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Mobile Genetic Elements of Malaria Vectors and Other Mosquitoes

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Mosquitoes are important vectors of a number of disease agents including malarial and filarial parasites as well as many types of viruses. A wide spectrum of both RNA-mediated and DNA-mediated transposable elements (TEs) have been discovered in the African malaria mosquito, Anopheles gambiae, and other mosquito species. Mosquito TEs are potentially useful as tools for genetic manipulation, or as markers for population studies. Such genetic and population studies are relevant to the long-term strategy to control mosquito-borne infectious diseases through the introduction and spread of refractory mosquitoes in natural populations. Here we present an overview of the characteristics of mosquito TEs. We highlight several mosquito TEs that appear to be transpositionally active and a few newly discovered elements that offer interesting perspectives on TE diversity, classification, and transposition. TE display, a PCR-based genome scan method, is also described in the context of uncovering polymorphism at TE insertion sites and detecting new transposition events. We conclude the review outlining questions that are of fundamental and applied significance in mosquito TE research and providing promising new research avenues in light of a growing number of mosquito genome projects and systems biology methods.

Introduction

Transposable elements (TEs) are mobile genetic elements that are widely distributed in bacteria, archaea, and eukaryotes.1 TEs are generally thought to replicate and spread in their host genomes as primarily “selfish” genetic units.2,3 However, recent genomic and experimental data suggest that the “selfish” TEs could evolve a spectrum of relationships with their hosts, ranging from “junk parasites” to “molecular symbionts”.4,5 Some TEs have been shown to perform important biological functions in their hosts. For example, the RAG1 and RAG2 proteins, which are enzymes that are involved in V(D)J recombination in jawed vertebrates, originate from an ancient transposase.6 In fact, a recent analysis has identified a Transib transposon as the modern-day relative of RAG1.7 V(D)J recombination is very important to the vertebrate immune system as it significantly contributes to the diversity of antibodies and T-cell receptors.

There are two classes of TEs that utilize different transposition mechanisms. Class I RNA-mediated TEs synthesize cDNA molecules that are integrated in the genome. The cDNA molecules are reverse transcribed from TE transcripts, which serve as the retrotransposition intermediates.8 Class II DNA-mediated TEs transpose directly from DNA to DNA and they do not need an RNA intermediate.1 Instead, DNA-mediated TEs transpose through either “cut and paste” or “rolling circle” mechanisms. In most cases, insertion of both classes of TEs causes the duplication of the insertion target. Such target site duplications (TSDs) flank the actual TE sequence and serve as a hallmark of TE insertion.

RNA-mediated TEs include long terminal repeat (LTR) retrotransposons, nonLTR retrotransposons, and short interspersed elements (SINEs). NonLTR retrotransposons are also referred to as retroposons or long interspersed elements (LINEs). The structural features of the three groups of RNA-mediated TEs are illustrated in (Fig. 1A-C). The LTRs in the LTR retrotransposons are normally 200 to 500 bp long and provide promoter sequences and transcription termination signals.8 LTR retrotransposons encode a polymerase (pol) protein that contains reverse transcriptase (RT), ribonuclease H (RNase H), protease (PR), and integrase (IN) domains that are important for their retrotransposition. The RT domain catalyzes reverse transcription and its sequence is used for phylogenetic classification of LTR retrotransposons.8 Like the LTR retrotransposons, most nonLTR retrotransposons also have a pol-like protein that includes a RT domain that is essential for retrotransposition. Some nonLTR elements also have an RNase H and/or endonuclease domain encoded in the pol open reading frame. In addition to the pol-like protein, many nonLTR elements encode a protein related to the retroviral group-associated antigen (gag) protein. NonLTR retrotransposons are transcribed from internal Pol II promoters. Some contain AATAAA polyadenylation signals, poly (A) tails, or simple tandem repeats at their 3' ends. Target Primed Reverse Transcription has been proposed as the mechanism of retrotransposition for the nonLTR elements.9,10 SINEs, the third group of Class I TEs, are generally between 100 to 500 bp long and they do not have any coding potential. It has been shown that some SINEs retrotranspose by “borrowing” the machinery from autonomous nonLTR retrotransposons, and that this process may be facilitated by the presence of similar sequences or structures at the 3' ends of a SINE and its “partner” nonLTR retrotransposon.11-14 Unlike nonLTR retrotransposons that use internal Pol II promoters, SINE transcription is directed from Pol III promoters that are similar to those found in small RNA genes.

