiol. Immunol. 1978, 79, 215–259. [Google Scholar] [PubMed]
  45. Rasheed, S.; Gardner, M.B. Resistance to fibroblasts and hematopoietic cells to ecotropic murine leukemia virus infection; an Akvr-1r gene effect. Int. J. Cancer 1983, 31, 491–496. [Google Scholar] [CrossRef] [PubMed]
  46. Boursot, P.; Auffray, J.C.; Britton-Davidian, J.; Bonhomme, F. The evolution of house mice. Ann. Rev. Ecol. Syst. 1993, 24, 119–152. [Google Scholar] [CrossRef]
  47. Cloyd, M.W.; Hartley, J.W.; Rowe, W.P. Lymphomagenicity of recombinant mink cell focus-inducing murine leukemia viruses. J. Exp. Med. 1980, 151, 542–552. [Google Scholar] [CrossRef] [Green Version]
  48. Oldstone, M.B.; Jensen, F.; Elder, J.; Dixon, F.J.; Lampert, P.W. Pathogenesis of the slow disease of the central nervous system associated with wild mouse virus. III. Role of input virus and MCF recombinants in disease. Virology 1983, 128, 154–165. [Google Scholar] [CrossRef]
  49. Kozak, C.A. Naturally occurring polymorphisms of the mouse gammaretrovirus receptors CAT-1 and XPR1 alter virus tropism and pathogenicity. Adv. Virol. 2011, 975801. [Google Scholar] [CrossRef] [Green Version]
  50. Davey, R.A.; Zuo, Y.; Cunningham, J.M. Identification of a receptor-binding pocket on the envelope protein of friend murine leukemia virus. J. Virol. 1999, 73, 3758–3763. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Jung, Y.T.; Wu, T.; Kozak, C.A. Novel host range and cytopathic variant of ecotropic Friend murine leukemia virus. J. Virol. 2004, 78, 12189–12197. [Google Scholar] [CrossRef] [Green Version]
  52. Voytek, P.; Kozak, C. HoMuLV: A novel pathogenic ecotropic virus isolated from the European mouse, Mus hortulanus. Virology 1988, 165, 469–475. [Google Scholar] [CrossRef]
  53. Jung, Y.T.; Kozak, C.A. Generation of novel syncytium-inducing and host range variants of ecotropic moloney murine leukemia virus in Mus spicilegus. J. Virol. 2003, 77, 5065–5072. [Google Scholar] [CrossRef] [Green Version]
  54. Ferrarone, J.; Knoper, R.C.; Li, R.; Kozak, C.A. Second site mutation in the virus envelope expands the host range of a cytopathic variant of Moloney murine leukemia virus. Virology 2012, 433, 7–11. [Google Scholar] [CrossRef] [Green Version]
  55. Park, B.H.; Matuschke, B.; Lavi, E.; Gaulton, G.N. A point mutation in the env gene of a murine leukemia virus induces syncytium formation and neurologic disease. J. Virol. 1994, 68, 7516–7524. [Google Scholar] [CrossRef] [Green Version]
  56. Masuda, M.; Hanson, C.A.; Hoffman, P.M.; Ruscetti, S.K. Analysis of the unique hamster cell tropism of ecotropic murine leukemia virus PVC-211. J. Virol. 1996, 70, 8534–8539. [Google Scholar] [CrossRef] [Green Version]
  57. Morse, H.C., III (Ed.) Introduction. In Origins of Inbred Mice; Academic Press: New York, NY, USA, 1978; pp. 1–31. [Google Scholar]
  58. Gross, L. “Spontaneous” leukemia developing in C3H mice following inoculation in infancy, with AK-leukemic extracts, or AK-embryos. Proc. Soc. Exp. Biol. Med. 1951, 76, 27–32. [Google Scholar] [CrossRef]
  59. Moloney, J.B. Biological studies on a lymphoid-leukemia virus extracted from sarcoma 37. I. Origin and introductory investigations. J. Natl. Cancer Inst. 1960, 24, 933–951. [Google Scholar] [PubMed]
  60. Craigie, J. Sarcoma 37 and ascites tumours. Ann. R. Coll. Surg. Engl. 1952, 11, 287–299. [Google Scholar]
  61. Friend, C. Cell-free transmission in adult Swiss mice of a disease having the character of a leukemia. J. Exp. Med. 1957, 105, 307–318. [Google Scholar] [CrossRef] [PubMed]
