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Vol. 96, Issue 18, 10254-10260, August 31, 1999
Department of Molecular Microbiology, Tufts University School of
Medicine, Boston, MA 02111
Contributed by John M. Coffin, July 6, 1999
The genomes of modern humans are riddled with thousands of
endogenous retroviruses (HERVs), the proviral remnants of
ancient viral infections of the primate lineage. Most HERVs are
nonfunctional, selectively neutral loci. This fact, coupled with their
sheer abundance in primate genomes, makes HERVs ideal for exploitation as phylogenetic markers. Endogenous retroviruses (ERVs)
provide phylogenetic information in two ways: (i) by
comparison of integration site polymorphism and (ii) by
orthologous comparison of evolving, proviral, nucleotide sequence. In
this study, trees are constructed with the noncoding long terminal
repeats (LTRs) of several ERV loci. Because the two LTRs of an ERV are
identical at the time of integration but evolve independently, each ERV
locus can provide two estimates of species phylogeny based on molecular
evolution of the same ancestral sequence. Moreover, tree topology is
highly sensitive to conversion events, allowing for easy detection of sequences involved in recombination as well as correction for such
events. Although other animal species are rich in ERV sequences, the
specific use of HERVs in this study allows comparison of trees to a
well established phylogenetic standard, that of the Old World primates.
HERVs, and by extension the ERVs of other species, constitute a unique
and plentiful resource for studying the evolutionary history of the
Retroviridae and their animal hosts.
Retroviruses are unique among RNA viruses in their ability to
integrate DNA copies of their genomes into the genome of the infected
cell. On occasion, integration takes place in a germ-line cell, giving
rise to an endogenous retrovirus (ERV), which can be
inherited by the offspring of the infected host, and may eventually become fixed in the gene pool of the host population (1). The genomes
of vertebrate species contain dozens to thousands of ERV sequences (2),
some of which were acquired in evolutionarily recent times, whereas
others derive from "ancient" times, as indicated by their
identical site of integration in more than one species (1, 3, 4).
Typically, ancient proviruses have sustained numerous point mutations,
deletions, and insertions, rendering them incapable of expressing
virus. No biologically active viruses have been associated with the
ancient proviruses.
Despite their abundance in vertebrate genomes, and some other
especially useful features described below, ERVs have rarely been
exploited as phylogenetic markers (5-10). In a few instances integration site polymorphisms have served as a source of phylogenetic signal (6), or as markers for linkage analysis (11), but the usefulness
of orthologous ERV nucleotide sequences has never been fully explored.
Here we report the application of ancient human endogenous
retrovirus (HERV) sequences to phylogenetic analysis on a time scale
spanning recent primate evolution.
HERVs can be organized into at least a dozen distinct groups, which
vary in size from one to thousands of members (1, 12). Cross-hybridization and PCR studies consistently reveal that most HERV
families are also found in other primates, including apes and Old World
monkeys (OWMs) (12-19). Many HERVs, including the ones used in this
study, are the result of integration events that took place between 5 and 50 million years ago, as indicated by the distribution of specific
proviruses at the same integration sites (or "loci") among
related species. The evolution of primates has been the subject of
intense study for well over a century, providing a well established
phylogenetic consensus with which to compare and evaluate the
performance of ERVs as phylogenetic markers.
Preparation of Genomic DNA Samples.
Human DNA samples came
from the National Institute of General Medical Sciences Human Genetic
Mutant Cell Repository. Great-ape genomic DNA was extracted from whole
blood (Yerkes Regional Primate Research Center) or immortalized cell
lines, including WES (chimpanzee), ROK (gorilla), PUTI (orangutan),
MLA144 (gibbon), and COS-7 (African green monkey) cells (American Type
Culture Collection; Manassas, VA). Additional blood samples were
purchased from the New England Regional Primate Research Center
(Southborough, MA) and included rhesus macaque, cynomolgus macaque,
baboon, marmoset, and spider monkey samples. Genomic DNA was extracted
from cells by digestion with SDS/Pronase and extraction with phenol
or from whole blood by using the QIAamp Blood Kit (Qiagen, Santa
Clarita, CA.).
PCR and Sequencing. All PCR mixtures contained 200-400 ng of
genomic DNA, 1.5-2.0 mM MgCl2, 200 µM each
dNTP, 0.2 µM each primer, and 4 units of Taq DNA
polymerase (Perkin-Elmer).
HERV-K(HML6.17) (GenBank accession nos. U60268 and U60269).