Figure 1. Structural characteristics of TE representatives in mosquitoes.

Figure 1

Structural characteristics of TE representatives in mosquitoes. Representatives of RNA-mediated TEs are shown from three major groups, long terminal repeat (LTR) retrotransposons (A), nonLTR retrotransposons (B), and short interspersed elements (SINEs, (more...)

As shown in (Fig. 1D-F), DNA-mediated TEs include cut and paste DNA transposons, miniature inverted-repeat TEs (MITEs), and Helitrons.15,16 DNA transposons such as P, Hermes, piggyBac and MosI are typically characterized by 10-200 bp terminal inverted-repeats (TIRs), flanking one or more open reading frames that encode a transposase. They usually transpose by a cut-and-paste mechanism and their copy number may be increased through a repair mechanism.1,17 MITEs are short nonautonomous TEs that share common structural characteristics such as TIRs, small size, and lack of coding sequence.18 MITEs are thought to transpose by “borrowing” the machinery of autonomous DNA transposons, taking advantage of shared TIRs.19-21 An alternative hypothesis suggests that they may transpose by a DNA hairpin intermediate produced from the folding-back of single-stranded DNA during replication.22 Helitrons, the third group of Class II TEs, appear to use a rolling-circle mechanism of transposition.15,16,23 Instead of a cut and paste transposase, Helitrons encode proteins similar to helicases, ssDNA-binding proteins, and replication initiation proteins. These proteins facilitate the rolling-circle replication of Helitrons, a mechanism previously described for the bacterial IS91 transposons.24

Because of the potential utility of TEs as genetic tools to manipulate mosquitoes and other important disease vectors, molecular analysis of mosquito TEs has attracted significant attention. The report of the An. gambiae genome sequence and the near completion of the genome assembly of the yellow fever mosquito, Aedes aegypti, made it possible to systematically study mosquito TEs and offered a great opportunity for comparative analysis. There are a few recent reviews on insect TEs and their use as genetic tools.25-27 In this chapter, we will review the different types of TEs in the African malaria mosquito, An. gambiae and other mosquitoes. We will focus on recent advances in mosquito TE research and provide a perspective for future investigations.

Overview of Mosquito TEs

A number of TEs have been discovered from An. gambiae, Ae. aegypti and other mosquitoes28-35 before the availability of genome sequence data. The publication of the An. gambiae genome sequence assembly36 included an initial survey of TEs. Several detailed characterizations of different groups of TEs in the An. gambiae genome have since been reported.37-43 TEs occupy at least 16% of the euchromatic region in An. gambiae36 and the nonLTR and LTR retrotransposon groups contain tremendously diverse TEs.37,41 Initial analyses of the early version of the Ae. aegypti assembly (The Institute for Genomic Research, February, 2005) indicate that more than 40% of the genome consists of TE derived sequences (Z. Tu, unpublished data). This number is likely to increase as more careful investigations are completed and a better assembly becomes available. NonLTRs, SINEs, and MITEs are the predominant types of TEs in Ae. aegypti with regard to copy number. JuanA, a nonLTR retrotransposon in Ae. aegypti, consists of more than 10,000 copies and occupies at least 3% of the entire genome. The majority of TEs reported in mosquitoes are from either An. gambiae or Ae aegypti. However, there are several reports of both classes of TEs in other mosquitoes and there are PCR surveys of TEs in a number of species.33,44-47 All major groups of TEs in both classes have been found in mosquitoes. Figure 1 shows the characteristics of representatives of the major groups of RNA-mediated and DNA-mediated TEs. Tables 1 and 2 provide the names, classification, and characteristics of the two classes of TEs in mosquitoes. The two tables include substantial updates that were not discussed in previous reviews.25,27

Table 1. RNA-mediated transposable elements in mosquitoes.

Table 1

RNA-mediated transposable elements in mosquitoes.

Table 2. DNA-mediated transposable elements in mosquitoes.

Table 2

DNA-mediated transposable elements in mosquitoes.

