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Genetics, Vol. 171, 1183-1194, November 2005, Copyright © 2005
doi:10.1534/genetics.105.043976
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Department of Molecular Microbiology and Program in Genetics, Tufts University School of Medicine, Boston, Massachusetts 02111
2 Corresponding author: Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111.
E-mail: john.coffin{at}tufts.edu
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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8% of its sequence content (LANDER et al. 2001; PACES et al. 2002). Most HERVs appear to have entered the genome of our ancestors between 30 and 45 million years ago, after the divergence of Old and New World monkeys (SVERDLOV 2000), although elements as old as 55 million years are known (BANNERT and KURTH 2004; LAVIE et al. 2004). Because of their relatively long residence in the genome, the majority of HERV elements are riddled with deleterious mutations, large deletions, and insertions of other repetitive elements. In addition, the exogenous viral counterparts of HERVs have most likely been extinct for many millions of years, but it is clear that these elements have expanded in copy number significantly throughout the course of primate evolution, perhaps through intracellular retrotransposition mechanisms (LEIB-MOSCH et al. 1993; GOODMAN et al. 1998; COSTAS and NAVEIRA 2000) as well as replication as viruses and reinfection (BELSHAW et al. 2004). The HERV-K family in particular has been actively expanding in our genome throughout the last 5–20 million years, during the period of radiation of hominids (MEDSTRAND and MAGER 1998; BARBULESCU et al. 1999; HUGHES and COFFIN 2001, 2004). Many human endogenous retrovirus families appear to have a complicated evolutionary history (JOHNSON and COFFIN 1999; COSTAS and NAVEIRA 2000). As is true for repetitive elements in general, in addition to expansion in the genome through transposition mechanisms, these elements can also undergo unequal crossing over and gene conversion (KASS et al. 1995; ROY et al. 2000; ROY-ENGEL et al. 2002). The capacity to mediate such ectopic recombination events has led to speculation that repetitive elements may be major contributors to the genome plasticity of their host species (LOWER et al. 1996).
It has been demonstrated that the unique structural features of endogenous retroviruses can be especially useful for the detection of ectopic recombination events and that these types of events may have occurred at a number of human endogenous retroviral loci (JOHNSON and COFFIN 1999). The process of reverse transcription generates a DNA copy of the retroviral RNA genome that is identical to the original, except that it is flanked by two identical long terminal repeat (LTR) sequences, which are 968 bp long in the case of HERV-K. Subsequent to integration, the two LTRs of the provirus evolve independently, acquiring mutations and diverging from each other. The longer the provirus has been resident in the genome of its host, the more divergent are its LTRs. Hence, LTRs can serve as a molecular clock estimate for the integration time of the provirus (DANGEL et al. 1995). However, estimates can be confounded if the assumption of an independent evolutionary history for the LTRs, specifically no significant sequence homogenization, is not correct.
One way to test this assumption is by examining the phylogenetic relatedness of these elements in their host species. A phylogenetic analysis of the LTRs of a given provirus that is shared in multiple species should result in two separate clusters containing the 5' and 3' LTR sequences separated by the deepest node in the tree, because the LTR sequences begin to diverge immediately after integration, prior to subsequent speciation events (Figure 1). The two main branches of the tree should then be independent estimations of the evolutionary history of the host species. Any deviations from a pattern of concordance of one LTR with the other or with the accepted evolutionary history of the host species indicate the occurrence of concerted evolution within the element or between elements. In the absence of such events, HERVs can serve as useful markers for studying the evolutionary relatedness of their primate hosts, because this type of analysis provides two estimates of phylogenetic relationships. However, when ectopic recombination events are detected, they can provide insight into the nature and mechanism of genome rearrangement that can occur during evolution.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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PCR and sequencing:
PCR reactions contained 200 ng genomic DNA, 1.5–3.5 mM MgCl2, 50 µM each dNTP, 0.2 µM each primer, and 2.5 units Taq DNA polymerase (Sigma, St. Louis). To amplify the 5' LTR, the left primer was designed to hybridize in the 5' genomic flanking region and the right primer was located just downstream of the 5' LTR. To amplify the 3' LTR, the left primer was located just upstream of the 3' LTR and the right primer was located in the 3' genomic flanking sequence. Primers and conditions used for each reaction are available upon request. PCR products were sequenced directly on both strands using an automated ABI 3100 DNA sequencer.
Estimation of integration time:
Mutation rates for each element were estimated independently for each HERV-K locus. First, pairwise distances were calculated using the Kimura two-parameter correction in the PAUP*4.0b program for all homologous sequence pairs among the species for which sequence information was available. Each distance was then divided by the years since the two species in each pair shared a last common ancestor on the basis of accepted primate divergence dates (GOODMAN et al. 1998). These were then averaged to obtain a mutation rate for each HERV-K locus (substitutions per site per year). Next, the divergences between the two LTRs of each element were calculated. The corrected distances between the 5' and 3' LTR sequences of each element within species were averaged to obtain LTR divergence values (substitutions per site) for each element. The LTR divergence value was then divided by the mutation rate to give the integration time estimate for each HERV-K element.