  62. Henzy, J.E.; Johnson, W.E. Pushing the endogenous envelope. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2013, 368, 20120506. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Albritton, L.M.; Tseng, L.; Scadden, D.; Cunningham, J.M. A putative murine ecotropic retrovirus receptor gene encodes a multiple membrane-spanning protein and confers susceptibility to virus infection. Cell 1989, 57, 659–666. [Google Scholar] [CrossRef]
  64. Eiden, M.V.; Farrell, K.; Wilson, C.A. Glycosylation-dependent inactivation of the ecotropic murine leukemia-virus receptor. J. Virol. 1994, 68, 626–631. [Google Scholar] [CrossRef] [Green Version]
  65. Tavoloni, N.; Rudenholz, A. Variable transduction efficiency of murine leukemia retroviral vector on mammalian cells: Role of cellular glycosylation. Virology 1997, 229, 49–56. [Google Scholar] [CrossRef] [Green Version]
  66. Closs, E.I.; Graf, P.; Habermeier, A.; Cunningham, J.M.; Forstermann, U. Human cationic amino acid transporters hCAT-1, hCAT-2A, and hCAT-2B: Three related carriers with distinct transport properties. Biochemistry 1997, 36, 6462–6468. [Google Scholar] [CrossRef]
  67. Eiden, M.V.; Farrell, K.; Warsowe, J.; Mahan, L.C.; Wilson, C.A. Characterization of a naturally occurring ecotropic receptor that does not facilitate entry of all ecotropic murine retroviruses. J. Virol. 1993, 67, 4056–4061. [Google Scholar] [CrossRef] [Green Version]
  68. Yan, Y.; Kozak, C.A. Novel postentry resistance to AKV ecotropic mouse gammaretroviruses in the African pygmy mouse, Mus minutoides. J. Virol. 2008, 82, 6120–6129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Yoshimoto, T.; Yoshimoto, E.; Meruelo, D. Identification of amino acid residues critical for infection with ecotropic murine leukemia retrovirus. J. Virol. 1993, 67, 1310–1314. [Google Scholar] [CrossRef] [Green Version]
  70. Albritton, L.M.; Kim, J.W.; Tseng, L.; Cunningham, J.M. Envelope-binding domain in the cationic amino acid transporter determines the host range of ecotropic murine retroviruses. J. Virol. 1993, 67, 2091–2096. [Google Scholar] [CrossRef] [Green Version]
  71. Taylor, G.M.; Gao, Y.; Sanders, D.A. Fv-4: Identification of the defect in Env and the mechanism of resistance to ecotropic murine leukemia virus. J. Virol. 2001, 75, 11244–11248. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Levy, J.A. Xenotropic viruses: Murine leukemia viruses associated with NIH Swiss, NZB, and other mouse strains. Science 1973, 182, 1151–1153. [Google Scholar] [CrossRef]
  73. Hartley, J.W.; Wolford, N.K.; Old, L.J.; Rowe, W.P. New class of murine leukemia-virus associated with development of spontaneous lymphomas. Proc. Natl. Acad. Sci. USA 1977, 74, 789–792. [Google Scholar] [CrossRef] [Green Version]
  74. Kozak, C.A. The mouse “xenotropic” gammaretroviruses and their XPR1 receptor. Retrovirology 2010, 7, 101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Giovannini, D.; Touhami, J.; Charnet, P.; Sitbon, M.; Battini, J.L. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans. Cell Rep. 2013, 3, 1866–1873. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Kozak, C.A. Evolution of different antiviral strategies in wild mouse populations exposed to different gammaretroviruses. Curr. Opin. Virol. 2013, 3, 657–663. [Google Scholar] [CrossRef] [Green Version]
  77. Marin, M.; Tailor, C.S.; Nouri, A.; Kozak, S.L.; Kabat, D. Polymorphisms of the cell surface receptor control mouse susceptibilities to xenotropic and polytropic leukemia viruses. J. Virol. 1999, 73, 9362–9368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Yan, Y.; Liu, Q.; Kozak, C.A. Six host range variants of the xenotropic/polytropic gammaretroviruses define determinants for entry in the XPR1 cell surface receptor. Retrovirology 2009, 6, 87. [Google Scholar] [CrossRef] [Green Version]