Primers for amplifying the 5' long terminal repeat (LTR) from human,
chimpanzee, bonobo, gorilla, and gibbon were HML1 (5'-TTGCCTTCTCAAGACAATATGGGC-3') and HML2
(5'-AGGCGCTGACCTCATGTGCGC-3'). The 5' LTR from orangutan, African green
monkey, baboon, cynomolgus macaque, and rhesus macaque was amplified
with HML7 (5'-GGGCAAAGTGAGTACATTTAGTGG-3') and HML8
(5'-GTTCAGACTGTCGCCTGTTTGAG-3'). The 3' LTR from human, chimpanzee,
bonobo, gorilla, orangutan, and African green monkey was amplified with
HML5 (5'-GTCTCTGTCTTCTGTTTATAGTCTG-3') and HML6
(5'-GTTTTGTGCCTTTACAACATAGGTAC-3'); from baboon, cynomolgus macaque,
and rhesus macaque, with HML5 and HML4
(5'-ATAGGTACTAACTTAACTTCAACAAC-3'). Screening for cellular target
sequence in marmoset and squirrel monkey used primers HML1 or HML7
(forward) and HML4 or HML6 (reverse).
This contribution is part of the special series of Inaugural
Articles by members of the National Academy of Sciences elected on
April 27, 1999.
Evolution
Constructing primate phylogenies from ancient
retrovirus sequences
and
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Phylogenetic Analysis. Sequences were aligned with CLUSTAL W (ref. 20; version 1.7) and adjusted by hand. Maximum parsimony, neighbor-joining, and maximum likelihood trees were generated by using PAUP* (21).
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RESULTS AND DISCUSSION |
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Building Phylogenetic Trees from ERV LTR Sequences
Endogenous retrovirus loci provide no less than three sources of phylogenetic signal, which can be used in complementary fashion to obtain much more information than simple distance estimates of homologous sequences. First, the distribution of provirus-containing loci among taxa dates the insertion. Given the size of vertebrate genomes (>1 × 109 bp) and the random nature of retroviral integration (22, 23), multiple integrations (and subsequent fixation) of ERV loci at precisely the same location are highly unlikely (24). Therefore, an ERV locus shared by two or more species is descended from a single integration event and is proof that the species share a common ancestor into whose germ line the original integration took place (14). Furthermore, integrated proviruses are extremely stable: there is no mechanism for removing proviruses precisely from the genome, without leaving behind a solo LTR or deleting chromosomal DNA. The distribution of an ERV among related species also reflects the age of the provirus: older loci are found among widely divergent species, whereas younger proviruses are limited to more closely related species. In theory, the species distribution of a set of known integration sites can be used to construct phylogenetic trees in a manner similar to restriction fragment length polymorphism (RFLP) analysis.
Second, as with other sequence-based phylogenetic analyses, mutations in a provirus that have accumulated since the divergence of the species provide an estimate of the genetic distance between the species. Because, for any given provirus, it is highly unlikely that there will be selection for or against any specific sequence, it is safe to assume that the rate of accumulation of mutations approximates the rate of their occurrence, with appropriate corrections for reversion. Analysis of closely related proviruses integrated at different sites should also reveal regional differences in mutation rates.
Third, sequence divergence between the LTRs at the ends of a given provirus provides an important and unique source of phylogenetic information. The LTRs are created during reverse transcription to regenerate cis-acting elements required for integration and transcription. Because of the mechanism of reverse transcription, the two LTRs must be identical at the time of integration, even if they differed in the precursor provirus (Fig. 1A). Over time, they will diverge in sequence because of substitutions, insertions, and deletions acquired during cellular DNA replication. Although it has been noted that the divergence between the two LTRs of an ERV can serve as a molecular clock (8, 15, 18, 25), there are no reported prior attempts to utilize the LTRs of individual ERV loci as a source of phylogenetic signal.
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Assuming that the LTRs of an ERV are evolving independently, at approximately the same rate, and in the absence of rearrangement events, a phylogenetic tree containing 5' and 3' LTRs derived from the same ERV locus is predicted to have a topology similar to that depicted in Fig. 1B. The most useful feature of the predicted tree is the separate clustering of the 5' and the 3' LTRs. The node joining the 5' and 3' LTR clusters must be the deepest within the ingroup, since it represents the time of integration, when the two LTRs were identical. Furthermore, both clusters are predicted to have similar branching patterns as determined by the phylogenetic history of the host species, with similar branch lengths. Thus, each tree displays two estimates of host phylogeny, both of which are derived from the evolution of an initially identical sequence (compare the 5' LTR and 3' LTR clusters in Fig. 1B). As we shall see, deviation of actual trees from this prediction provides a powerful means of testing the assumptions and detecting events other than neutral accumulation of mutations in the evolutionary history of a species.
