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Functional Characterization of Piggybat from the Bat Myotis Lucifugus Unveils an Active Mammalian DNA Transposon

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Functional Characterization of Piggybat from the Bat Myotis Lucifugus Unveils an Active Mammalian DNA Transposon Functional characterization of piggyBat from the bat Myotis lucifugus unveils an active mammalian DNA transposon Rupak Mitraa,b,1,2, Xianghong Lia,b,1, Aurélie Kapustac, David Mayhewd, Robi D. Mitrad, Cédric Feschottec, and Nancy L. Craiga,b,3 aHoward Hughes Medical Institute and bDepartment of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; cDepartment of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112; and dDepartment of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63108 Contributed by Nancy L. Craig, November 21, 2012 (sent for review September 4, 2012) A revelation of the genomic age has been the contributions of the Here we functionally characterize the transposition activity of mobile DNA segments called transposable elements to chromo- piggyBat, a member of the piggyBac superfamily, which likely re- some structure, function, and evolution in virtually all organisms. presents the most recently active family of DNA transposons in Substantial fractions of vertebrate genomes derive from transpos- the M. lucifugus genome. The founding member of the super- able elements, being dominated by retroelements that move via family, hereafter referred to as insect piggyBac, was originally RNA intermediates. Although many of these elements have been identified in the cabbage looper moth (Trichoplusiani ni) (9) and inactivated by mutation, several active retroelements remain. has been thoroughly studied both in vivo (10) and in vitro (11). Vertebrate genomes also contain substantial quantities and a high Insect piggyBac is known to transpose by a canonical cut-and- diversity of cut-and-paste DNA transposons, but no active repre- paste mechanism promoted by an element-encoded transposase sentative of this class has been identified in mammals. Here we with a catalytic site resembling the RNase H fold shared by many show that a cut-and-paste element called piggyBat, which has re- recombinases (11, 12). The insect piggyBac transposon system cently invaded the genome of the little brown bat (Myotis lucifugus) has been shown to be highly active in a wide range of animals, GENETICS and is a member of the piggyBac superfamily, is active in its native including Drosophila and mice, where it has been developed as form in transposition assays in bat and human cultured cells, as well a powerful tool for gene tagging and genome engineering (10). as in the yeast Saccharomyces cerevisiae. Our study suggests that Other transposons affiliated to the piggyBac superfamily are some DNA transposons are still actively shaping some mammalian common in arthropods (13) and vertebrates (14, 15) including genomes and reveals an unprecedented opportunity to study the humans (2), but none in vertebrates have been functionally ex- mechanism, regulation, and genomic impact of cut-and-paste trans- amined. piggyBac elements present in the human genome have position in a natural mammalian host. ceased transpositional activity about 40 My ago (16). Here we show directly that piggyBat is capable of transposition in bat, human, genome evolution | mobile genetic element and yeast cells, thereby providing direct experimental evidence for a naturally active mammalian cut-and-paste DNA transposon. wo major classes of transposable elements that move be- Thus, the piggyBat family offers an unprecedented opportunity to Ttween nonhomologous positions are known: retroelements investigate directly the mechanism, regulation, and genomic im- that move via an RNA intermediate that is converted to DNA pact of endogenous DNA transposition in a mammal. by reverse transcription and DNA-only cut-and-paste elements that move by excision of the DNA segment from a donor site, Results followed by integration into a target site (1). DNA-only elements Multiple Recent piggyBac Families in the Bat. Previous bioin- are widespread in nature, being found in a wide range of pro- formatics mining of the M. lucifugus genome revealed several karyotes and eukaryotes. DNA transposons or their remnants families of piggyBac elements as being most recently mobilized have been identified in all vertebrate genomes examined, where and the best candidates for still being active. In particular, Ray they are represented by diverse superfamilies and account for a et al. (7) identified two potentially active copies (with intact ORF substantial fraction of the genomic space, e.g., 3% in human (2), and identifiable target site duplication) of a family designated 9.1% in Anolis (3),andupto25%intheAfricanclawedfrog, piggyBac1_Ml in the 2× genome assembly available at the time. In Xenopus tropicalis (4). Despite the apparent evolutionary success addition, numerous short nonautonomous copies from two sub- of DNA elements in vertebrates, we know very little about their families called npiggy_156 and npiggy_239 were found to be transposition mechanism or genomic impact in these taxa. This