ISSN 0006-2979, Biochemistry (Moscow), 2023, Vol. 88, No. 11, pp. 1739-1753 © The Author(s) 2023. This article is an open access publication.
Published in Russian in Biokhimiya, 2023, Vol. 88, No. 11, pp. 2109-2126.
1739
REVIEW
Retrotransposons and Telomeres
Alla I. Kalmykova
1,a
* and Olesya A. Sokolova
1
1
Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 119334 Moscow, Russia
a
e-mail: allakalm@idbras.ru
Received June 19, 2023
Revised July 24, 2023
Accepted August 12, 2023
Abstract— Transposable elements (TEs) comprise a significant part of eukaryotic genomes being a major source of ge-
nome instability and mutagenesis. Cellular defense systems suppress the TE expansion at all stages of their life cycle.
Piwi proteins and Piwi-interacting RNAs (piRNAs) are key elements of the anti-transposon defense system, which con-
trol TE activity in metazoan gonads preventing inheritable transpositions and developmental defects. In this review, we
discuss various regulatory mechanisms by which small RNAs combat TE activity. However, active transposons persist,
suggesting these powerful anti-transposon defense mechanisms have a limited capacity. A growing body of evidence sug-
gests that increased TE activity coincides with genome reprogramming and telomere lengthening in different species. In the
Drosophila fruit fly, whose telomeres consist only of retrotransposons, a piRNA-mediated mechanism is required for telo-
mere maintenance and their length control. Therefore, the efficacy of protective mechanisms must be finely balanced in order
not only to suppress the activity of transposons, but also to maintain the proper length and stability of telomeres. Structural
and functional relationship between the telomere homeostasis and LINE1 retrotransposon in human cells indicates a close
link between selfish TEs and the vital structure of the genome, telomere. This relationship, which permits the retention of
active TEs in the genome, is reportedly a legacy of the retrotransposon origin of telomeres. The maintenance of telomeres
and the execution of other crucial roles that TEs acquired during the process of their domestication in the genome serve
as a type of payment for such a “service.”
DOI: 10.1134/S0006297923110068
Keywords: retrotransposons, telomeres, telomerase, polyploidy, Piwi, piRNA, germline, chromatin, LINE1, Drosophila
* To whom correspondence should be addressed.
INTRODUCTION
Currently, a bulk of data has been accumulated to
demonstrate a close relationship between the key cellular
processes and the regulation of the activity of transpos-
able elements (TEs). This relationship enables survival
of TEs in the genomes despite strong defense mecha-
nisms limiting their activity. What mechanism underlies
this global genomic trade-off? TEs serve as a rich source
of evolutionary changes in the genome: they offer en-
hancers, promoters, exons, splicing sites, architectural
elements and participate in the key mechanisms of de-
velopment and immune response [1-4]. TEs contribute
to the maintenance of essential chromosome structures
such as centromeres and ribosomal RNA gene loci [5-8].
In this review, we focus on the origin and maintenance
of telomeres, one of the most compelling cases of the
role of retrotransposons in genome evolution.
Telomeres – the ends of linear chromosomes – have
captivated attention of many scientists for more than
50years. In 1971-1973, Aleksey M. Olovnikov published
his brilliant prediction regarding the “Achilles’ heel of
the double helix,” or chromosome end under-replica-
tion [9, 10]. He also suggested existence of a specialized
DNA polymerase, which compensates for the shortening
of telomeric DNA. Much later this enzyme, now known
as telomerase, was discovered. It turned out that this was
a reverse transcriptase, which acts in a complex with
the RNA template [11]. The ends of the primary linear
chromosomes are thought to be protected by the attach-
ments of retroelements. From this point of view, the
telomerase ribonucleoprotein complex can be consid-
ered as a specialized retroelement that evolved to protect
the chromosome ends [12]. In fact, phylogenetic analy-
sis of the reverse transcriptase of retrotransposons and
telomerase revealed that they originated from a common
ancient retroelement enzyme [13-15]. Telomerase main-
tains telomeres in most organisms, but there are other
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ways to elongate chromosome ends. There are many
modern species of animals whose telomeres are support-
ed by the retrotransposon attachments. These are many
species of insects and, in particular, the Drosophilidae
family. It is believed that Drosophila has lost telomerase,
and the specialized telomeric retrotransposons are used
to maintain telomeres. The telomeres of the silkworm
Bombyx mori are of mixed type, and they are maintained
by the specific telomeric retroelements and low-activity
telomerase. Under certain conditions, retroelements are
also attached to the human telomeres and to telomeres
of other species using telomerase [16, 17]. In these cases,
the double strand break at the chromosome end is used
as a convenient target for TE retrotranspositions. How-
ever, mosquitoes do not have telomerase or telomeric
retroelements, and the telomeres lengthening appeared
to be mediated by the recombination of short satel-
lite-like repeats [18,19].
