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Journal of Virology, December 1998, p. 9782-9787, Vol. 72, No. 12
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Human-Specific Integrations of the HERV-K
Endogenous Retrovirus Family
Patrik
Medstrand and
Dixie L.
Mager*
The Terry Fox Laboratory, British Columbia
Cancer Agency, Vancouver, British Columbia, Canada V5Z 1L3, and
Department of Medical Genetics, University of British Columbia,
Vancouver, British Columbia, Canada V6T 1Z1
Received 3 June 1998/Accepted 10 September 1998
 |
ABSTRACT |
Several distinct families of endogenous retrovirus-like sequences
(HERVs) exist in the genomes of humans and other primates. One of these
families, the HERV-K group, contains members that encode functional
proteins and that have been implicated in the etiology of
insulin-dependent diabetes mellitus (IDDM). Because of potential
functional and disease relevance, it is important to determine if there
are HERV-K-associated genetic differences between individuals. In this
study, we have investigated the divergence and evolutionary age of
HERV-K long terminal repeats (LTRs). Thirty-seven LTRs, taken primarily
from random human clones in GenBank, were aligned and grouped into nine
clusters with decreasing sequence divergence. Cluster 1 sequences are
8.6% divergent, on average, whereas cluster 9 LTRs, represented by the
LTRs of the fully sequenced HERV-K10 clone, show an average of only
1.1% divergence from each other. The evolutionary age of 18 LTRs from
different clusters was then investigated by genomic PCR to determine
presence or absence of the retroviral element in different primate
species. LTRs from clusters of higher divergence were detected in
monkeys and apes, whereas LTRs in clusters with lower divergence were acquired later in evolution. Notably, LTRs of cluster 9 were found only
in humans at all nine loci examined. Genomic Southern analysis with an
oligonucleotide probe specific for cluster 9 LTRs suggests that HERV-K
elements with this type of LTR expanded independently in the genomes of
humans and the great apes. This is the first report of endogenous
retroviral integrations that are specific to humans and indicates that
some HERVs have amplified much later than previously thought. These
elements may still be actively transposing and may therefore represent
a source of genetic variation linked to disease development.
| |
INTRODUCTION |
Human endogenous retroviral (HERV)
elements comprise 1 to 2% of human DNA (26), but their
biological relevance is largely unknown. The genomic presence of most
HERVs is presumably without a major effect, but it is possible that
some could be involved in normal or pathogenic processes (18,
29). Recently, the HERV-K (K denoting a lysine tRNA primer
binding site) family of viral sequences has gained attention because a
HERV-K env-encoded superantigen was reported to be
associated with type I diabetes (7). This autoantigen was
detected in insulin-dependent diabetes mellitus (IDDM) patients and
raises the possibility that a genetic susceptibility for developing
IDDM could be linked to variation in the expression or presence of
HERV-K elements in humans. The HERV-K element group (also referred to
as HML-2 elements) (21) is present in about 30 full-length
copies (18) and approximately 2,000 solitary long terminal
repeats (LTRs) (unpublished data). Unlike most HERV families, they have
been shown to encode functional enzymatic proteins (14, 22),
viral particles (6), and autoimmune antigens (7),
indicating that some HERV-K elements have retained retroviral
functions. Previous evolutionary analyses suggested that most HERV-K
elements found in humans integrated prior to the divergence of
hominoids from the Old World monkey lineages (20, 27).
Indeed, no retroviral integrations specific to humans have been
reported to date. Interestingly, the LTRs flanking the originally
sequenced full-length element HERV-K10 are only 0.2% divergent in
sequence (24). Integrated LTR sequences will acquire mutations after insertion (19), so this low degree of
divergence suggests that HERV-K10 integrated relatively recently, but
this possibility has not been investigated. In this study, we have examined different subgroups of HERV-K LTRs to determine their divergence and evolutionary age. Our results indicate that HERV-K elements have spread throughout primate evolution and demonstrate that
a subset specifically integrated and amplified in the human lineage.
| |
MATERIALS AND METHODS |
Sequence analysis.