Highlights and Recent Developments

Herves, an Active hAT-Like Transposon in An. gambiae

One exiting development in mosquito TE research is the report of an active DNA-mediated transposon in An. gambiae.59 This element, named Herves, is a member of a subfamily within the hobo-Ac-Tam3 (hAT) family. Herves was discovered during a whole-genome computational analysis for active DNA transposons. Herves was shown to be transpositionally active in mobility assays performed in Drosophila melanogaster S2 cells and developing embryos. Herves was also successfully used as a germline transformation vector in D. melanogaster. It remains to be determined whether Herves is currently active in An. gambiae populations. However, Herves insertion patterns in individuals of an East African population are at least consistent with it being active in mosquitoes. The few TEs that are used to transform mosquitoes are DNA transposons mainly from nonmosquito insects. Herves may be developed as an additional transformation vector for genetic manipulation of mosquitoes. Perhaps more importantly, if Herves is indeed actively transposing in An. gambiae populations, researchers will for the first time have the opportunity to study how active endogenous DNA transposons are regulated in mosquitoes and how this active element behaves in natural populations, which will be of great practical significance (see section on Practical Applications).

Gambol, a Novel Family of Transposons in the IS630-Tc1-Mariner Superfamily

Eukaryotic DNA transposon families Tc1 and mariner and the bacterial IS630 element and its relatives in prokaryotes and ciliates comprise a superfamily, the IS630-Tc1-mariner superfamily.35,69-71 As shown in (Table 2), the common motif of the transposase in this superfamily is a conserved D(Asp)DE(Glu) or DDD catalytic triad. Tc1-like elements identified in fungi, invertebrates and vertebrates all contain a DD34E motif. Analysis of the An. gambiae genome revealed a novel family of transposons named gambol, which uses a DD34E catalytic triad but are phylogenetically distinct from all Tc1 transposons (Table 2).42 Gambol and Tc1 transposons are distinct clades that are separated by mariner (DD34D catalytic triad) and other families of the IS630-Tc1-mariner superfamily. Although gambol appears to be related to a few DD34E transposons from cyanobacteria and fungi, no gambol-like elements have been reported in any other insects or animals thus far. It is possible that gambol may be the founding member of a deep lineage of widely distributed DD34E transposons and additional gambol-like transposons from diverse organisms may be discovered as more genome sequences become available. Another family in the IS630-Tc1-mariner superfamily, DD37E, has also only been found in mosquitoes so far.35 The mosquito-specific distribution of these unique transposon families is intriguing, although there is no obvious reason to suggest that mosquito genomes are particularly fertile grounds for unique families of DNA transposons.

LTR Retrotransposons: Diversity and Potentially Active Elements

A large number of LTR retrotransposons exist in the An. gambiae genome. For example, a detailed analysis uncovered 63 LTR retrotransposons in the Ty3/gypsy clade, although the copy number of these elements tends to be low (less than 30 copies).41 This characteristic of low copy number but high diversity appears to be shared by elements in the Ae. aegypti genome (S. Li and Z. Tu, unpublished data). Approximately 75% of the An. gambiae Ty3/gypsy elements appear to have been at least recently active, on the basis of sequence analysis. There is experimental evidence of activity for three different LTR retrotransposons in An. gambiae. Biessmann et al32 showed strong RNA expression of a LTR retrotransposon named Moose in the male and female gonads. Rohr et al48 showed that mtanga, a Ty1/copia retrotransposon specific to the Y chromosome, was actively transcribed. One-LTR circles, which are potential replication intermediates, were detected of mtanga. Recently, a Bel-like element named Belly, was also shown to be potentially active in An. gambiae (M. Alvarez, M. Davenport, M. Jacobs-Lorena, and Z. Tu, unpublished data). Two short peptide sequences that are parts of the Belly protein were detected in the midgut. One-LTR circles of Belly were recovered from An. gambiae cells. The An. gambiae genome may be a rich source of active LTR retrotransposons that could be developed as genetic tools.