  79. Bamunusinghe, D.; Liu, Q.; Plishka, R.; Dolan, M.A.; Skorski, M.; Oler, A.J.; Yedavalli, V.R.K.; Buckler-White, A.; Hartley, J.W.; Kozak, C.A. Recombinant origins of pathogenic and nonpathogenic mouse gammaretroviruses with polytropic host range. J. Virol. 2017, 91. [Google Scholar] [CrossRef] [Green Version]
  80. Lavignon, M.; Evans, L. A multistep process of leukemogenesis in Moloney murine leukemia virus-infected mice that is modulated by retroviral pseudotyping and interference. J. Virol. 1996, 70, 3852–3862. [Google Scholar] [CrossRef] [Green Version]
  81. Evans, L.H.; Alamgir, A.S.; Owens, N.; Weber, N.; Virtaneva, K.; Barbian, K.; Babar, A.; Malik, F.; Rosenke, K. Mobilization of endogenous retroviruses in mice after infection with an exogenous retrovirus. J. Virol. 2009, 83, 2429–2435. [Google Scholar] [CrossRef] [Green Version]
  82. Chattopadhyay, S.K.; Oliff, A.I.; Linemeyer, D.L.; Lander, M.R.; Lowy, D.R. Genomes of murine leukemia viruses isolated from wild mice. J. Virol. 1981, 39, 777–791. [Google Scholar] [CrossRef] [Green Version]
  83. Kozak, C.A.; Hartley, J.W.; Morse, H.C., 3rd. Laboratory and wild-derived mice with multiple loci for production of xenotropic murine leukemia virus. J. Virol. 1984, 51, 77–80. [Google Scholar] [CrossRef] [Green Version]
  84. Bahrami, S.; Duch, M.; Pedersen, F.S. Change of tropism of SL3-2 murine leukemia virus, using random mutational libraries. J. Virol. 2004, 78, 9343–9351. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Hartley, J.W.; Yetter, R.A.; Morse, H.C. A mouse gene on chromosome 5 that restricts infectivity of mink cell focus-forming recombinant murine leukemia viruses. J. Exp. Med. 1983, 158, 16–24. [Google Scholar] [CrossRef] [Green Version]
  86. Jung, Y.T.; Lyu, M.S.; Buckler-White, A.; Kozak, C.A. Characterization of a polytropic murine leukemia virus proviral sequence associated with the virus resistance gene Rmcf of DBA/2 mice. J. Virol. 2002, 76, 8218–8224. [Google Scholar] [CrossRef] [Green Version]
  87. Wu, T.; Yan, Y.; Kozak, C.A. Rmcf2, a xenotropic provirus in the Asian mouse species Mus castaneus, blocks infection by polytropic mouse gammaretroviruses. J. Virol. 2005, 79, 9677–9684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Lilly, F. Susceptibility to two strains of Friend leukemia virus in mice. Science 1967, 155, 461–462. [Google Scholar] [CrossRef] [PubMed]
  89. Yang, W.K.; Kiggans, J.O.; Yang, D.M.; Ou, C.Y.; Tennant, R.W.; Brown, A.; Bassin, R.H. Synthesis and circularization of N- and B-tropic retroviral DNA Fv-1 permissive and restrictive mouse cells. Proc. Natl. Acad. Sci. USA 1980, 77, 2994–2998. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Yap, M.W.; Colbeck, E.; Ellis, S.A.; Stoye, J.P. Evolution of the retroviral restriction gene Fv1: Inhibition of non-MLV retroviruses. PLoS Pathog. 2014, 10, e1003968. [Google Scholar] [CrossRef] [Green Version]
  91. Benit, L.; DeParseval, N.; Casella, J.F.; Callebaut, I.; Cordonnier, A.; Heidmann, T. Cloning of a new murine endogenous retrovirus, MuERV-L, with strong similarity to the human HERV-L element and with a gag coding sequence closely related to the Fv1 restriction gene. J. Virol. 1997, 71, 5652–5657. [Google Scholar] [CrossRef] [Green Version]
  92. Best, S.; LeTissier, P.; Towers, G.; Stoye, J.P. Positional cloning of the mouse retrovirus restriction gene Fv1. Nature 1996, 382, 826–829. [Google Scholar] [CrossRef] [PubMed]
  93. Boso, G.; Buckler-White, A.; Kozak, C.A. Ancient evolutionary origin and positive selection of the retroviral restriction factor Fv1 in Muroid Rodents. J. Virol. 2018, 92. [Google Scholar] [CrossRef] [Green Version]