GenBank was screened with the HERV-K10 5'
LTR (accession no. M12851) by using BLASTN (1). Identified
sequences with structures corresponding to a complete HERV-K LTR were
aligned by using CLUSTALW (28). After sequence alignment
optimization and sequence divergence calculations, programs NEIGHBOR
and DRAWGRAM of PHYLIP (10) were used to calculate the
branch length and to draw the neighbor-joining dendrogram,
respectively. Statistical significance evaluation of the branching
pattern was done with 100 random samplings of the input sequence
alignment by using SEQBOOT of PHYLIP. Consensus sequences were derived
from clusters 1, 3, 8, and 9, respectively, where a nucleotide had to
be present in >60% of the sequences to be considered as a consensus
position. CG dinucleotides were excluded in the consensus.
DNA samples and locus-specific typing.
Genomic DNA was
prepared by using standard protocols from the same primate cell lines
used previously (11). Human DNAs were derived from different
healthy individuals. Primer sequences were specified from regions
flanking integrated LTRs, and a total of 18 primate loci were
investigated for the presence or absence of an LTR, as described
previously (11, 25). The primer sequences and annealing
temperatures used for the amplification of each locus are available
upon request. PCR amplification conditions were as described previously
(21). The first primate species having a particular
integrated LTR is indicated in Table 1. The absence of an integrated
LTR was determined for all 18 loci investigated.
Southern hybridizations.
Primate DNAs were digested with 5 U
of EcoRI per µg of DNA, separated on 0.7%
Tris-acetate-EDTA gels, and transferred by alkali onto nylon
membranes. Hybridization was carried out as previously described
(21). A final high-stringency wash at 68°C was done in
1.25× SSPE (5× SSPE is 0.9 M NaCl, 0.05 M
NaH2PO4, 5 mM Na2EDTA), 0.1%
sodium dodecyl sulfate for 20 min. The oligonucleotide used (5'-CTCAGTAGATGGAGCATACAATCGGGTT-3') was specified to detect
sequences of cluster 9 only (Fig. 1). A complement of this was used in
the hybridizations. The washing stringency (described above) was
determined by dot hybridizations towards identical and related
sequences. Only cluster 9 sequences were detected at this temperature.
| |
RESULTS |
Alignment of HERV-K LTRs.
By searching GenBank with the 968-bp
5' LTR of the HERV-K10 element, we identified 35 additional LTRs. Two
of these came from element K18, from which the LTRs and a short
internal sequence have been determined (23). The remaining
LTRs represented solitary units (17) and were derived from
either random genomic clones or sequences described by others (see
legend to Fig. 1). At the time of the search (December 1997), no other
full-length HERV-K elements were found in GenBank. Solitary LTRs are
the result of homologous recombination between the 5' and 3' LTRs of a
full-length proviral element (11, 17). Therefore, their
sequences and integration patterns can be treated the same way as
full-length elements in an evolutionary analysis of this type. A
dendrogram derived from sequence alignments of the identified LTRs is
shown in Fig. 1. Based on clustering
patterns supported by bootstrap analysis, nine subgroups were
recognized. The branch lengths within a cluster vary substantially,
with cluster 1 sequences being quite divergent and cluster 9 sequences
being much more similar to each other. The LTRs of the full-length
HERV-K10 element belong to the least-divergent subgroup (cluster 9).
The AF012335 GenBank entry from the IDDM-associated element
(7) does not correspond to a complete LTR but has typical
consensus positions of cluster 8 sequences.
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FIG. 1.