Species Distribution of HERV Loci
Fig. 1C depicts the PCR strategy used to determine the distribution of 6 unlinked HERV proviruses among the genomes of 12 primate species. The presence of each HERV in a given species was determined by PCR amplification of both the 5' and 3' LTRs of the HERV from genomic DNA. Two genomic DNA samples from each species were screened, except for humans (12 individuals) and bonobo (1 individual). In some cases, the absence of a HERV from a species was confirmed by PCR amplification of the uninterrupted cellular target sequence (Fig. 1C). Three of the loci, HERV-KC4, HERV-KHML6.17, and RTVL-Ia, were detectable in the genomes of OWMs and hominoids, but not New World monkeys, and therefore integrated into the germ line of a common ancestor of the Old World lineages. HERV-K18, RTVL-Ha, and RTVL-Hb were found exclusively in humans, gorillas, chimpanzees, and bonobos, and thus are consistent with a gorilla/chimpanzee/human clade. None of the loci was detected in New World monkeys.
Evolution of HERV LTR Sequences
For each HERV locus, the amplified LTRs from each species were directly sequenced, and the aligned sequences were used to generate phylogenetic trees (Fig. 2). The 5' and 3' LTRs of HERV-KHML6.17 fell into two distinct clusters, in accord with prediction (Fig. 2A). Moreover, both LTR cluster topologies are consistent with established versions of primate species phylogeny (26-29). As has been the case with numerous nuclear DNA markers, there was no consensus among the HERV trees for the relationship among humans, chimpanzees, and gorillas (30). The remaining trees displayed interesting deviations from the predicted separation of the 5' and 3' LTR sequences.
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Fig. 2B shows the trees for the HERV-K18 LTR sequences. Contrary to expectation, the 5' and 3' LTRs of the gorilla provirus cluster together instead of with their counterparts from the other three species (compare Fig. 1B and Fig. 2B). The gorilla LTRs are separated from the other HERV-K18 LTRs by substitutions at 11 sites (Fig. 3A). Assuming that the two LTRs of an HERV locus are evolving independently, every substitution within the ingroup should be manifest as a difference between the 5' and 3' LTRs (compare the 5' and 3' LTR patterns above the white arrows in Fig. 3A). Substitution patterns at the 11 sites in question, however, do not differ between the 5' and 3' LTRs within a species (black arrows in Fig. 3A). For example, a substitution at site 242 appears in both the 5' and 3' gorilla LTRs. Although it is possible that any one position may suffer an identical substitution in both LTRs by chance, the probability of 11 positions undergoing identical substitutions in both LTRs is exceedingly low. It is far more likely that most of the 11 substitutions occurred only once, and that the two LTRs were homogenized by gene conversion. The tree in Fig. 2B is consistent with gene conversion between both LTRs of either the gorilla provirus or the human/chimpanzee provirus.
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Alternatively, the topology of the tree in Fig. 2B may indicate that the HERV-K18 provirus of gorillas and the HERV-K18 provirus of humans/chimpanzees are not true orthologues. There are at least two mechanisms to explain this possibility:
(i) The proviruses are derived from two independent
integration events (xenology). This possibility would require two
nearly identical viruses (differing by no more than 11 substitutions within the LTRs) to integrate into precisely the same nucleotide position in two different lineages
a highly unlikely possibility. A
similarly unlikely variation on this possibility is independent integrations into very similar cellular target sequences.
(ii) In one of the two lineages, HERV-K18 was largely replaced by recombination with a separate (but nearly identical) provirus. Such recombination would have been restricted to sequences within the provirus, as the flanking cellular sequences are identical in both lineages. It should be noted that there are hundreds of HERV-K LTR sequences within the primate genome (31-34).
The HERV-K(C4) LTR sequences (Fig. 2C) give the predicted topology; however, as noted previously (15, 16), the provirus was missing altogether from gorilla and chimpanzee DNA, in which only an unoccupied integration site was detectable. HERV-K(C4) is found in some ape and OWM species, proving that integration occurred in a common ancestor of apes and OWMs (15, 16). The provirus is located within the human C4B gene, which arose by duplication before the separation of the apes and OWMs. The absence of HERV-K(C4) from some species is most likely caused by frequent homogenization of the C4-CYP21 locus (35), resulting in conversion back to the unoccupied integration site. Both alleles of the C4 locus (with and without the HERV-K(C4) provirus) have been identified within more than one species, suggesting that such conversions have occurred multiple times during primate evolution (35).