Phylogenetic analysis and sequence analysis:
Dot matrix plots were generated in MacVector 7.0. Multiple sequence alignments were performed using the CLUSTAL-W algorithm in MacVector 7.0, using open and extend gap penalties of 20 and 0, respectively. Resulting alignments were adjusted by hand. Maximum-parsimony and maximum-likelihood analyses were performed using PAUP*4.0b. Bootstrap values were calculated from 100 replicate trees. Trees were edited using MacClade 3.08. The human 5' and 3' LTR sequences of a closely related HERV-K provirus were used as outgroups in the primate phylogenetic analyses.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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Of the 15 elements, only nine estimated ages correlated with the observed species distribution. Two elements (HERV-K22q11 and 19p13.11B) had LTRs that were more divergent and therefore appeared to be more ancient than their species distribution indicated. Two elements, HERV-K20q11 and HERV-K6p21, which were the only elements in this study that we were able to amplify from the genomes of Old World monkeys, gave significant underestimates, while HERV-K(II) and HERV-K9q34.3 showed relatively modest discrepancies. Homogenization of the 5' and 3' LTR sequences of these elements through interelement recombination and/or gene conversion events could account for their low level of divergence. To address this issue, phylogenetic analyses of all elements were performed as described in the next section.
Phylogenetic analyses:
Deviation from the predicted evolutionary relationships among the LTRs in the different species should indicate whether recombination or gene conversion events have occurred and if they can account for the incorrect estimates of evolutionary distance. For this reason, separate trees were constructed using maximum-parsimony analysis for the LTR sequences of each element amplified from the various primate species. Figure 3 shows the phylogenetic analyses for the nine elements whose trees conformed to the predicted topology. The 5' and 3' LTR sequences of these elements formed separate clusters, and the species relationships in both sections of the tree were similar to one another and to the expected primate phylogeny. These results indicate that the two LTRs of these elements evolved independently, along with their hosts, and their evolutionary history did not involve detectable ectopic recombination or gene conversion events.
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HERV-K10p14:
The tree for HERV-K10p14 deviates from the predicted topology because, although the sequences of the two LTRs form separate clusters, each cluster gives a different estimate of host phylogeny. Grouping the chimpanzee and bonobo sequences into one clade, the 5' LTR sequences give the branching pattern (H/G)C, while the 3' LTR sequences give the branching pattern (C/G)H. This pattern was also seen when a maximum-likelihood approach was used (data not shown). One explanation for this discrepancy might be the occurrence of a recombination event between two different alleles of the HERV element in the common ancestor of all three species and then the segregation of the two different alleles into the chimpanzee and human lineages and the recombinant allele in the gorilla lineage. However, examination of the substitutions along each of the lineages reveals that support for each of the branching patterns is weak, as is also indicated by the low bootstrap values. In the 5' LTR cluster, there are only two changes along the lineage leading to humans and gorillas. Both of these substitutions occur in CpG dinucleotides, which have been shown previously to be mutational hot spots in HERV elements (JOHNSON and COFFIN 1999), so they may reflect instances of homoplasy. In the 3' LTR cluster, three apparent substitutions are common to chimpanzees, bonobos, and gorillas, two of which are also in CpG dinucleotides.
HERV-K(II):
The analysis of the HERV-K(II) sequences deviated quite strikingly from the predicted topology. The 5' and 3' LTR sequences did not cluster separately and there was no clear indication of species relatedness, indicating that a high level of concerted evolution between the LTRs has occurred at this locus and that these events probably occurred independently in the different species. The two LTRs in the gorilla cluster together, with the human 5' LTR forming a sister taxon. The 5' LTRs of the chimpanzee and bonobo form a distinct cluster, while the human, chimpanzee, and bonobo 3' LTRs cluster together. Examination of the substitution pattern along the different lineages reveals a rather complex evolutionary history. First, only 4 changes appear to have occurred in the LTRs after integration and prior to speciation events. This is in comparison to 10 such changes that occurred between the LTRs independently in the lineage leading to chimpanzees and bonobos prior to their separation. An estimated time frame for the accumulation of these mutations in the chimpanzee and bonobo common ancestor is 4 million years, perhaps indicating that this element integrated just prior to the radiation of all three lineages (gorillas, chimpanzees/bonobos, and humans).