Dendrogram derived from 37 HERV-K LTR sequences. The
names of each sequence refer to the GenBank accession numbers from
which the HERV-K LTRs were identified. The names of previously
described HERV-K elements are shown in parentheses, where 5' and 3'
refer to the LTRs flanking the proviral element. GenBank entries
containing more than one LTR sequence are indicated by an a or a b
following the accession number. All LTRs used were complete sequences
of approximately 970 bp, except for the IDDM-associated element, for
which only 809 bp of LTR sequence is available in GenBank (accession
no. AF012335). The values at the nodes indicate the percentage of the
bootstrapped trees supporting the branching pattern, and the numbers in
parentheses indicate the clusters referred to in the text. The length
of the bar corresponds to a nucleotide sequence divergence of 2%.
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|
Integration analysis.
The structure of the HERV-K LTR
dendrogram suggests that sequences of the different clusters represent
integrations separated in time during primate evolution. To determine
whether the clustering pattern and sequence divergence reflect the age
of the LTRs, the approximate time of integration of specific LTRs
belonging to different clusters was determined by examining selected
loci in different primates. Specific primers flanking the sites of the integrated LTRs at 18 loci were used in PCRs of various primate DNAs.
Because each primer set flanks the site of an integrated LTR,
amplification products from DNA having an LTR at a certain locus will
result in a product approximately 970 bp larger than products from DNA
lacking the LTR at the corresponding site. Results, shown in Fig.
2 and Table
1, support the branching pattern. In general, LTR sequences of clusters 1 to 5 were first identified in Old
World monkey and gibbon DNAs, whereas LTRs of cluster 8 first appeared
in DNAs of gorilla and chimpanzee. For example, the AF001550 LTR of
cluster 3 is not present in Old World monkeys but is present in gibbon
and all higher primates. In contrast, the AC003023 cluster 8 LTR is
found only in chimpanzee and human, indicating a more recent
integration (Fig. 2). Initial results with primers flanking three of
the integrated LTRs of cluster 9 resulted in the expected amplification
products in human DNA but not in any of the other primate DNAs (Fig.
2). To demonstrate that sequences of cluster 9 were unique to human
DNA, primers flanking the other six identified LTRs of this cluster,
including the full-length HERV-K10 element, were used in the
amplification of primate DNA. Indeed, all were detected only in human
DNA (Table 1), indicating that sequences derived from this cluster
integrated after the divergence of the human lineage from the great
apes.
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FIG. 2.
Examples of PCR amplification results with
locus-specific primers flanking the integrated LTR of the sequences
indicated. Numbers in parentheses following GenBank accession numbers
refer to the sequence clusters in Fig. 1. Numbers to the left
correspond to the comigrating DNA size markers of each primate panel.
N, New World monkey; O, Old World monkey; Gi, gibbon; Or, orangutan; G,
gorilla; C, chimpanzee; H, human. Expected amplification products were
always obtained for DNA with integrated LTRs or without an integrated
retroviral sequence. A slightly larger product than expected was
observed in the gibbon, using primers flanking sequence AF001550.
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|
The loci of the human-specific LTR cluster 9 were investigated by PCR
amplification with DNA of 10 different individuals.
All individuals
were homozygous for the presence of these LTRs
except for the Z80898a
LTR. This LTR is located upstream of the
DQB1 gene of the MHC cluster
and is the same as the DQ-LTR reported
before (
12).
Individuals (
n = 25) were either heterozygous for
the
integrated LTR (LTR/locus only) or homozygous for the absence
of the
LTR in a ratio of about 1:1 (Fig.
2). Presence of the LTR
does not
appear to be correlated with racial differences. We also
found another
GenBank entry (
U92032), which is about 96% identical
in both the DQB1
gene and the flanking region compared to
Z80898.
This entry did not
have the LTR integrated at the corresponding
position. DQB1 alleles are
highly polymorphic and originated at
least 30 million years ago
(
3), indicating that the polymorphism
of this LTR is likely
due to its association with the
MHC.
