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Copyright C 1992, American Society for Microbiology
MINIREVIEW
Short, Interspersed Repetitive DNA Sequences
in Prokaryotic Genomes
JAMES R. LUPSKI1,2 AND GEORGE M. WEINSTOCK3*
Institute for Molecular Genetics' and Department of Pediatrics,2 Baylor College of Medicine, Houston, Texas
77030, and Department of Biochemistry and Molecular Biology, The University of Texas Health Science
Center, P.O. Box 20708, 6431 Fannin Street, Houston, Texas 772253
Repeated sequences are present in the genomes of all
organisms. The DNA sequence organization of eukaryotic
genomes consists of numerous repeats interspersed with
single-copy sequences. This organization has been elucidated through renaturation rate studies of denatured DNA
(2). The best-characterized eukaryotic interspersed repetitive DNA sequences are the repeats in the Alu family that
have been characterized in mammalian genomes (29, 55). In
the human genome of 3 x 109 bp, the 300-bp Alu sequence
represents approximately 3 to 6% of the mass, indicating that
there are approximately 300,000 copies per haploid genome
(55). Interspersed repetitive sequences in numerous prokaryotic and eukaryotic microorganisms have recently been
described (Table 1). The ubiquitous nature and seemingly
random chromosomal distribution of these repeats in prokaryotic genomes suggests that like more-complex eukaryotes, the DNA sequence arrangement in the genomes of
eubacteria may consist of short repeats interspersed with
longer single-copy sequences. Although the precise functions of repetitive sequences in prokaryotic genomes are
obscure, their presence can be exploited for several applications and molecular genetic manipulations.
Prokaryotic genomes contain a variety of low-copy-number repeated sequences, such as insertion elements, rRNA
operons, tRNA genes, and other genes such as those belonging to the rhs gene family (32, 51, 52). These sequences may
contribute to the evolution of chromosome structure through
DNA rearrangements such as chromosomal deletions, duplications, and inversions (44). Repeated genes also provide
mechanisms to enhance bacterial virulence, such as antigenic variation in Neissena gonorrhoeae (21) and other
pathogens. The subject of this minireview is an additional
group of repeated sequences, the interspersed repetitive
sequence elements which are characterized as being short
(usually <200 bp), noncoding, intercistronic, and apparently
widely distributed throughout prokaryotic genomes.
The repeated sequence that was first described and most
intensively studied is the repetitive extragenic palindrome
(REP), or palindromic unit (PU) sequence (12, 24), initially
identified in Salmonella typhimurium and Escherichia coli.
The REP sequence was identified through DNA sequence
comparisons of intercistronic regions of different operons
(12, 24). The REP sequence structure consists of a 38nucleotide consensus sequence which is a palindrome and
can form a stable stem-loop structure with a 5-bp variable
loop in the central region of the consensus sequence (58). In
*
Corresponding author.
4525
REP sequences in which a base pair change from the
sequence has occurred in the region of dyad
symmetry, a compensatory change is usually found in the
symmetric portion of the sequence to maintain the palindrome. The initial analysis of REP sequences in E. coli
showed that the REP sequence was frequently present in
complex clusters of a few copies of the sequence (58). These
clusters are present and transcribed in about 25% of transcription units and may account for as much as 1% of the
total genome. It was estimated that there are between 500
and 1,000 copies of the REP sequence organized into clusters on the E. coli chromosome (58). Subsequent studies
showed these clusters could contain as many as 10 elements
(34). Recently it has been reported that the clusters could
also contain other repeated elements in specific arrangements (17, 18). These latter complex repeats were termed
bacterial interspersed mosaic elements (BIMEs). The E. coli
chromosome was estimated to have about 500 BIME structures, always found in extragenic locations, or about one
BIME for every six genes (17, 18).