NonLTR Retrotransposons: Unprecedented Diversity and Potentially Active Elements

An unprecedented diversity of nonLTR retrotransposons was discovered by analysis of the An. gambiae genome assembly.37 More than 100 nonLTR retrotransposons were found by a reiterative and exhaustive search using the conserved reverse transcriptase (RT) domains of representatives of known nonLTRs as the starting queries. These nonLTRs range from a few to approximately 2000 copies and occupy at least 3% of the genome. An. gambiae nonLTRs represent eight of the 15 previously defined clades plus two novel clades Loner and Outcast. Five belong to the L1 clade, the first such elements in an invertebrate. Although most nonLTR elements appear to be inactive, there are approximately 20 elements that showed characteristics of recent activity. The incredible diversity and the maintenance of multiple recently active lineages within different clades are intriguing. Preliminary analysis of the Ae. aegypti genome assembly revealed more than 150 nonLTR retrotransposons that belong to 11 clades (J. Biedler and Z. Tu, unpublished data). This represents the greatest diversity in any reported genome. Penelope, an interesting group of retrotransposons that contain introns,72 was also found in Ae. aegypti (Biedler and Tu, unpublished data). Some of the Ae. aegypti nonLTR retrotransposons are highly repetitive. For example, JuanA, an element in the Jockey clade, consists of more than 10,000 copies and occupies at least 3% of the entire genome. This high copy number is unexpected as previous estimation by Southern blot suggested approximately 200 copies.30

Gecko and MosquI

Gecko is a novel SINE discovered in Ae. aegypti.57 It is shown that SINE transcripts are recognized by the retrotransposition machinery of its partner nonLTR retrotransposon through shared sequences or structures at their 3' termini.11,12 The 3' regions of gecko and MosquI are similar in sequence and identical in secondary structure. MosquI is a potentially autonomous nonLTR retrotransposon in Ae. aegypti that is related to the Drosophila I factor.53 It is possible that MosquI is the nonLTR retrotransposon “partner” of gecko. With respect to 3' termini, nonLTR retrotransposons are classified as poly(dA) elements such as human L1 or elements with 3' tandem repeats such as the Drosophila I factor.73 Some SINEs such as Alu end with poly(dA) while others including Ae. aegypti Feilai end with simple tandem repeats. What is unique about gecko is that it has different types of 3' termini, either poly(dA) or tandem repeats with variable sequences. Many of the gecko copies that end with different termini could not be differentiated when the 3' poly(dA) or repeats were excluded in phylogenetic and sequence analyses. Alteration of 3' termini during retrotransposition has been experimentally demonstrated using artificial constructs of the Drosophila I factor and the human Alu elements.11,12 The analysis of gecko represents the first report of natural alterations between 3' tandem repeats and a poly(dA) tail in a SINE family. The 3' tandem repeats and poly(dA) tails may be generated by similar mechanisms during retrotransposition and gecko provides genomic and evolutionary support for the previously proposed slippage retrotransposition model.57 The error-prone reverse transcription may generate the initial change in a 3' repeat unit in a retrotransposed copy of nonLTR element or SINE and the altered repeat unit could subsequently be replicated during slippage reverse transcription. Thus the distinction between poly(dA) and nonpoly(dA) elements may not be informative with regard to their origin and evolutionary relationship.

TE Display

TE display is a recently developed experimental method to detect TE insertions and it has the potential to significantly impact mosquito TE research.74-76 It is a variation of Amplified Fragment Length Polymorphism (AFLP), the difference being that one primer is designed according to a TE sequence. First, genomic DNA is digested using a four-base restriction enzyme such as BfaI and then ligated to an adapter sequence. This is followed by two rounds of PCR with a radioactive-labeled nested primer specific for the TE sequence in the second round. Products are run on a sequencing gel and visualized by autoradiography. When conditions are optimized, each band represents a TE insertion site. Because TE display is a PCR-based approach, hundreds or more reactions can be run using genomic DNA isolated from individual mosquitoes. Therefore, many different TEs could be tested using the same DNA sample. TE display offers a higher degree of sensitivity and resolution than genomic Southern analysis. After TE display, one side of the TE insertion and its associated flanking sequence can be recovered because the band can be reamplified and sequenced. The insertion site may be precisely located if the genome sequence is available. TE display has been established with several families of MITEs,76 SINEs (Y. Qi, A. della Torre, T. Scott, L. Harrington, G. Yan, and Z. Tu, unpublished data), and nonLTR retrotransposons77 in An. gambiae and/or Ae. aegypti. The highly polymorphic nature of the insertions of Herves59 and several nonLTR retrotransposons77 was used as indirect evidence for current or recent transposition. One important advantage of TE display is the ability to rapidly scan a large number of TE insertions across a genome. Therefore TE display is useful to screen for polymorphic insertion sites and to detect new insertions that result from transposition.78,79 For example, TE Display has been used to detect somatic cell transposition,78 simply by looking for the presence of new bands that represent newly transposed copies of a TE. The same method may also be used to identify germline transposition by comparing TE display patterns of parent insects with the patterns of a large number of offspring.