Telomeres maintained by TE transpositions differ
in the nature of telomeric repeats from telomeres main-
tained by telomerase, but they serve as a reminder of
the retrotransposon origin of telomeres. The study of
the regulation of Drosophila telomeres, which consist of
retrotransposons, reveals a surprising similarity, if not
identity, between the mechanisms that control telomere
maintenance and TE activity. This similarity leads us to
the conclusion that there is a close functional link be-
tween retrotransposons and telomeres in the genome,
which, according to recent evidence, is found not only
in Drosophila but also in mammals.
WHY IS TELOMERASE LOST
IN MANY INSECT AND DROSOPHILA SPECIES?
Telomerase has been lost in many plants and ani-
mals in the process of evolution. Instead, telomeres are
extended by other mechanisms in these cases. In Dip-
tera the telomerase gene was lost about 270 million years
ago[20]. Members of the Diptera group are one of the
most numerous and prosperous species of animals, de-
spite their lack of telomerase. The gene coding for telo-
merase has not been detected in the genome of Drosoph-
ila, and telomere elongation occurs due to transpositions
of specialized TEs. The most thoroughly studied are the
telomeric retroelements of Drosophila melanogaster. They
are represented by three families of LINE retrotrans-
posons (Long Interspersed Nuclear Elements)– HeT-A,
TART, and TAHRE [21, 22]. At the same time, Bombyx
mori has low-activity telomerase, with telomeric niches
actively filled with specialized telomere retrotransposons
SART and TRAS [23]. At present, the evolutionary pres-
sures underlying the apparent reverse evolution and re-
jection of telomerase remain unknown.
Alexey M. Olovnikov was always interested in ex-
ceptions to the rules as he endeavored to explain vari-
ous mysterious phenomena of nature. In this chapter,
we would like to cite his interesting ideas concerning the
loss of telomerase in Drosophila, which he expressed in
personal correspondence: “It is known that the chromo-
somes of the salivary gland cells in D. melanogaster lar-
va are able to undergo many of endoreplication rounds.
In addition, there is a somatic synapse of homologous
chromosomes. Therefore, the lateral conjugation of sis-
ter chromatids, tightly connected together along their
entire length, should necessarily create a mechanical
barrier for the formation of a telomerase telomere. Such
telomere should have a three-dimensional telomere loop.
In the formation of a three-dimensional telomeric com-
plex, hundreds of conjugated chromatid ends, tightly
united in a single polytenic bunch, would create com-
pelling steric obstacles to each other in the formation of
their 3D telomeric complex. Therefore, polytenization
forced Drosophila to abandon telomerase. In contrast,
the G-quadruplex formation, which protects the telo-
meric retrotransposon end on each chromatid, does not
require the telomeric loop and is therefore easily com-
patible with lateral chromatid conjugation. Presumably,
polytenization was the main reason for choosing an
alternative method of protecting Drosophila telomeres.
As it is well known, chromosome polytenization in sali-
vary gland cells in Drosophila larva is necessary for pro-
duction of large amounts of glue before pupation. It is
likely that organisms that need increased gene copy
number and have telomerase telomeres do not use dense
chromatid packaging. For example, in ciliates that have
a polyploid macronucleus and telomerase, chromo-
somes are fragmented. In theory, the following alterna-
tive is also acceptable: if telomeres, unlike the rest of the
polytenized chromatids, are not side-conjugated (and,
therefore, free from the previously mentioned steric hin-
drance), then this expands the possibilities of using the
telomerase method of telomere protection. Therefore,
there may be species in which polytene chromosomes
and telomerase-like proteins are used at some develop-
mental stages, but the ends of the chromosomes are not
paired. Such termini have been cytogenetically observed,
for example, in specialized polytene cells and at the ends
of meiotic pachytene chromosomes of the legume plant
Vigna unguiculata [24, 25]. A tendency to split some
chromosomal ends into oligotene bundles, can be seen
in the polytene chromosomes of certain species [26]”
(from the letter of A. M. Olovnikov to A.I. Kalmykova,
September 2017).