The REP element has been shown to be located between
genes within an operon or at the end of an operon, in
different orientations and in tandem arrays, and in operons
distributed throughout the E. coli genome (12, 58). Hybridization experiments, using the E. coli Gene Mapping Membrane (41) containing an ordered library of the E. coli
genome (30), in conjunction with analysis of GenBank and
the E. coli sequence data base EcoSeqS (47, 48), more
accurately mapped the distribution of REP sequences
throughout the genome (6a). This study detected fewer total
REP sequences (563 sequences in 295 clusters). It is difficult
to know which numbers are more accurate, since the hybridization and computer search procedures were known to miss
some sequences, while in earlier studies some REP sequences were duplicated in the data bases used. In any case,
it is clear that REP sequences are distributed throughout the
E. coli genome.
In some but not all cases, the REP element is present in
the same intergenic region of analogous operons from different bacterial species (5, 25). Although REP sequences were
initially described in two members of the family Enterobacteriaceae, S. typhimurium and E. coli, for which substantial
sequence information is available in the DNA sequence data
base, REP-like sequences have been shown to exist throughout the eubacterial kingdom, although consensus sequences
may differ among different bacteria (6a, 11, 63). By using
DNA-DNA hybridization and the polymerase chain reaction
(PCR), REP-like sequences were documented in 7 of the 10
consensus
4526
J. BAcTERIOL.
MINIREVIEW
TABLE 1. Microorganisms shown to carry interspersed
repetitive sequences in their genomes
Organism(s)
Reference(s)
Agrobacterium spp .....................9
19
Bordetella pertussis....................
Brucella spp .................... 22
54
Candida albicans ....................
Cyanobacteria ....................
Deinococcus radiodurans ....................
Escherichia coli....................
TABLE 2. Well-defined interspersed repetitive sequences in
prokaryotic genomes
35
31
12, 24, 27, 56
45
Halobacterium spp .................... 53
73
Leptospira interrogans ....................
8, 46
Mycobacterium tuberculosis ....................
68
Mycoplasma pneumoniae ....................
10
Myxococcus xanthus ....................
Neisseria gonorrhoeae .....................4
Neisseria meningitidis .....................4
60
Pneumocystis carinii ....................
Rhizobium spp .........................9
50
Rhodomicrobium vannielili ....................
Salmonella typhimurium ....................
12, 24, 27, 56
42
Spiroplasma spp ....................
Eukaryotic microorganisms ....................
phyla defined by Woese (69) on the basis of analysis of 16S
rRNA sequences.
Postulated functions for the REP or PU sequence have
included roles in gene regulation by differential translation
within polycistronic operons and retroregulation by stabilization of translationally active mRNA (39, 40, 58, 59). These
functions may be a consequence of the formation of a
stem-loop structure in a specific chromosome location. Although the 3' ends of some mRNAs are found near REP
sequences, the REP sequence does not appear to function as
a transcription terminator (16, 58, 59). One possible exception to this is the report that the REP sequence acts as a
bidirectional transcription terminator between the convergentpheA and tyrA genes (26). It has been proposed that this
REP element is a member of a subclass of REP sequences
termed PU* sequences that have a slightly different sequence and may be transcription terminators (16). The fact
that REP elements are not always present in the same
intergenic regions in different species indicates that they are
not an essential element in the mechanism of gene expression. However, when present they can influence the amount
or regulation of expression of a gene or operon. Additional
proposed functions have related to chromosome structure
(13, 14, 58). It has been shown that the REP sequence binds
DNA gyrase (70) and DNA polymerase I (15) and that the
HU protein stimulates binding of gyrase to the REP sequence (71). These studies have led to the proposal that the
PU or REP sequence is involved in the folding of the
bacterial nucleoid into independent supercoiled looped domains (13, 58). The REP sequence has also been implicated
in chromosomal rearrangements (12, 58) and has been identified at the junction of tandem duplications (57). Any
proposed function(s) must explain the conserved primary
sequence, conserved palindromic structure, location in noncoding regions, inclusion in transcribed sequences, distribution throughout the bacterial chromosome, presence in different species, and ubiquitous nature of the REP sequence.
These characteristics, as well as the lack of a single unified
proposed function, are reminiscent of the Alu family of
repetitive sequences in mammalian genomes.
An additional interspersed repetitive DNA sequence ele-
Size (bp)
Sequence
REP (PU)
38
ERIC (IRU)
126 (124-127)
Ng-rep
26
Dr-rep
150-192
Aft-rep
87
300
RepMP1
SDC1
400
Organism in
which originally
identified
E. coli
S. typhimurium
E. coli
S. typhimurium
N. gonnorhoeae
N. meningitidis
D. radiodurans
M. xanthus
M. pneumoniae
M. pneumoniae
Reference(s)
12, 24
27, 56
4
31
10
68
3
ment in prokaryotic genomes has been identified in E. coli,
S. typhimurium, and other members of the family Enterobacteriaceae. This repetitive element has alternately been
called an intergenic repeat unit (IRU) (56) or enterobacterial
repetitive intergenic consensus (ERIC) (27) sequence. The
ERIC or IRU sequence is approximately 126 bp in length.