  94. Young, G.R.; Yap, M.W.; Michaux, J.R.; Steppan, S.J.; Stoye, J.P. Evolutionary journey of the retroviral restriction gene Fv1. Proc. Natl. Acad. Sci. USA 2018, 115, 10130–10135. [Google Scholar] [CrossRef] [Green Version]
  95. Hartley, J.W.; Rowe, W.P.; Huebner, R.J. Host-range restrictions of murine leukemia viruses in mouse embryo cell cultures. J. Virol. 1970, 5, 221–225. [Google Scholar] [CrossRef] [Green Version]
  96. Kozak, C.A. Analysis of wild-derived mice for Fv-1 and Fv-2 murine leukemia virus restriction loci: A novel wild mouse Fv-1 allele responsible for lack of host range restriction. J. Virol. 1985, 55, 281–285. [Google Scholar] [CrossRef] [Green Version]
  97. Kozak, C.A.; Chakraborti, A. Single amino acid changes in the murine leukemia virus capsid protein gene define the target of Fv1 resistance. Virology 1996, 225, 300–305. [Google Scholar] [CrossRef] [Green Version]
  98. Bishop, K.N.; Bock, M.; Towers, G.; Stoye, J.P. Identification of the regions of Fv1 necessary for murine leukemia virus restriction. J. Virol. 2001, 75, 5182–5188. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Yang, H.; Bell, T.A.; Churchill, G.A.; Pardo-Manuel de Villena, F. On the subspecific origin of the laboratory mouse. Nat. Genet. 2007, 39, 1100–1107. [Google Scholar] [CrossRef]
  100. Qi, C.F.; Bonhomme, F.; Buckler-White, A.; Buckler, C.; Orth, A.; Lander, M.R.; Chattopadhyay, S.K.; Morse, H.C., 3rd. Molecular phylogeny of Fv1. Mamm. Genome 1998, 9, 1049–1055. [Google Scholar] [CrossRef] [PubMed]
  101. Gautsch, J.W.; Elder, J.H.; Schindler, J.; Jensen, F.C.; Lerner, R.A. Structural markers on core protein p30 of murine leukemia virus: Functional correlation with Fv-1 tropism. Proc. Natl. Acad. Sci. USA 1978, 75, 4170–4174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Hopkins, N.; Schindler, J.; Hynes, R. Six-NB-tropic murine leukemia viruses derived from a B-tropic virus of BALB/c have altered p30. J. Virol. 1977, 21, 309–318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Ishimoto, A.; Hartley, J.W.; Rowe, W.P. Fv-1 restriction of xenotropic and amphotropic murine leukemia virus genomes phenotypically mixed with ecotropic virus. Virology 1979, 93, 215–225. [Google Scholar] [CrossRef]
  104. Jung, Y.T.; Kozak, C.A. A single amino acid change in the murine leukemia virus capsid gene responsible for the Fv1nr phenotype. J. Virol. 2000, 74, 5385–5387. [Google Scholar] [CrossRef] [PubMed]
  105. Stevens, A.; Bock, M.; Ellis, S.; LeTissier, P.; Bishop, K.N.; Yap, M.W.; Taylor, W.; Stoye, J.P. Retroviral capsid determinants of Fv1 NB and NR tropism. J. Virol. 2004, 78, 9592–9598. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. McCubrey, J.; Risser, R. Genetic interactions in the spontaneous production of endogenous murine leukemia virus in low leukemic mouse strains. J. Exp. Med. 1982, 156, 337–349. [Google Scholar] [CrossRef] [Green Version]
  107. Moll, B.; Hartley, J.W.; Rowe, W.P. Induction of B-tropic and N-tropic murine leukemia virus from B10.BR/SgLi mouse embryo cell lines by 5-iodo-2’-deoxyuridine. J. Natl. Cancer. Inst. 1979, 63, 213–217. [Google Scholar]
  108. Rosenke, K.; Lavignon, M.; Malik, F.; Kolokithas, A.; Hendrick, D.; Virtaneva, K.; Peterson, K.; Evans, L.H. Profound amplification of pathogenic murine polytropic retrovirus release from coinfected cells. J. Virol. 2012, 86, 7241–7248. [Google Scholar] [CrossRef] [Green Version]
Viruses 13 01864 g001 550
Figure 1. Variation in E-MLV env genes. The matrix shows percent sequence identity of representative E-MLVs in SU and RBD.
Figure 1. Variation in E-MLV env genes. The matrix shows percent sequence identity of representative E-MLVs in SU and RBD.