Practical Applications

TEs and Genetic Manipulation of Mosquitoes

Active TEs can be used as vectors to insert genes of interest into the genome of a species to change its genetic makeup. TEs can also be used for gene trapping, enhancer trapping, and genome-wide insertional mutagenesis studies, which are powerful ways to investigate gene function and regulation on a genome scale.80-82 A small number of DNA transposons such as Hermes, MosI, minos, and piggyBac, which are exogenous to mosquito species, show varied degrees of utility as transformation tools in mosquitoes.26 Interestingly, Hermes, MosI, and piggyBac display noncanonical integration in the germline of Ae. aegypti and/or Culex pipiens quinquefaciatus.83-86 For example, when a plasmid that contains an autonomous Hermes element was introduced into the Ae. aegypti germline, a complete copy of the plasmid was integrated as well as an adjoined rearranged partial copy.85 Although somatic mobilization events were detected in the above transformants, no remobilization was detected in the germline. Improvement of current transformation vectors and development of new vectors are urgently needed and a better understanding of mosquito TEs will facilitate this effort. For example, a better understanding of mosquito TEs will help mitigate the interactions between exogenous vectors and endogenous transposons that share similar TIRs, which has been shown to be potentially problematic.87,88 In addition, analysis of TEs in mosquito genomes will expand the pool of active TEs, which may be used to design a suite of tools with unique and useful features. As discussed earlier, Herves, a hAT-like transposon discovered in the An. gambiae genome was shown to be able to mobilize in D. melanogaster.59 Therefore, Herves has the potential to be a new transformation vector. Because TEs has the potential to replicate in germline and rapidly spread in a population, scientists are exploring the possibility to use TEs to “drive” beneficial transgenes into insect populations.89,90 This strategy is being investigated in the context of “driving” refractory genes into mosquito populations to control mosquito-borne infectious diseases.91,92 A better understanding of the activity and regulation of endogenous TEs and their behavior in mosquito populations is critical to help achieve the sustained success of such sophisticated genetic approaches.

TE Insertions As Population Markers

TE display of a number of DNA and RNA-mediated elements showed high levels of insertion site polymorphism in An. gambiae and Ae. aegypti populations.59,76,77 In most cases, TE display bands may only be used as dominant markers because individuals with insertions at both alleles cannot be distinguished from individuals that have TE insertion at only one of the two alleles. To mitigate this disadvantage, TE display can be used to identify and isolate TE insertion sites that are polymorphic in mosquito populations. Once such insertion sites are identified, sequences flanking a TE at a specific locus may be used as primers to amplify genomic DNA isolated from an individual. When the PCR products are run on an agarose gel, individuals with insertions at both alleles will show a single high molecular mass band while individuals with no insertions at either allele will give a single low molecular mass band. Individuals that have heterozygous alleles will display both bands. SINEs including the human Alu elements have been shown to be extremely powerful genetic markers using this locus-specific PCR method (e.g., refs. 93-96). SINE insertion markers have a few potential advantages over other interspersed markers such as microsatellite and Single Nucleotide Polymorphism.96 The same SINE insertions at a specific locus are considered identical by descent and the ancestral state of SINE insertion polymorphism is known, which is the absence of a SINE. However, one has to be cautious because SINE excision and other rare confounding events do occur.97 As shown in (Table 1), several families of SINEs have been described in Ae. aegypti, C. pipiens, and An. gambiae. It is possible to efficiently screen for SINE insertion polymorphism in mosquitoes using TE display (Y. Qi, A. della Torre, T. Scott, L. Harrington, G. Yan, and Z. Tu, unpublished data).76 TE display and TE-based locus-specific PCR are being used as genome-wide markers to investigate the genetic differences between An. gambiae populations, which is significant because genetic heterogeneity between mosquito populations can affect both the efficiency of disease transmission and the effectiveness of mosquito control measures.98,99 There is genetic discontinuity in sympatric populations of An. gambiae.100 Two “molecular forms”, M and S, were defined on the basis of single nucleotide differences in rDNA sequences and this grouping was supported by the virtual absence of hybrid rDNA genotypes in nature. Microsatellite surveys suggest that the two forms are in the process of incipient speciation, with low levels of gene flow between forms homogenizing regions of the genome that are not directly involved in the speciation process. TE (or SINE) based markers may prove to be powerful new tools for population genomic analysis of the divergence between the M and S molecular forms of An. gambiae.