Like the REP sequence, it appears from analysis of DNA
sequence information in the data bases that the ERIC or IRU
sequence is located in noncoding transcribed regions of the
chromosome, in either orientation with respect to transcription, and includes a conserved inverted repeat. The chromosomal locations of the ERIC sequence can differ in different
species. In analogous locations, regardless of whether or not
the IRU or ERIC sequence is present in different species, the
surrounding sequence is not disturbed, suggesting either a
precise deletion or insertion relative to the other species
(56). No base pair duplication of surrounding sequence can
be identified, arguing against a classic transposition mechanism for dispersion of these repetitive sequences. ERIC-like
repetitive sequence elements have recently been demonstrated throughout the eubacterial kingdom (63).
Several other small, dispersed repeated sequences have
been characterized in bacteria (Table 2). A 26-bp repetitive
sequence was identified from N. gonorrhoeae by utilizing a
two-dimensional S1 nuclease heteroduplex mapping protocol. A consensus sequence, with five variant positions, was
proposed on the basis of the nucleotide sequences of this
repeat determined from four different locations (4). By
hybridization experiments using a 21-nucleotide oligomer,
sequences related to this repetitive sequence (Ng-rep) were
demonstrated in several N. gonorrheae strains as well as in
the species Neisseria meningitidis (4). By using synthetic
oligonucleotides matching the consensus sequence for the
repeat as primers in the PCR, Ng-rep-like sequences were
detected in many microorganisms (64a). Control experiments indicate that this result was more specific than an
arbitrarily primed PCR assay (66, 67); thus, the Ng-rep
sequence is a candidate for another widely dispersed repeated sequence element.
Additional repetitive sequence elements that have recently been identified from prokaryotic genomes have been
found by hybridization experiments. Typically, a cloned
DNA fragment is used as a probe of total genomic DNA and
produces a complex hybridization pattern, consistent with
multiple copies of all or part of the cloned sequence being
present in the genome. A highly conserved repetitive sequence was identified in this manner from the radioresistant
bacterium Deinococcus radiodurans SARK (31). When an
VOL. 174, 1992
EcoRI-digested D. radiodurans genomic library was constructed in the pUC18 vector, about 3% of all E. coli colonies
hybridized with an insert containing the repetitive sequence.
This repetitive element (Dr-rep) is variable in length, ranging
from 150 to 192 bp, and contains dyad symmetries near each
end based on the nucleotide sequence obtained from five
different repeats.
Hybridization experiments using a restriction fragment in
the intergenic region between the ops and tps genes of
Myxococcus xanthus as a probe of genomic blots identified
many strongly hybridizing genomic fragments (10). The
same restriction fragment was used to screen a M. xanthus
cosmid library containing 30- to 40-kb inserts in the pHC79
vector, and about 3% of the clones hybridized. DNA sequence analysis of six cloned repeats revealed a consensus
sequence with an 87-bp core. Interestingly, by sequence
analysis one of the MX-rep repeats was located downstream
from the rpoD gene (10) in a position analogous to that of a
REP element in E. coli (12).
At least five different repeated elements in Mycoplasma
pneumoniae have been described (3, 49, 61, 68). All of these
are present in 8 to 10 copies per cell and are larger than the
elements discussed previously. The smaller elements are the
300-bp RepMP1 (68) and 400-bp SDC1 (3) elements; the
other elements are from 1.1 to 2.2 kb in size. It is remarkable
that at least 6% of the 840-kb M. pneumoniae genome
consists of repeated sequences (49).
In addition to the repetitive sequences REP (PU), ERIC
(IRU), Ng-rep, Dr-rep, Mx-rep, and those of M. pneumoniae
described above, simple sequence repeats have been identified in eubacteria. In the cyanobacterium Calothrix genome,
three different simple heptanucleotide sequence repeats
were identified and named short tandemly repeated repetitive (STRR) sequences (35). The STRR sequence was initially identified by hybridization experiments. A 413-bpXbaI
restriction fragment located upstream of the cpeBA operon
was used to probe an EcoRI-digested Calothrix genomic
DNA blot. A smear corresponding to multiple hybridization
bands was obtained, suggesting the occurrence of a highly
repeated sequence. The STRR sequences were also found to
be present in the genome of other cyanobacteria.
