Sequence Diversity, Intersubgroup Relationships, and Origins of the Mouse Leukemia Gammaretroviruses of Laboratory and Wild Mice

Abstract

Mouse leukemia viruses (MLVs) are found in the common inbred strains of laboratory mice and in the house mouse subspecies ofMus musculus Receptor usage and envelope (env) sequence variation define three MLV host range subgroups in laboratory mice: ecotropic, polytropic, and xenotropic MLVs (E-, P-, and X-MLVs, respectively). These exogenous MLVs derive from endogenous retroviruses (ERVs) that were acquired by the wild mouse progenitors of laboratory mice about 1 million years ago. We analyzed the genomes of seven MLVs isolated from Eurasian and American wild mice and three previously sequenced MLVs to describe their relationships and identify their possible ERV progenitors. The phylogenetic tree based on the receptor-determining regions ofenvproduced expected host range clusters, but these clusters are not maintained in trees generated from other virus regions. Colinear alignments of the viral genomes identified segmental homologies to ERVs of different host range subgroups. Six MLVs show close relationships to a small xenotropic ERV subgroup largely confined to the inbred mouse Y chromosome.envvariations define three E-MLV subtypes, one of which carries duplications of various sizes, sequences, and locations in the proline-rich region ofenv Outside theenvregion, all E-MLVs are related to different nonecotropic MLVs. These results document the diversity in gammaretroviruses isolated from globally distributedMussubspecies, provide insight into their origins and relationships, and indicate that recombination has had an important role in the evolution of these mutagenic and pathogenic agents.

Importance: Laboratory mice carry mouse leukemia viruses (MLVs) of three host range groups which were acquired from their wild mouse progenitors. We sequenced the complete genomes of seven infectious MLVs isolated from geographically separated Eurasian and American wild mice and compared them with endogenous germ line retroviruses (ERVs) acquired early in house mouse evolution. We did this because the laboratory mouse viruses derive directly from specific ERVs or arise by recombination between different ERVs. The six distinctively different wild mouse viruses appear to be recombinants, often involving different host range subgroups, and most are related to a distinctive, largely Y-chromosome-linked MLV ERV subtype. MLVs with ecotropic host ranges show the greatest variability with extensive inter- and intrasubtype envelope differences and with homologies to other host range subgroups outside the envelope. The sequence diversity among these wild mouse isolates helps define their relationships and origins and emphasizes the importance of recombination in their evolution.

FIG 1

Phylogenetic trees of four domains of the MLV genome. The optimal tree is shown, and the percentages of replicate trees in which associated taxa clustered together in the bootstrap test (500 replicates) are shown next to the branches (83). The trees are drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. Each analysis included at least 30 MLV DNA sequences. Colored arrows identify the newly sequenced wild mouse E-MLVs (red) and X/P-MLVs (blue). Cz524 X/P-MLV is not included in the gag tree because it contains MoMLV segments in this region.

FIG 2

Sequence relationships of four X/P-MLVs from wild mice and the laboratory mouse NZB X-MLV to various ERVs. At the top is a schematic representation of the viral genome. For each of the five genomes, staggered horizontal lines represent regions of greatest identity (over 90%) with ERVs or other MLVs, and these percentages are bolded. Numbering begins with the first nucleotide of the R region of the U5 LTR. Sequence positions are given for the last base pair in each segment of homology. A separate green line is used to show segmental homologies between CAST-X and Cz524.

FIG 3

Characterization of the five full-length XmvIV ERVs and the Asian mouse origins of XmvIV1. (A) Protein identity matrix for env genes of five XmvIV ERVs and selected Xmv proviruses. At the bottom are average identities between and within groups. Clade and VRA type were taken from Lamont et al. and Jern et al. (40, 53). (B) XmvIV1 (Xmv45) originated in Asian mice. The horizontal tracks represent a 30-Mb segment of Chr 5 for 28 inbred strains of laboratory mice. The mice were typed by PCR for XmvIV1 as indicated to the right. The map location of this ERV, Chr 5:23.7 (NCBI37/mm9 assembly), is marked by a yellow arrow and line. Chromosomal regions originating from M. m. domesticus are in blue; segments from M. m. musculus are in red.

FIG 4

Relationships of two ERVs from CZECHII/EiJ mice with CAST-X X-MLV and Cz524 X/P-MLV. Mmm1 and Mmm2 ERV pol sequences amplified from CZECHII/EiJ mice are indicated by the central horizontal line and delimited by their positions in Cz524 X/P-MLV. Sequence homologies between these ERVs and the two MLVs are given as percentages (above for CAST-X and below for Cz524). These ERVs include three of the four regions of greatest divergence between the two viruses.

FIG 5

Similarities in the env, gag, and pol genes among members of the three E-MLV subtypes. Similarities are given as percent nucleotide identities. Cas-Br-E, Cast17/18, Frg3, and Fv4 are Cas subtype E-MLVs and are compared with representatives of the other subtypes, AKV and HoMuLV.

FIG 6

Sequence relationships of three wild mouse E-MLVs and the laboratory mouse AKV E-MLV to ERVs and MLVs. At the top is a schematic representation of the viral genome. For each of the four genomes, horizontal lines represent regions of greatest identities (>90%) with ERVs or other MLVs, annotated as described for Fig. 2. The env genes and some other viral regions are E-MLV subtype specific.

FIG 7

Segmental duplications in the PRR regions of Cas subtype E-MLVs. Three different nucleotide duplications are marked by pink, blue, and yellow (A), and two amino acid duplications are marked by pink and blue (B). The nine Mm entries represent unique ERV PRR sequences amplified from M. m. castaneus or Lake Casitas (LC) mice. Asterisks mark sequence identities. At the bottom is a diagram of env showing the surface (SU) and TM domains, the RBD, the three variable domains within RBD (variable region A to variable region C [VRA-VRC]), and PRR.