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Viruses 13 01864 g002 550
Figure 2. Distribution of AKV and Cas/Frg E-MLV env subtypes and the Fv4 restriction gene env in Eurasian M. musculus.
Figure 2. Distribution of AKV and Cas/Frg E-MLV env subtypes and the Fv4 restriction gene env in Eurasian M. musculus.
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Viruses 13 01864 g003 550
Figure 3. Phylogeny of E-MLV env RBD sequences. Sequences corresponding to the RBD of the indicated E-MLVs were aligned and a maximum likelihood tree was generated using RaxML with 500 replicates. Bootstrap values are shown at each node. The tree was midrooted. Lines on the right side of the tree identify the five E-MLV subtypes.
Figure 3. Phylogeny of E-MLV env RBD sequences. Sequences corresponding to the RBD of the indicated E-MLVs were aligned and a maximum likelihood tree was generated using RaxML with 500 replicates. Bootstrap values are shown at each node. The tree was midrooted. Lines on the right side of the tree identify the five E-MLV subtypes.
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Viruses 13 01864 g004 550
Figure 4. Positive selection and critical functional sites in retroviral restriction factors and their virus gene targets. Brackets define interacting virus/host pairs. Sites of positive selection in MLVs, and in host genes, are identified by black arrows; sites identified in rodent orthologs by gray arrows; red arrows and bars mark residues or regions critical for restriction or that are restriction targets. Numbers identify residues involved in virus/host interactions that are also under positive selection. VRA, VRB, variable domains; PRR, proline rich region; ECL, extracellular loop; MHR, major homology region; n and b identify alternative C-termini of Fv1.
Figure 4. Positive selection and critical functional sites in retroviral restriction factors and their virus gene targets. Brackets define interacting virus/host pairs. Sites of positive selection in MLVs, and in host genes, are identified by black arrows; sites identified in rodent orthologs by gray arrows; red arrows and bars mark residues or regions critical for restriction or that are restriction targets. Numbers identify residues involved in virus/host interactions that are also under positive selection. VRA, VRB, variable domains; PRR, proline rich region; ECL, extracellular loop; MHR, major homology region; n and b identify alternative C-termini of Fv1.
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Viruses 13 01864 g005 550
Figure 5. Variation in X/P-MLV env genes. (a) Matrix showing percent sequence identity of representative X/P-MLVs in SU and RBD. (b) Protein alignment of the N-terminal end of VRAenv for a P-ERV and three representative X-MLVs identifying three indels. (c,d) Differences in VRAenv sequence variation in X- and P-MLVs and the number of individual MLVs with each variation. (e) Summary of the extent of sequence variation in these two sets of MLVs.
Figure 5. Variation in X/P-MLV env genes. (a) Matrix showing percent sequence identity of representative X/P-MLVs in SU and RBD. (b) Protein alignment of the N-terminal end of VRAenv for a P-ERV and three representative X-MLVs identifying three indels. (c,d) Differences in VRAenv sequence variation in X- and P-MLVs and the number of individual MLVs with each variation. (e) Summary of the extent of sequence variation in these two sets of MLVs.
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Viruses 13 01864 g006 550
Figure 6. Distribution of Fv1 variants in mouse strains and species. (a) Fv1b is embedded in a segment of Chromosome 4 derived from M. m. musculus (Japan). The left panel shows subspecies origins in the chromosome regions surrounding the location of Fv1 indicated by a black bar. Blue tracks, M. m. domesticus; red, M. m. musculus. The right panel shows SNP-defined haplotype regions defined by different colors. (b) Geographic distribution of Fv1 variants having C-termini that are Fv1b-like (blue) or Fv1n-like (red).
Figure 6. Distribution of Fv1 variants in mouse strains and species. (a) Fv1b is embedded in a segment of Chromosome 4 derived from M. m. musculus (Japan). The left panel shows subspecies origins in the chromosome regions surrounding the location of Fv1 indicated by a black bar. Blue tracks, M. m. domesticus; red, M. m. musculus. The right panel shows SNP-defined haplotype regions defined by different colors. (b) Geographic distribution of Fv1 variants having C-termini that are Fv1b-like (blue) or Fv1n-like (red).
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Table
Table 1. Phenotypic changes in viruses, with replacement mutations, at receptor critical sites.
Table 1. Phenotypic changes in viruses, with replacement mutations, at receptor critical sites.