Future Perspectives

This is an exciting time for mosquito TE research. The diversity of recent discoveries highlighted in the previous sections represent only a modest beginning. The publication of the An. gambiae genome assembly36 has propelled mosquito TE research into the genomic era. The nearly completed Ae. aegypti genome assembly has already become a tremendous resource for TE discovery and genomic and evolutionary comparisons of TEs in highly divergent mosquito species. In addition, sequencing of the C. pipiens quinquefaciatus genome, supported by the National Institute of Allergy and Infectious Diseases (NIAID), has already begun. The National Human Genome Research Institute (NHGRI) has approved the sequencing of the M and S forms of An. gambiae. A proposal is being considered which calls for sequencing of six additional species of Anopheline mosquitoes including two additional members of the An. gambiae complex (Nora Besansky at the University of Notre Dame, personal communication). Accompanying the genome sequencing of a growing list of mosquito species is the development of a number of powerful computational tools for the discovery and characterization of TEs on a whole-genome scale. These include several computational approaches that have been previously reviewed27 and a few new tools that employ different strategies.101,102 There are also efforts to develop systems biology methods to study mosquito TEs that are described below. The ongoing accumulation of genomic resources and recent advances in research methodology make it possible to address a number of exciting questions of fundamental and applied significance.

Impact on Gene Expression

There are a number of different ways by which TEs may affect host biology. It has been argued that TE insertions may interact with the regulatory elements of nearby genes and thus alter their expression.5,103 The availability of a number of mosquito genomes offers the opportunity to systematically investigate the effect of TEs on nearby genes. Comparison of TE insertions in the genome assembly of M and S forms of An. gambiae and closely related species will reveal which fixed insertions are conserved. These TE insertions may affect the expression of nearby genes or provide new variation in transcripts/proteins, which may be examined experimentally. A large number of EST or cDNA sequences are often generated concurrently with genome sequencing projects. Indeed many TEs are found in EST or cDNA sequences in both An. gambiae and Ae. aegypti (Z. Tu, unpublished data), which begs the question of the functions of these TEs in expressed sequences.

Impact on Chromosomal Inversions

TE insertions may serve as substrates for recombination events that could lead to chromosomal inversions that are common in Anopheline mosquitoes.104 A DNA TE named Odysseus was found adjacent to the distal breakpoint of a naturally occurring paracentric chromosomal inversion that is characteristic of An. arabiensis, one of the species in the An. gambiae ccomplex.105 TEs may indeed be important in generating chromosomal rearrangements in nature, which might lead to reproductive isolation and genetic changes that allow An. gambiae to exploit a range of ecological niches.105 The availability of genome sequence data from the M and S forms of An. gambiae and related mosquitoes will be invaluable in studying the contribution of TEs on chromosomal inversions.