Indeed, recently it was reported that telomeric ret-
rotransposons tend to form G-quadruplexes (secondary
structures formed by guanine-rich DNA sequences) not
only in the Drosophila species, but also in other spe-
cies [27]. Such structures can protect the ends of linear
chromosomes in the absence of a telomeric loop typi-
cal for the telomeres maintained by telomerase. Exis-
tence of alternative ways of telomere maintenance gives
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BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
a unique opportunity to explore emergence of the func-
tional analogues in nature. Researching Drosophila telo-
meres allowed us to take a fresh look at the protective
mechanisms of TE control and their roles in telomere
function. The most striking example is the involvement
of small Piwi-interacting RNA (piRNA) and the piRNA
pathway in the control of Drosophila telomere length in
the germline.
piRNA PATHWAY:
SOURCES AND TARGETS OF piRNAs
TEs were found in all studied species and are rep-
resented by several classes and numerous families [28].
TEs make up half of the human genome and 20% of the
D.melanogaster genome [29] and are the primary source
of mutations that can cause both cancer and severe de-
velopmental disorders [30, 31]. Various mechanisms are
used to limit the activity of TEs in somatic cells and
prevent inherited transpositions in the germline. Mech-
anisms which work at the level of transcription of TEs
are key to prevent the initial stage of their reproduction.
Transcriptional silencing is achieved by two main mech-
anisms leading to the formation of an inactive chromatin
structure. The first and most conservative mechanism
of chromatin compaction is associated with changes in
histone modifications, in particular with methylation
of lysine 9 of histone 3 (H3K9me), which next leads to
the binding and spread of the heterochromatin pro-
tein 1 (HP1) [32]. Another powerful mechanism of re-
pression of transcription is DNA methylation by cyto-
sine-5′-methyltransferases [33]. In the genome, both
DNA methylation and histone modifications target TEs
to prevent their transcription. The main question is how
are these general mechanisms recruited to the TEs?
The KRAB-ZFP (KRAB-containing zinc finger pro-
teins) family proteins play an important role in the recog-
nition and methylation of DNA and histones at endoge-
nous retroviruses in somatic cells of vertebrates [34, 35].
For most plants and animals, RNA interference
is the most conservative and nearly universal mecha-
nism for distinguishing between “self” and “non-self”.
The pathways involving Argonaute family proteins and
associated short RNAs are termed nucleic acid immuni-
ty because these mechanisms may recognize and elimi-
nate foreign nucleic acids belonging to viruses, TEs, or
transgenes based on nucleic acid sequence. siRNA (small
interfering RNA) of 21 nucleotides in length and RNA
interference protect somatic cells from viruses. The pro-
teins of the Piwi subfamily of the Argonaute family and
the associated piRNAs with a length of 24-30 nucleotides
provide protection against TEs and viruses in the animal
gonads [36, 37]. The distinctive feature of this system
is that the Piwi–piRNA complex is able to induce TE
chromatin modifications in a sequence-specific manner,
i.e., to cause transcriptional silencing. Piwi nuclear pro-
teins in complex with piRNAs induce the formation of
heterochromatin, using the complementarity of piRNA
and nascent mRNA of TEs. This is a multi-stage process
that requires the interaction of several linker and acces-
sory proteins, post-translational modifications that result
in assembly, conformational changes, and eventually sta-
bilization of the Piwi-piRNA-driven chromatin protein
complex, and, finally, recruitment of universal heteroch-
romatin factors to TEs [36,38]. Such tight regulation is
essential to turn off the TEs and prevent erroneous re-
pression of cellular genes.
piRNA-mediated silencing is a multi-stage pro-
cess. The main steps of this process are the formation of
long single-strand RNA precursors in the nucleus, their
processing into mature piRNAs in the cytoplasm, and
piRNA-mediated silencing, which can occur both in the
nucleus (transcriptional silencing) and in the cytoplasm
(post-transcriptional silencing).