Polymorphisms at Receptor Critical SitesMLV or ERVPhenotypeReference
S76Δ,S77ΔMoMLVReduces infection of M. dunni cells[52]
S84AF-S MLVInduces syncytia in M. dunni, infects hamster cells[51]
Cas/Frg E-ERVsUnknown
S82F 1Mo-Spl574Induces syncytia in M. dunni, restricted in other mouse cells[53]
S82F, E114G 1Spl574-E114GCorrection of host range restriction of Spl574[54]
W102GTR1.3 (FrMLV)Syncytia formation in SC-1 cells, neurologic disease[55]
E116G, W129KPVC-211 (FrMLV)Enhanced ability to infect hamster cells[56]
1 Numbering in MoMLV variants reflects the two codon upstream deletion.
Table
Table 2. Restriction critical residues in sequenced wild mouse Fv1 genes.
Table 2. Restriction critical residues in sequenced wild mouse Fv1 genes.
Fv1 Sites
Fv1 Type 1Subspecies, Name (Location)270352358399C-Terminus 2
n or n-likedomesticus, SK/Cam (UK) SKVn
domesticus, CalWM (USA)KSKVn
musculus, PWK (Czech Republic)KSKVn
musculus, SKIVE (Denmark)KSKVn
nr or nr-likemusculus, (Novobirsk, Russia) FKVn
musculus, CZII (Slovakia)KFKVn
spp., Aks (China)KFKVn
spp., Las (China)KFKVn
spp., (Vladivostok, Russia)KFKVn
domesticus, ZALENDE (Switzerland FKVn
domesticus, CLA (USA) FKVn
d-likedomesticus, PRAE (Morocco)QSKVn
b or b-likemolossinus, MOM (Japan)KSERb
bactrianus, (Iran) SKVb
castaneus, (Philippines) SKVb
castaneus, H12 (India) 5K/Q 3SKVb/b2 3
castaneus, H30,34 (India) 5K/Q 3SKVb3
castaneus, H15,27 (India) 5K/R 3SKVb
castaneus, H24,26,28,36 (India) 5KSKVb
molossinus, MOLD (Japan)KSKRb
molossinus, MOLC (Japan)KFKRb
molossinus, MAE (Japan)KFKRb
molossinus, JF1/Ms (Japanese fancy mouse)KFKRb
molossinus, (Saitama, Japan) FKRb
spp., IAS3 (Korea) FKRb
spp., Wuh (China) SKRb
domesticus LEWES (USA)QSKVb3
castaneus, CAST/EiJ (Thailand)QSKVb4
castaneus, H14 (India) 5Q- 4- 4- 4- 4
1 Based on C-terminus for b, 352 for n and nr, 270 for d. 2 C-terminus types: n, ELSLKPTAATKL; b, ELSLKPTAAGLTSVGSVGVLSLSPWKHQSNS; b2, ELSLKPTAAGLTAGLAPVGSVGVLSLSPWKHQSNS; b3, ELRGQR; b4, ELSLKPTAAGLPAGLASVGSVGVLSLSPWHKH. 3 Heterozygous. 4 Stop gain variant at position 327 (TGG > TAG) in both H14 alleles, resulting in predicted protein truncation or lack of expression of the corresponding allele. This variant has the b2 C-terminus. 5 The ten Fv1b-like castaneus H genes are identical to Fv1b except where indicated and a 137T/S substitution in H34.
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Boso, G.; Lam, O.; Bamunusinghe, D.; Oler, A.J.; Wollenberg, K.; Liu, Q.; Shaffer, E.; Kozak, C.A. Patterns of Coevolutionary Adaptations across Time and Space in Mouse Gammaretroviruses and Three Restrictive Host Factors. Viruses 2021, 13, 1864. https://doi.org/10.3390/v13091864

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Boso G, Lam O, Bamunusinghe D, Oler AJ, Wollenberg K, Liu Q, Shaffer E, Kozak CA. Patterns of Coevolutionary Adaptations across Time and Space in Mouse Gammaretroviruses and Three Restrictive Host Factors. Viruses. 2021; 13(9):1864. https://doi.org/10.3390/v13091864

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Boso, Guney, Oscar Lam, Devinka Bamunusinghe, Andrew J. Oler, Kurt Wollenberg, Qingping Liu, Esther Shaffer, and Christine A. Kozak. 2021. "Patterns of Coevolutionary Adaptations across Time and Space in Mouse Gammaretroviruses and Three Restrictive Host Factors" Viruses 13, no. 9: 1864. https://doi.org/10.3390/v13091864

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