TEs and Genome Evolution

It has been proposed that variable TE abundance may account for the “C-value paradox”, which reflects the discrepancy between genome size of an organism (as indicated by the C value) and its biological complexity.106 It is not well established to what extent and how TEs affect genome evolution. Genome size and organization varies significantly between different mosquitoes. The genome of An. gambiae is 270 Mbp in size and is organized in a pattern of “long period interspersion”.107 In contrast, the 1200 Mbp Ae. aegypti genome is organized in a pattern of mainly “short period interspersion”108 (TIGR Ae. aegypti genome project website, http://www.tigr.org/tdb/e2k1/aabe/). The C. pipiens genome is approximately 540 Mbp.107 Systematic analyses of the An. gambiae, Ae. aegypti and C. pipiens genomes will reveal how TEs contribute to the size and organization of divergent mosquito genomes. Intriguing intraspecific variation of genome size was reported during surveys of 47 populations of the Asian tiger mosquito, Ae. albopictus, ranging from 620 Mbp to 1660 Mbp.107 This phenomenon offers a rare window into an early stage of genome size evolution. The availability of sequences of a large number of mosquito TEs will allow the use of systems biology tools such as TE microarray to study the contribution of TEs to such intraspecific variations using a Comparative Genomic Hybridization (CGH)109 approach. A TE microarray including oligos of a few hundred mosquito TEs is being tested in our laboratory. The relative abundance of a large number of TEs may be compared between different populations/strains.

TEs in Mosquito Populations

One major challenge to our understanding of TE evolution is to determine how TEs are maintained and spread in natural populations. Moreover, TEs have been proposed as tools to drive the spread of beneficial genes through mosquito populations to control infectious diseases.91,92 For such a sophisticated approach to work, it is critical to understand the natural population dynamics of TEs in their mosquito hosts. The combination of experimental methods such as TE display and locus-specific PCR, and the availability of a number of mosquito genomes such as the different forms of An. gambiae, may offer an excellent opportunity to investigate TE evolutionary dynamics in natural populations. Identification and isolation of insertions that are fixed in mosquito populations will be of special interest because of their evolutionary significance.

Evolutionary Origin of TE Diversity

High levels of diversity have been reported for both RNA-mediated and DNA-mediated TEs in An. gambiae and Ae. aegypti37,41,42 (Z. Tu, unpublished data). The evolutionary process that generated this diversity is of great interest. It is possible that some TEs may be transmitted by a complex mix of horizontal transfer and vertical inheritance. It is also possible that some TEs may be under pressure to diversify within a genome to escape the fate of inactivation.110 Parsing out the results of intra-genomic diversification from those of horizontal transfer events has been difficult. However, comparative analysis of the TE landscape in sequenced genomes from a number of mosquitoe species having diverse evolutionary distance will provide opportunities to better understand the scenarios under which mosquito TEs evolve. As the number of characterized mosquito TEs increases, rare horizontal transfer events may also be uncovered through experimental surveys in which genomic DNA samples from a wide range of mosquito species are hybridized to all known mosquito TEs on a TE microarray.

Activity and Regulation

In the past, a majority of actively transposing TEs were discovered through fortuitous events such as the characterization of a mutant. As summarized in an earlier review,27 it is now possible to use a systematic approach, combining computational and experimental methods, to uncover active TEs in a sequenced genome. A successful example of using such an approach to isolate active TEs in An. gambiae is provided by Arensburger and colleagues.59 It is anticipated that more active TEs will be discovered this way as more genomes are sequenced. As described above, a TE array is being developed for comparative genomic hybridization. The same array is also used to detect transcription of a large number of TEs in mosquito cells. Transcription of a TE may indicate active transposition, although alternative explanations are possible. These new developments in conjunction with established methods such as plasmid mobility assays, germline transformation assays, and TE display will greatly facilitate the discovery of active TEs.

Another very interesting fundamental question about TEs is their regulation and interaction with host genome. There are a number of ways by which TEs are regulated in insects.27 RNA interference (RNAi), a mechanism that confers post-transcriptional degradation of mRNA on the basis of homology to small fragments of double stranded RNA, has been implicated as a host defense mechanism against a broad spectrum of TEs in a nematode Caenorhabditis elegans.111,112 RNAi has been shown to suppress viral infections in mosquitoes.113 The above-mentioned TE array is also being used to compare the level of TE transcription in normal and RNAi-deficient mosquito cells. It is possible that release of suppression will increase transcription of potentially active TEs, leading to the identification of novel active TEs.

In summary, newly developed computational and experimental methods and the expanding genome revolution provide an exciting opportunity for the discovery and in-depth analysis of mosquito TEs, which will greatly improve our basic understanding of mosquito genetics and provide powerful tools for genetic manipulation of mosquitoes to help control mosquito-borne infectious diseases.

Acknowledgement

This work was supported by NIH grants AI42121, AI063252, and AI053203 and the Virginia Agricultural Experimental Station.

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