The RTVL-Ia tree (Fig. 2D) deviates from expectation by the joining of the outgroup to the ingroup at a node that separates the 5' African green monkey sequences from all the other ingroup sequences. Inspection of the alignment reveals 10 substitutions on the RTVL-Ia tree that contribute to this unexpected branching pattern (dashed line in Fig. 2D). Seven of these sites fall within a 52-bp stretch (arrows in Fig. 3B). Within this segment, the gibbon 5' LTR is identical to the 3' LTRs (including the gibbon 3' LTR). After the gibbon lineage branched off from the other primate lineages, a portion of the 3' LTR must have been transferred to the 5' LTR by gene conversion. Because of this conversion, the most parsimonious tree identifies the gibbon 5' LTR as the progenitor of all the 3' LTRs, and incorrectly invokes parallel evolution (homoplasy) to explain the appearance of identical substitutions in the African green monkey 5' LTR and the 5' LTRs of orangutan and apes. After eliminating the hybrid gibbon 5' LTR from the analysis, the most parsimonious explanation for the sequence at these sites is shared, derived evolution (Fig. 2E). Moreover, all the new trees have the predicted topology (including those derived by neighbor-joining and maximum likelihood methods), with the root of the tree separating the 5' and 3' LTRs of the ingroup into two distinct lineages.
The trees in Fig. 2 F, G, and H contain proviruses of the very large RTVL-H family (36, 37). The two loci were identified by searching the genome databases for RTVL-H-related sequences and are referred to here as RTVL-Ha and RTVL-Hb. The RHTVL-Ha provirus tree conforms well to the expected topology (Fig. 2F); however, the RTVL-Hb cluster (Fig. 2G) bears no resemblance to primate species phylogeny. Most of the substitutions fall on terminal branches and provide no phylogenetic signal. One interpretation is that the RTVL-Hb sequences are recombining with other RTVL-H loci, which would have the effect of homogenizing the sequences in a type of concerted evolution. RTVL-H is the largest known HERV family, containing over 1,000 members (18), which may serve as a source of sequences for recombination.
The tree in Fig. 2H is a particularly effective illustration of the principle that LTRs derived from the same provirus cluster together. This tree contains LTRs from four related proviruses, RTVL-Ha, RTVL-Hb, and the proviruses designated as outgroups, RTVL-H and RTVL-H2. All LTRs cluster exclusively with sequences from the same provirus, with a high level of bootstrap support for the nodes separating the four loci. The RTVL-Ha and RTVL-Hb clades do not differ significantly from the trees generated for the two proviruses separately in Fig. 2 F and G, respectively.
Nucleotide Substitution Patterns
Some authors have suggested that methyl-CG deamination has evolved
as a specific defense against colonization of the genome by ERVs (38).
Existence of such a mechanism should be manifest as a bias toward
C·G 
T·A transitions within CG dinucleotides. Tracing the
pattern and direction of shared derived substitutions on each of the
HERV trees revealed such a bias. Table 1
shows the distribution of C·G T·A changes among the
C/G-containing dinucleotides in the ancestral LTR sequence. In every
case, the number of C·G T·A substitutions per CG
dinucleotide is 5- to 10-fold higher than for any of the six other
dinucleotide contexts. Indeed, over 40% of the total C T and G A transitions are attributable to CG changes, despite the fact that CG
is much less frequent than any other dinucleotide. This imbalance is
consistent with methyl-CG deamination as a mechanism for generating
C·G T·A transitions (39); however, the issue of whether a
mechanism for promoting CG deamination has evolved specifically as a
defense against ERVs requires a careful comparison of the substitution patterns in ERV sequences with those of other nuclear DNA markers.
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Estimating the Time of Integration
The genetic distance between the 5' and 3' LTRs of an ERV reflects
mutations accumulated since the time of integration and should
therefore be proportional to the age of the provirus. HERV-KC4, HERV-KHML6.17, and RTVL-Ia are found in both OWMs and hominoids, which
are estimated to have last shared a common ancestor over 31 million
years ago. By contrast, HERV-K18, RTVL-Ha, and RTVL-Hb are found only
in humans, chimpanzees, and gorillas, which are thought to have
diverged around 5 million years ago (40-42). To estimate the age of
each provirus the human/chimpanzee distances from each tree were used
to calibrate the rate of molecular evolution at each locus (Table
2). The most recent common ancestor of
humans and chimpanzees lived approximately 4.5 million years ago
(40-42), so dividing the distance between the human and chimpanzee
sequences (substitutions per site) by this number gives rates ranging
from 2.3 to 5.0 × 10
9 substitutions per
site per year. These numbers are similar to the estimated rates of
evolution for pseudogenes and noncoding regions of mammalian genes
(43-45). Applying each rate to the divergence between the 5' and 3'
LTRs of the same locus gives integration times consistent with
estimates based on species distribution (Table 2).