To gain insight into the evolutionary history of HERV-K sequences, the
divergence values between LTR sequences within a cluster
were
determined. In a master gene element model, such as that
proposed to
explain the dispersion of alu sequences (
9), the
divergence
values between sequences within a cluster should reflect
the number of
nucleotide substitutions that occurred since their
dispersion within
the primate genomes. Indeed, the observed changes
for LTRs of clusters
1, 3, 8, and 9 correspond well to the expected
pseudogene divergence
rates (
5) with respect to their first
appearance in the
primate lineage (Table
1). Comparison of the
divergence rates between
the consensus sequences derived from
each of these clusters also showed
expected divergence rates.
Therefore, the results obtained with the
sequences used here support
an expansion of HERV-K elements according
to a master element
model (
9), with different master
progenitors being active at
different times in
evolution.
Independent amplification of cluster 9 sequences in hominids.
The cluster 9 sequences represent elements that have retrotransposed
relatively recently. This cluster also contains one LTR (M57950) that
is present in the chimpanzee but not at the corresponding locus in
humans (8). Thus, the cluster 9 sequences may represent elements that have expanded independently in the different primate lineages. To investigate this possibility, an oligonucleotide probe
specific for the cluster 9 sequences was used in Southern hybridization
to a panel of primate DNAs. We estimate that there are at least 300 to
400 of these LTRs in human DNA, assuming that the eight sequences of
cluster 9, which were identified in random genomic clones, are a
representative number present in the ca. 2% of the human genome
sequenced to date. As expected, many hybridizing fragments were seen in
the DNAs used, even after stringent hybridization conditions (Fig.
3), making interpretations regarding
common and unique hybridizing fragment sizes between the DNAs
difficult. The very intense bands of sizes greater than 3.5 kb must
represent multiple hybridizing fragments. This pattern suggests that
some of these LTRs are part of larger DNA segments that have amplified by other mechanisms. This intense banding pattern precludes examination of bands representing single LTRs in the size range above 3.5 kb.
However, several discrete hybridizing fragments in the sizes of 1.5 to
3.5 kb were detected in the DNAs analyzed and likely represent single
integrants. Of the fragments in this region, only one was in common for
gorilla, chimpanzee, and human DNA, whereas 11 were unique in human
DNA, 8 were unique in the chimpanzee, and 6 were unique in the gorilla.
These differences are higher than can be explained by restriction
enzyme site differences alone, because the expected divergence between
human and great ape DNAs is only 2% (5). Even though only a
fraction of the total number of cluster 9 LTRs can be analyzed by
conventional Southern hybridizations, it is evident that several unique
fragments are present in the different primates examined, suggesting an
independent amplification of cluster 9 sequences in different primate
lineages.
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FIG. 3.
Southern hybridization with an oligonucleotide specific
for cluster 9 LTRs with a panel of primate DNAs digested with
EcoRI (see legend to Fig. 2 for abbreviations). To the left
are sizes of the comigrating DNA size markers (in kilobases), and to
the right an arrow indicates a hybridizing DNA fragment common to the
gorilla, chimpanzee, and human within the 1.5- to 3.5-kb region
indicated with a bracket. Fragments larger than 3.5 kb were too
numerous to analyze.
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|
| |
DISCUSSION |
The endogenous retroviral sequences found in the human genome are
a heterogeneous group of retroelements that were presumably derived
from ancient germ line infections of exogenous retroviruses which
became fixed in the species. In this study, we have defined distinct
subgroups of HERV-K LTRs of different ages. Figure
4 illustrates the approximate time of
integration of the particular LTRs investigated by locus-specific PCR
analysis. These results, in combination with the cluster analysis,
showed a correlation between sequence divergence and the age of the
different element subgroups and supports an expansion of HERV-K
elements similar to a master gene model (9). That is, the
data suggest that different progenitor HERV-K elements amplified in the
genome at different stages in primate evolution. The division of HERV-K sequences into subgroups has also been suggested in two recent reports
(16, 30) in which other sequence sets were used, derived from either the polymerase gene or from chromosome 19 LTR sequences. However, those previous studies did not investigate the integration time of different subgroups.