To perform their functions, mature piRNAs should
complementarily interact with the transcripts of TE, i.e.,
they should be antisense to the mRNA of TEs. Indeed,
a significant portion of piRNAs in the gonads corre-
sponds to TEs, but are not generated from the mRNA
of TEs. The origin of such antisense TE RNAs in the
genome is not quite clear but may involve the follow-
ing mechanisms. piRNAs are thought to be formed
from long single-strand endogenous RNAs known as
piRNAs precursors (pre-piRNAs) [39, 40]. Our knowl-
edge on this issue is mainly obtained from the D. mela-
nogaster oogenesis model. Studies of the genomic ori-
gin of piRNAs in Drosophila have led to the conclusion
that the sources of piRNAs and their targets are locat-
ed at different genomic loci (Fig. 1a). This assumption
was based on the small RNA sequencing data that re-
vealed the regions in pericentromeric heterochromatin
with high density of the single-mapped (in other words,
unique) piRNAs. Such loci were termed piRNA clus-
ters [39]. These extended regions of the genome, up to
200kb in size, enriched in damaged TE copies, encode
unusually long read-through transcripts that are pro-
cessed into mature piRNAs that target euchromatic ac-
tive TEs. This is a remarkable illustration of how the ge-
nome regions that were previously thought of as “junk”
DNA are really being used functionally. It should be
mentioned that this scenario has not been proved to be
universal.
In Drosophila, there are two types of piRNA clusters,
uni-strand and dual-strand, which are transcribed in
one or two directions, respectively. Both types of piRNA
clusters produce predominantly antisense piRNA rela-
tive to TEs. The reason why they are antisense is easier
to understand considering the uni-strand piRNA clus-
ters, in which all TE remnants are in an inverted position
relative to the pre-piRNA transcription direction. The
best-known uni-strand piRNA cluster is the Drosophila
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BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
Fig. 1. Where do piRNA precursors come from? a)Heterochromatic pericentromeric piRNA clusters are the sources of anti-transposon piRNAs
that target the TE active copies. The mapping of small RNAs to the chromosome is schematically shown with the activity of uni- and dual-strand
piRNA clusters depicted below. The Piwi–piRNA complex recognizes and silences TE active copies (black triangle). b)TE active copies form
denovo piRNA clusters. piRNA signature of the TE-associated piRNA clusters is schematically shown. sRNAseq – small RNA sequencing.
c)Transgenic model demonstrates how active TEs in euchromatin could become piRNA clusters. Piwi protein in complex with endogenous piRNA
to I-element recognizes RNA in the complementary transgenic locus, promoting generation of transcripts from both genomic strands, which
are then processed into mature piRNAs.
flamenco locus, which operates in ovarian follicular cells.
It contains many inactive TE copies on the minus genomic
strand relative to the direction of transcription, therefore
the piRNAs processed from long precursor transcripts
are complementary to the transposon mRNAs and guide
their transcriptional silencing [39, 41]. flamenco-like loci
generate piRNAs against endogenous retroviruses related
to the gypsy family. This intricate scenario nevertheless is
recurring in evolution. flamenco-like uni-strand piRNA
clusters have been found in mosquitoes and other Dro-
sophila species [42-44]. Moreover, during mouse sper-
matogenesis, two flamenco-like uni-strand piRNA clus-
ters produce anti-transposon piRNAs [45]. The second
type of heterochromatic piRNA clusters – dual-strand
clusters– are considered as principal players in the an-
ti-transposon defense in the Drosophila germline. These
loci contain chaotically oriented TE copies disrupted by
other TE insertions. Dual-strand piRNA clusters are bi-
directionally transcribed resulting in the generation of
long non-coding piRNA precursors from both genomic
strands [46]. Long piRNA precursors are exported to the
cytoplasm where they are processed into mature piRNAs.
piRNA processing is a conserved well-established mech-
anism in different species. The outer mitochondrial mem-
brane and perinuclear compartment serve as platform for
compartmentalization of piRNA generation and matura-
tion. piRNAs are cleaved as a result of activity of various
specialized ribonucleases. Cytoplasmic Piwi subfamily
proteins perform piRNA amplification using sense and
antisense TE transcripts and piRNA precursors from
clusters, which leads to the formation of both sense and
antisense piRNAs. This mechanism, known as “ping-
pong,” is found in the gonads of all the species stud-
ied, and leads not only to cleavage of TE mRNA (post-
transcriptional silencing), but also to production of new
piRNAs. Recent comprehensive reviews describe in details
the processes of piRNA formation and amplification, as
well as the piRNA processing machinery [36, 37, 47].