The integration time estimate for this element indicates that the LTRs might have undergone some homogenization, reducing their degree of divergence. However, because the 5' and 3' LTRs do not have enough shared derived substitutions to distinguish the different lineages, clear cases of gene conversion could not always be identified. Another method for the detection of gene conversion is to look for the presence of "co-double" sites in the sequences under examination (BALDING et al. 1992). These sites reflect the independent acquisition of a mutation in one LTR in a species and the subsequent transfer of that mutation to the other LTR through gene conversion. The occurrence of homoplastic mutations in both LTRs of a provirus in any given species would be an exceedingly rare event, so the appearance of multiple co-doubles in a species would be more likely explained by single-mutation events in one LTR followed by homogenization between the LTRs. Table 2 shows the number of sites in the different species showing evidence of gene conversion because of the presence of co-double substitutions. The test statistic is the frequency of co-double sites, given a random distribution of mismatches among the sequences. Using this test, all of the species demonstrate statistically significant evidence for gene conversion.
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HERV-K9q34.3:
Examination of the LTR sequences at the HERV-K9q34.3 locus, which also gave an underestimated integration time estimate indicating sequence homogenization, shows evidence of possible gene conversion events occurring in the orangutan (Figure 5B). Two regions along the length of both orangutan LTRs are identical even though at these same positions the two LTRs have diverged in the human, chimpanzee, bonobo, and gorilla. This difference may indicate a sequence transfer in the orangutan subsequent to the mutation event differentiating the LTRs. Alternatively, if the time of integration was very close to the speciation event, these LTR mutations could have arisen after the orangutan lineage diverged from that of the African great apes. The relatively high genetic distance between the LTRs in the orangutan, 0.084 as compared to an average of 0.063 in the other four species, indicates that the LTR sequences have not undergone a significant amount of sequence homogenization, which would be indicative of gene conversion events. The position of the orangutan LTRs in the phylogenetic analysis (Figure 4) of this element is congruent with the interpretation that this element integrated just prior to the branching event that led to the orangutan lineage.
HERV-K6p21:
The final element in this analysis, HERV-K6p21, was detected in all species examined except the New World squirrel monkey, suggesting an age of at least 25 million years. However, its relatively low level of LTR divergence suggested that it represents a much more recent integration event. The estimated age of 10 million years would place integration in the African ape lineage. Examination of the sequence alignment showed no clear evidence for gene conversion. However, the phylogenetic analysis of the LTR sequences of this element revealed a possible explanation for this inconsistency. The 5' and 3' LTR sequences in the human, chimpanzee, bonobo, and gorilla conform to the predicted topology (Figure 4). However, the 3' LTR sequences from the remaining species form a separate cluster, suggesting that they may be from a different provirus, even though the elements are in identical genomic locations.
Given that the probability that a provirus would integrate more than one time into the same genomic location is extremely low, this locus could represent the replacement of an ancient provirus by a new element in the common ancestor of the great apes. Such an event could have occurred by homologous recombination between a newly integrating HERV-K element or another provirus located elsewhere in the genome (Figure 6). The recombination event would generate an element with chimeric LTRs consisting of sequence from both the old and the new provirus. A prediction of this scenario is that most of the divergence between the two LTRs of this element in the African great apes and humans should be located near the ends of the LTR sequence, because these regions would be remnants of the ancient provirus. Figure 6B shows the location of the base pair positions where the two LTRs differ in humans, chimpanzees, bonobos, and gorillas for HERV-K6p21 as well as HERV-K20q11 for comparison. Indeed, there is a distinct pattern in the location of the LTR differences for HERV-K6p21, with a clustering of mutations at both ends of the alignment and relatively few in the central portion, while the differences for HERV-K20q11 are more uniformly distributed along the LTR length.
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Phylogenetic analysis may not be a sensitive enough detector of gene conversion events, so the sequence alignments of all of the HERV-K elements were examined for evidence of LTR-LTR sequence transfers. Gene conversion must involve at least two apparent transfer events in close proximity to each other and the limit of statistically significant clustering (at the 95% confidence limit) is 24 bp for LTR sequences, which are approximately 968 bp in length (STEPHENS 1985). Only two elements examined exhibited evidence for gene conversion under these criteria. At the HERV-K1q23 locus, base pair positions 529 and 530 in the 3' LTR of the gorilla were apparently converted to the 5' LTR. A sequence transfer also occurred in the chimpanzee and bonobo lineage at the HERV-K6p22 locus where the 3' sequence at positions 421 and 428 was converted to the 5' sequence. Neither of these events led to significant deviation from the "normal" phylogenetic structure (Figure 3).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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Of the 15 HERV-K elements studied, 9 had LTRs whose divergence was consistent with the minimum age estimated from the species distribution, implying that the inferred distribution is likely correct, despite our failure to amplify unoccupied integration sites from more distant species. This failure may be a consequence of the fact that the majority of HERV-K integrations are into repetitive DNA, making them difficult to amplify cleanly. In this set, two proviruses had LTRs that were significantly more divergent than predicted from their species distribution. In such cases, the element may be present in more distantly related species but not detected because of sequence divergence in the primer sequence, deletion of both LTRs, or solo LTR formation in more distant lineages. A BLAST search of the rhesus trace sequence archives (http://www.ncbi.nlm.nih.gov/Traces) was performed to search for the presence of these two elements but was inconclusive because the flanking sequences were not found. Alternatively, discrepancies in the estimated ages of the provirus and their species distributions might reflect a period of rapid evolution at that locus after integration but prior to speciation, increasing the evolutionary distance between the HERV LTRs as compared to the interspecies divergences. The idea of an episodic rather than static molecular clock was proposed some time ago (GILLESPIE 1984), and there are several well-documented examples of loci in the primate genome undergoing this kind of evolution (MESSIER and STEWART 1997; LIU et al. 2001; SCHANER et al. 2001). The data from this analysis do not allow distinction between the two possibilities.