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FIG. 4.
Approximate integration times of HERV-K elements. Arrows
indicate the lineage in which a particular LTR was first detected, and
numbers refer to the cluster as identified in Fig. 1. Time estimates
for divergence of the different primate lineages were taken from Bailey
et al. (5).
|
|
During the course of our analysis, we identified a subset of endogenous
retroviral elements that has integrated specifically in the human
lineage. Interestingly, besides representing a subset with mobile
capacity in humans, cluster 9 sequences were shown by Southern analysis
to exist in similar numbers in the genomes of humans and the great
apes. However, the different banding patterns and the fact that none of
the nine specific loci containing cluster 9 elements in humans were
occupied in the great apes indicate that most HERV-K cluster 9 elements
have amplified independently in chimpanzee and gorilla. This study is
the first demonstration of endogenous retroviral integrations specific
to humans. Subgroups of another HERV family, HERV-H (formerly RTVL-H),
have also been defined based on LTR structure and shown to be of
different ages (11). However, the HERV-H subgroups
identified to date are older than the HERV-K cluster 9 elements, since
their LTRs are more divergent and no human-specific integrations have
been detected.
An L1 retrotransposon sequence was earlier shown to have integrated
into the factor VIII gene, although the master copy is present at the
same chromosomal locus in gorillas, chimpanzees, and humans
(13). This finding indicates that retroelements may retain
their mobile properties despite a relatively old age. The LTR of the
element linked to IDDM falls into cluster 8 (Fig. 1) and is probably of
the same age as other sequences of this cluster. This cannot be
investigated directly, however, because the corresponding locus has not
been cloned. The LTR sequence alignments reveal that regions involved
in HERV-K transcription
the hormone-responsive element, the TATA, and
polyadenylation motifs (23)are conserved in sequences
belonging to both clusters 8 and 9, suggesting conserved functional
properties of these LTRs. Thus, it is possible that some HERV-K
elements belonging to cluster 8 have spread after the divergence of
humans and the great apes, as was shown for cluster 9 sequences.
Efforts are under way to screen a larger set of human DNA samples to
determine whether a copy number variation of cluster 8 or 9 HERV-K
elements exists. One polymorphic human cluster 9 LTR locus associated
with HLA was identified here. The presence of this LTR was originally
described by Kambhu et al. (12) and was also shown to be
linked to haplotypes with susceptibility for the development of IDDM
(4). The presence of a functionally transposing subset of
HERV-K in the human lineage strengthens the possibility that
polymorphic HERV-K alleles may be associated with the development of
IDDM in some individuals. It is evident that the acquisition of
proviruses at novel chromosomal locations may lead to an altered
expression pattern of both viral and cellular genes. However, they
could also represent alleles fixed in the primate genome that at some
stage become transcriptionally activated. Several studies have
reported differential expression of HERV-K in leukocytes of
different individuals (2, 15). Thus, it is possible that
copy number polymorphism or transcriptional activation contributes to
variations in gene expression which may lead to the development of
diseases having a genetic basis.
| |
ACKNOWLEDGMENTS |
We thank Doug Freeman for technical support, Mats Lindeskog and
Garvin Hunter for valuable discussions, and Robert Kay for critical
reading of the manuscript. We also thank Christine Kelly and Melissa
Hudson for help with manuscript preparation.
This work was supported by the Medical Research Council of Canada and
the Crafoord Foundation, Lund, Sweden. P.M. received a postdoctoral
fellowship from the Cancer Research Society of Canada and an award from
the Tage Blücher Foundation, Helsingborg, Sweden.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Terry Fox
Laboratory, B.C. Cancer Agency, 601 West 10th Ave., Vancouver, B.C.
V5Z1L3. Phone: (604) 877-6070, ext. 3185. Fax: (604) 877-0712. E-mail: dixie{at}unixg.ubc.ca.
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0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