Dual-strand piRNA clusters are thought to repre-
sent a repository of information in the genome about
prior TE invasions, as well as a kind of trap for TEs, be-
cause their insertions in the piRNA cluster would lead
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BIOCHEMISTRY (Moscow) Vol. 88 No. 11 2023
to the production of piRNAs and the suppression of
the activity of cognate copies in the genome [48]. While
dual-strand piRNA clusters were shown to be species-
specific for Drosophila and a few arthropod species,
these types of transposon-specific piRNA sources have
not been identified in other investigated species, includ-
ing mammals. The existence of a conservative mecha-
nism for the synthesis of piRNA precursors that are an-
tisense to TEs is still a matter of debate. For example,
sense and antisense piRNAs are produced from indi-
vidual copies of evolutionarily young active retrotrans-
posons in mammals, despite the presence of a signifi-
cant number of damaged TE copies in the genome [45].
In the piRNA pathway mechanism for transposon
silencing, active transposons are expected to be the pri-
mary targets of piRNAs. A more thorough examination
of small RNA libraries derived from D. melanogaster
ovaries revealed that not only heterochromatic piRNA
clusters, but also full-length euchromatic TEs generate
short RNAs, both piRNAs and siRNAs. This shows that
at the sites of recent TE insertions, local dual-strand
piRNA clusters occur [49], which is similar to the sce-
nario of piRNA generation from the active copies of
LINE1 in mammals [45]. A distinctive feature of the
TE-associated piRNA clusters is a “piRNA signature”.
It is an asymmetric profile of small RNA distribution
upstream and downstream of TEs resulting from the
read-through transcription of piRNA precursors into the
TE flanking genomic regions (Fig. 1b). This signature
was successfully used for the prediction of non-annotat-
ed TE insertions. Moreover, the expansion of small RNA
production outside TEs can suppress the expression of
the neighboring genes [49]. Thus, active TEs serve not
only as targets for the piRNA system, which promotes
chromatin compaction, but also as a source of small
RNAs, as they can produce de novo si- and piRNAs.
The Drosophila telomeric retrotransposons, which are
arrayed as tandem repeats in the telomere, are also the
target and source of piRNAs, which allow feedback reg-
ulation of the telomeric retrotransposons expression, as
addressed in more depth in the following section.
The mechanism underlying the formation of new
TE-associated piRNA clusters, particularly the mech-
anism of activation of bidirectional transcription, is not
totally understood. Antisense promoters are known only
for a few TEs and are rather an exception. For example,
the LINE1 human retrotransposon antisense promoter
and the transcripts derived from it are involved in siRNA-
mediated LINE1 transposition suppression [50, 51].
When the Piwi–piRNA complex recognizes complemen-
tary transcripts, an uncommon type of transcription,
convergent transcription, is thought to be triggered at
genomic loci harboring active copies of TEs. This pro-
cess depends on the genomic environment of the TE in-
sertion: endogenous convergent transcription at the TE
insertion locus promotes the formation of a new piRNA
cluster [52]. Transcripts generated from both genomic
strands are then processed into mature pi/siRNAs. Such
a scenario has an obvious biological significance, as it
would result in amplification of protective small RNAs
against most dangerous, transcriptionally active TEs.
Atransgenic model containing a DNA fragment target-
ed by endogenous piRNAs elucidated some details of the
denovo piRNA cluster formation [53-55]. It was shown
that transgenic constructs containing a fragment of I-ele-
ment can become new piRNA clusters. The formation of
piRNA clusters de novo is accompanied by the appear-
ance of weak transcription from the minus strand and the
generation of sense and antisense pi/siRNAs from the
entire transgene and from genomic sequences at a dis-
tance of 1 to 10kb from the transgene [56,57] (Fig.1c).