These observations are reminiscent of the simple sequence repeats, consisting of tandemly amplified sequences,
that have been identified in the human genome. Hypervariable minisatellite regions (28) and variable-number-of-tandem-repeat markers (36) have been useful in fingerprinting
human genomes. Short tandem repeats, or microsatellites
such as (GT)n (33, 65), as well as trimeric and tetrameric
tandem repeats (7), are highly polymorphic and useful in
genetic mapping and DNA typing in humans. In addition,
tandemly reiterated heptanucleotide sequences have been
shown to be a structural sequence component of chromosome telomeres in eukaryotes (1, 72).
Repetitive sequences are ubiquitous in prokaryotic genomes. Their precise function has not been determined.
How repetitive sequences have become dispersed throughout genomes and how their high degree of sequence similarity is maintained are not known. A postulated mechanism for
their propagation and dissemination is as "selfish" DNA by
gene conversion (13, 25). Regardless of how these repetitive
sequences are maintained and dispersed, their presence and
widespread distribution in both prokaryotic and eukaryotic
genomes strongly suggests that they are important to the
structure and evolution of genomes. A functional role in
genome structure for a repetitive sequence from the mouse
has been proposed on the basis of the interaction with
MINIREVIEW
4527
nuclear polypeptides by nitrocellulose filter binding assays
(38). The hypothesized role involves loop anchorage to the
nuclear matrix. This is analogous to some of the proposed
roles for the REP sequence discussed above.
The highly conserved primary sequence structure and
widespread distribution of these repetitive sequences in
prokaryotic genomes can be exploited for several applications and molecular genetic manipulations, as has been done
with the short repeated sequences in mammalian genomes
(20, 23, 37, 43). Recently it has been demonstrated that
synthetic oligonucleotides matching the consensus sequence
for REP and ERIC sequences, with the base inosine placed
at the nonconserved positions, could be used as primers in
the PCR using prokaryotic genomic DNA as a template (63).
In this technique, known as rep-PCR (for repetitive sequence element PCR), the primers bind to the repetitive
sequences in the prokaryotic genome, and if those primer
binding sites are in the proper orientation and within a
distance that can be spanned by Taq polymerase extension,
an amplification product is obtained. Size fractionation of
the amplification products by agarose gel electrophoresis
reveals a specific pattern or genomic DNA fingerprint. These
fingerprints appear to be species and even strain specific
(63). Multiple colonies isolated from the same culture, as
well as repeated isolates over time from the same strain,
reveal a specific pattern (64), demonstrating that the fingerprint is stable and specific to a given bacterial strain.
Fingerprinting by rep-PCR may have multiple applications in
epidemiological studies of microorganisms as well as for
quality assurance or quality control of microorganisms used
in medical, agricultural, and industrial applications (6, 64).
In addition to enabling the generation of strain-specific
fingerprints, primers to repetitive sequences in prokaryotic
genomes may be useful for the mapping of insertion sequences, such as mutations caused by transposon insertions.
By using a REP primer that corresponds to either half of the
REP palindrome, a TnS-specific primer (both of which are
oriented to allow synthesis to proceed into the neighboring
genomic DNA), and chromosomal DNA from a TnS insertion mutant strain as a template, PCR amplification products
that contained an unique sequence located between the
transposon and an adjacent REP sequence were obtained
(62). The unique sequence amplification product was used as
a probe for the TnS-mutated locus by screening an ordered
E. coli genomic library (41), and the insertion was mapped
quickly to a specific region of the chromosome (62). This
rapid physical mapping technique should complement already useful methods for genetic mapping in E. coli. This
procedure should also be important in other bacteria that do
not have as sophisticated genetic techniques for mapping as
E. coli.
In conclusion, it has become clear that the genomes of
prokaryotic and simple eukaryotic microorganisms contain
numerous classes of short repeated sequences, just as was
found a quarter of a century ago for the genomes of higher
organisms. The functions of these sequences are not yet
clear, and notions as to their origin and mechanism of
dispersion are likewise only speculative. Nevertheless, these
sequences are beginning to provide new methodologies for
the identification and genetic analysis of microorganisms and
are likely to play an increasingly important role in studies of
microorganisms in the future, as they have in higher eukaryotes.
4528
MINIREVIEW
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