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A number of authors have pointed out that molecular clock calibrations are subject to a wide margin of error, and are usually based on imprecise estimates of divergence dates (46-48). The calculations in Table 2 are therefore only rough estimates of absolute time, but they are nonetheless useful for comparing the relative ages and rates of evolution of different HERV loci.
Conclusions
The study reported here is, to our knowledge, the first to take advantage of special properties of retroelements to provide insight into evolutionary mechanisms. The HERVs analyzed above include six unlinked loci, representing five unrelated HERV sequence families. Except where noted, these sequences gave trees that were consistent with the well established phylogeny of the old world primates, including OWMs, apes, and humans. Within this time scale genetic distances were less than 10% for all orthologous comparisons, and correction for multiple substitutions did not significantly alter branch lengths or tree topologies (data not shown). As with other nuclear DNA sequences, analyses of older phylogenetic relationships by using ERVs are likely to require such corrections.
One surprising result is the high frequency of conversion we observed. Indeed, only two of the six loci analyzed had suffered no such events in any lineage. Solo LTRs, which arise by recombinational deletion of the intervening viral genes, and which are found by the thousands in the genomes of many animal species, are further evidence for high frequency of recombination involving ERV sequences (1, 49-51). The mechanism that gives rise to such events is unlikely to be provirus-specific, but probably reflects the likelihood of conversion among any repeated, nuclear DNA sequences. Because many ERVs belong to multicopy families, it is also possible that interlocus recombination gives rise to concerted evolution among some of these loci. This latter mechanism may explain the rather confusing topology of the RTVL-Hb tree (Fig. 2G).
The use of LTR-to-LTR divergence to estimate insertion times has been reported previously (8, 15, 18, 25), but such studies invariably ignore the possibility of sequence conversion. Only one report (25) discussed the concern that sequence conversion between LTRs can result in an underestimate of insertion time, and suggested that conversion events should be detectable as deletions or alterations of the sequences flanking the LTRs. However, most of the loci analyzed in our study have clearly undergone conversion/recombination, yet none of these events resulted in loss or alteration of flanking sequences (data not shown). Phylogenetic analysis using HERV LTR sequences gives rise to trees with a predictable topology, on which is superimposed the phylogeny of the host taxa, and allows ready detection of conversion events. Once aberrant sequences are identified, they can be eliminated from an analysis, and the remaining sequences can be used to calculate insertion times, delineate substitution patterns, and decipher host phylogeny. Because ERVs are abundant within the genomes of many animal species, including (but not limited to) plants, insects, mollusks, fish, rodents, domestic pets, and livestock, the ERV approach can be applied to an endless variety of phylogenetic puzzles (1, 2).
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ACKNOWLEDGEMENTS |
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We dedicate this paper to the memory of Igor Slobodkin, Ph.D. We thank Steve O'Brien for helpful comments and discussion. J.M.C. was supported by National Cancer Institute Grant R35CA44385 and is a Research Professor of the American Cancer Society. W.E.J. was supported by National Institutes of Health Training Grants T32GM07310 and T32AI07422.
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ABBREVIATIONS |
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ERV, endogenous retrovirus; HERV, human ERV; OWM, Old World monkey; LTR, long terminal repeat.
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FOOTNOTES |
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Present address: Division of Microbiology, New England
Regional Primate Research Center, Harvard Medical School, Southborough, MA 01772-9102.
To whom reprint requests should be addressed at: Tufts
University School of Medicine, Department of Molecular Biology and Microbiology, 136 Harrison Ave., Boston, MA 02111. E-mail:
JCoffin_PAR{at}OPAL.Tufts.edu.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. 172454-172500).
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).
(B) RTVL-Ia. Apes are depicted as a single branch. AGM,
African green monkey. The pattern of substitutions indicates that a
portion of the RTVL-Ia LTR was replaced by conversion with sequences
from the 3' LTR. The pattern between bases 417 and 469 of the gibbon 5'
LTR is identical to the 3' LTRs (boxed areas).