A scenario in which an active TE is a source of
piRNAs should be evolutionarily beneficial and have
selective advantages. It is unclear why extended hete-
rochromatic piRNA clusters, which are maintained by
aunique transcription mechanism, have survived through-
out evolution in Drosophila and other arthropods. There-
moval of the most extended pericentromeric piRNA
clusters in D. melanogaster were found to not lead to TE
derepression [58]. This suggests that TE silencing in the
stable laboratory line is not primarily mediated by heter-
ochromatic piRNA clusters. This function is most likely
carried out by TE-associated piRNA clusters, which are
generated via the assistance of piRNAs acquired from the
mother with the oocyte cytoplasm [59].
Differences in TE silencing strategies between spe-
cies may be related to different habitats. Horizontal TE
transfer has an impact on natural arthropod populations,
including the re-invasion of previously lost TEs in the
genome [60, 61]. The memory of earlier TE invasions,
which is kept in the form of TE fragments in piRNA
clusters, can protect the population from TE re-infec-
tion due to the existence of complementary piRNAs and
the activation of piRNA-silencing [39, 52, 57, 59, 62].
The idea that active TE copies serve as the prima-
ry targets of the piRNA pathway is emphasized by the
recently discovered mechanism of a co-transcriptional
degradation of TE transcripts [63]. Despite the estab-
lishment of heterochromatin in loci with active copies of
TEs, they can still be transcribed in the germline. Theex-
cess of the TE transcripts in the Drosophila germline is
removed through the activity of the nuclear Ccr4–Not
complex, which has deadenylase activity [64]. Ccr4–Not
is recruited to the transposon transcripts co-transcrip-
tionally by the Piwi-piRNA nuclear complex. Most
likely, the polyA tail at the 3′-end of the TE mRNA is
eliminated due to deadenylase activity of the Ccr4–Not
complex. The nuclear RNA quality control system can
identify these transcripts as aberrant and subject them
to exonuclease cleavage. Noteworthy, the targets of nu-
clear Ccr4–Not are mainly active full-length TEs and
telomeric retrotransposons [63].
KALMYKOVA, SOKOLOVA174 4
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Fig. 2. The piRNA silencing system is a multi-level mechanism. In Drosophila, piRNAs can induce the following processes: a)transcriptional
silencing and chromatin compaction; b)co-transcriptional degradation of nascent RNA in the nucleus via assistance of the deadenylase nuclear
complex Ccr4–Not; c)post-transcriptional RNA degradation and amplification of piRNAs in the cytoplasm; d)de novo piRNA production
at active TEs due to activation of antisense transcription; e)epigenetic transgenerational memory (transfer of maternal piRNAs in complex with
Piwi proteins to offspring through the germ plasm of the oocyte).
To summarize, piRNAs can trigger a number of
important processes aimed at suppressing TE activity
(Fig. 2). In the nucleus, piRNAs induce transcription-
al silencing leading to heterochromatin assembly at the
TE loci [65-67]. The piRNA system also functions at
the co-transcriptional level, causing nucleases to de-
grade TE transcripts at transcription sites [63]. In the
cytoplasm, the piRNA system cleaves TE transcripts
(post-transcriptional silencing), resulting in piRNA am-
plification and their subsequent inheritance through the
oocyte cytoplasm [39, 59, 68-71]. Importantly, piRNAs
can initiate denovo piRNA cluster establishment at full-
length euchromatic TE insertions leading to the expres-
sion of antisense TE transcripts and a burst of piRNA
production against most active TEs [49]. Furthermore,
the fast evolution of proteins participating in the piRNA
pathway allows this system to be highly adaptable to new
targets [72-74]. Despite the high capacity of piRNAs and
other anti-transposon defense systems, selfish TEs suc-
cessfully bypass them, continuing their propagation, re-
sulting in deleterious mutations, diseases, and develop-
mental disorders. A paradoxical situation has emerged in
which the suppression of TE activity requires its activity,
and as a result, the piRNA system operates. Apparently,
the far from perfect efficacy of these and other defense
systems allows TEs to multiply within the tolerable lim-
its, producing material for genome evolution and posi-
tive selection, while also allowing some critical systems,
such as telomeres, to function. The latter phenomenon
will be discussed below.
ROLE OF piRNAs IN REGULATION
OF Drosophila TELOMERES
In Drosophila, disruption of the piRNA system
causes not only TE activation but also excessive telo-
mere extension due to the increased frequency of retro-