Overall, we found that HERV-K sequences are subject to ectopic recombination events that occur at a relatively high frequency. Of the 15 HERV-K proviruses examined, 5 [HERV-K(II), 20q11, 6p21, 1q23, and 6p22] showed convincing evidence of involvement in gene conversion or recombination events in one or more species. Two additional elements, HERV-K12q24 and 10p14, have aberrant phylogenies but definitive explanatory data are lacking. Taken as a whole, all but three (20q11, 1q23, and 6p22) of the ectopic recombination events detected in this study took place in human ancestors. It is estimated that there are 3900 full-length HERVs in the human genome with intact 5' and 3' LTRs (BELSHAW et al. 2005). If the same fraction (4/15) of the entire complement of HERV elements has been involved in ectopic recombination events as was found in this study, then 1050 elements, composing nearly 10 Mb of sequence in the human genome, have mediated such events in the human lineage during the course of evolution.
Gene conversion may also account for the removal of HERV-K20q11 from the genome of several species. This element is present in the great apes, orangutan, and some Old World monkeys, indicating that its integration took place prior to the divergence of both lineages, which occurred 25 million years ago. However, its conspicuous absence in the gibbon as well as in two macaque species (BLAST search of the trace archive was also negative) is inconsistent with this interpretation, unless the element was lost in these species. The likeliness of the parallel loss of this provirus is increased by the fact that it is integrated into a member of the LINE family of repetitive elements, which are very abundant in the primate genome (SHEEN et al. 2000). The LINE sequences flanking the HERV-K element could have mediated a gene conversion event with another LINE element, lacking the insertional mutation, thereby removing the proviral sequence. Otherwise, identical and precise deletions of this sequence would have had to occur twice during primate evolution, which seems unlikely.
Repetitive sequence elements are the most dominant form of noncoding DNA in the human genome, but, because of their tendency to mediate ectopic recombination events and undergo concerted evolution, care must be taken when they are utilized in phylogenetic studies. HERV sequences provide a means to detect the occurrence of such events, however. When using LTR sequences as markers, homogenization by ectopic recombination events is readily apparent as aberrant clustering of the 5' and 3' sequences. In addition to LTR-LTR sequence transfers, confounding results can also arise if the integration of the HERV element occurred near the time of the divergence of the species under study. If the two LTRs of the integrated provirus have not been resident in the genome for sufficient time to acquire a number of mutations prior to the speciation event, the 5' and 3' LTRs will not have sufficient evolutionary history in the ancestral species to distinguish them from one another. Subsequent to speciation, they follow independent paths, so the resultant phylogenetic analysis would place the 5' and 3' LTR sequences from all of the species randomly within the tree. In the presence of concerted evolutionary forces such as gene conversion, however, the 5' and 3' LTR sequences within species would tend to cluster together.
This analysis has demonstrated the sensitivity of HERV loci as indicators of ectopic recombination events and has revealed multiple occurrences of these events during the course of primate evolution. There is no reason to presume that this family of repetitive elements is more prone to mediating such events, so it appears that as a whole these sequences, once regarded as "junk DNA," have had a profound effect in shaping our genome. The question arises as to whether HERV elements can continue to change our genomic landscape through active retrotransposition or recombination events. While no direct evidence indicates that such events are ongoing in the human genome, members of the HERV-K family appear to be the most likely candidates for playing such a role.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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1 Present address: Whitehead Institute, 9 Cambridge Center, Cambridge, MA 02142. 
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSLITERATURE CITED |
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95%. Human 5' and 3' LTR sequences of closely related HERV-K elements were used as outgroups in each analysis and are indicated by element name. HERV-K3p25 is not full length in the chimpanzee and bonobo, but a solitary LTR, which is formed by homologous recombination between the 5' and 3' LTRs, was found at this locus and included in the analysis.