strictly identical to each other, implying very recent transposition gap in knowledge may be attributed in part to the fact that only events and a possibly still active source of piggyBac transposase in a single, low-copy number family of vertebrate DNA elements, the genome. We took advantage of the recent release of a much Tol2, has been demonstrated to be transpositionally active in its natural host, the medaka fish (5). There remains no direct ev- idence of active DNA transposons in mammals or any other Author contributions: R.M., X.L., A.K., D.M., R.D.M., C.F., and N.L.C. designed research; amniotes. In fact, until recently, it was widely believed that all R.M., X.L., A.K., D.M., R.D.M., and C.F. performed research; R.M., X.L., A.K., D.M., R.D.M., mammalian DNA transposons had gone extinct for at least 37 C.F., and N.L.C. analyzed data; and R.M., X.L., A.K., D.M., R.D.M., C.F., and N.L.C. wrote million years (My) (2, 6–8). However, this picture started to the paper. change several years ago when multiple waves of recent DNA The authors declare no conflict of interest. transposon activity were identified through bioinformatic analy- Freely available online through the PNAS open access option. ses of the genome of the little brown bat Myotis lucifugus (6–8). 1R.M. and X.L. contributed equally to this work. The most recently active bat transposons include members of the 2Present address: Hindustan Unilever Research Center, Bangalore 560066, India. hAT and piggyBac superfamilies with signs of mobilization in the 3To whom correspondence should be addressed. E-mail: [email protected]. past few million years. However, it remained unknown whether This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. any of these elements are actually still capable of transposition. 1073/pnas.1217548110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1217548110 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 Fig. 1. piggyBac-like element demography versus other TEs in the M. lucifugus genome assembly. Percentage of divergence from consensus sequences are from RepeatMasker (47) (Methods) and corrected as in ref. 53, i.e., corrected %divergence = −300/4 × ln(1 − %divergence × 4/300). MITEs, nonautonomous elements. “All other TEs” corresponds to all se- quences masked in the genome as transposable elements minus all piggyBac-like elements. improved genome assembly (7×) for M. lucifugus to further study transposase. Below we validate this hypothesis functionally using the DNA transposon population of the genome and, in particular, a synthetic transposon system corresponding to the 1,716-bp characterize in more detail the structure and evolution of transposase ORF (Table S1) and to the 153-bp left and 208-bp piggyBac-like elements. Our analysis (Methods), which involved right ends of a representative full-length piggyBat copy identified remasking of the genome with previously identified transpo- in the genome sequence (Methods). The sequence of piggyBat is sons, as well as de novo mining and classification of repeats, compared with that of insect piggyBac in Table S2. revealed three distinct families of piggyBac-like elements. Each family includes transposase-encoding copies and two to seven piggyBat Can Transpose in Human and Bat Cells in Culture. As pre- subfamilies of nonautonomous copies or miniature inverted-re- viously described for insect piggyBac (17), we analyzed piggyBat peat transposable elements (MITEs) of homogenous length and transpositioninculturedHeLacellsusingatwo-plasmidco- diagnostic internal sequences. Two of these families correspond transfection assay in which a donor plasmid carries a transposon to the transposase-coding families designated as piggyBac1_Ml containing an antibiotic resistance marker and a helper plasmid and piggyBac2_Ml by Ray et al. (7), whereas the third one has not expressing the transposase, measuring the transposase-dependent been previously reported. We derived consensus sequences for all chromosomal integration of the transposon antibiotic marker. families and subfamilies and used Repeatmasker to detect all We find that the frequency of piggyBat integration was about copies closely related to these elements in the genome assembly 60% that of insect piggyBac (Fig. 2A). and compute the percentage divergence of each copy to its con- We used ligation-mediated PCR to recover 98,816 transpo- sensus sequence. The results of this analysis offer a demographic son end-genomic junctions (Methods and Table S3) and per- profile characteristic for each family that captures the relative age formed high-throughput sequencing of piggyBat insertions in of their amplification in the genome (Fig. 1). The three piggyBac- the human genome and compared the pattern of insertions to like families are younger than most other DNA transposon fami- that characterized previously for insect piggyBac (17). We found lies coexisting in the bat genome, with piggyBac1_Ml and its related that 92.8% of the bat piggyBat sites had a flanking TTAA, which MITEs emerging as the youngest family, in agreement with pre- is slightly lower than the 96% observed with insect piggyBac in vious results (7).
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