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Reexamining the P-Element Invasion of Drosophila Melanogaster Through the Lens of Pirna Silencing

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Reexamining the P-Element Invasion of Drosophila Melanogaster Through the Lens of Pirna Silencing | REVIEW Reexamining the P-Element Invasion of Drosophila melanogaster Through the Lens of piRNA Silencing Erin S. Kelleher1 Department of Biology and Biochemistry, University of Houston, Texas 77004 ORCID ID: 0000-0002-1827-067X (E.S.K.). ABSTRACT Transposable elements (TEs) are both important drivers of genome evolution and genetic parasites with potentially dramatic consequences for host fitness. The recent explosion of research on regulatory RNAs reveals that small RNA-mediated silencing is a conserved genetic mechanism through which hosts repress TE activity. The invasion of the Drosophila melanogaster genome by P elements, which happened on a historical timescale, represents an incomparable opportunity to understand how small RNA- mediated silencing of TEs evolves. Repression of P-element transposition emerged almost concurrently with its invasion. Recent studies suggest that this repression is implemented in part, and perhaps predominantly, by the Piwi-interacting RNA (piRNA) pathway, a small RNA-mediated silencing pathway that regulates TE activity in many metazoan germlines. In this review, I consider the P-element invasion from both a molecular and evolutionary genetic perspective, reconciling classic studies of P-element regulation with the new mechanistic framework provided by the piRNA pathway. I further explore the utility of the P-element invasion as an exemplar of the evolution of piRNA-mediated silencing. In light of the highly-conserved role for piRNAs in regulating TEs, discoveries from this system have taxonomically broad implications for the evolution of repression. KEYWORDS transposable element; piRNA; hybrid dysgenesis; P element RANSPOSABLE elements (TEs) are ubiquitous genetic of eukaryotic gene expression by acting as cis-regulatory ele- Tentities that populate almost all genomes. Particularly ments (Kunarso et al. 2010; Lynch et al. 2011). in eukaryotes, these mobile genetic elements selfishly Like any other type of mutation, TE insertions are occa- spread throughout the genome and achieve staggering sionally adaptive alleles that provide a selective advantage copy numbers, making them major players in genome evol- for their host (Daborn 2002; Aminetzach et al. 2005; ution. “Gigantic” genomes—particularly in plants—are of- González et al. 2008). Additionally, some “domesticated” ten predominantly TEs, indicating an important role for TEs TE families perform important cellular functions, such as in genome expansion (Vitte and Panaud 2005; Vitte and the retrotransposons that form Drosophila telomeres (re- Bennetzen 2006). Additionally, TEs fuel structural genome viewed in Silva-Sousa et al. 2012). However, these rare ex- evolution by generating inversions, duplications, and trans- amples of beneficial TEs, together with their evolutionary locations through nonhomologous recombination; and by success of TEs in populating host genomes, belie their par- inducing double-stranded breaks that are repaired by non- asitic nature. TEs rely partially or completely on host- homologous end joining (Lemaitre et al. 2008; Zichner et al. derived proteins for replication, thereby acting as sponges 2013; Grandaubert et al. 2014; Sarilar et al. 2014; Startek for critical host-cellular machinery (Nuzhdin 1999; Yang et al. 2015). Finally, TE insertions influence the architecture and Nuzhdin 2003; Pasyukova et al. 2004). TE propagation, furthermore, introduces new insertions nearly randomly Copyright © 2016 by the Genetics Society of America throughout the genome, many of which disrupt gene func- doi: 10.1534/genetics.115.184119 tion (Spradling et al. 1999; Dupuy et al. 2001). Once Manuscript received October 28, 2015; accepted for publication May 25, 2016. 1Address for correspondence: 3455 Cullen Blvd. Suite #342, Houston, TX 77204-5001. inserted, TEs continue to be mutagenic by producing struc- E-mail: [email protected] tural rearrangements (reviewed in Hedges and Deininger Genetics, Vol. 203, 1513–1531 August 2016 1513 2007). The combination of random insertion and structural P-element Molecular Genetics and Self-Encoded rearrangement may explain why TE deregulation has been Regulation associated with the onset and progression of certain classes P elements were one of the first families of metazoan trans- of tumors (Vilà et al. 2003; Howard et al. 2008; Belancio posons to be studied, and the genetic and molecular require- et al. 2010). ments for their transposition have been exceptionally well Perhaps in response to these manifold and multifaceted characterized (reviewed in Rio 1991, 2002; Castro and fitness costs, host genomes have acquired mechanisms to Carareto 2004). Here I review literature on the molecular regulate TE activity. In eukaryotes this is especially true in genetics of P elements, with particular focus on their regula- the germline, where TE-associated mutations can be trans- tion through self-encoded repressor proteins. mitted to offspring. Recent studies have revealed that small RNA-mediated silencing pathways provide a conserved and P-element structure and transposition critical strategy for TE control, acting as genomic immune systems that regulate endogenous TE families (reviewed in Full-length P elements (2.9-kb long, Figure 1A) consist of a Creasey and Martienssen 2010; Saito and Siomi 2010; protein-coding gene sandwiched between multiple inverted Blumenstiel 2011). Analogous to the vertebrate adaptive repeats at the 59 and 39 termini (O’Hare and Rubin 1983). immune system, these pathways are challenged to recog- The coding gene has four exons, 0, 1, 2, and 3 (Karess and nize and acquire regulation of new parasites as TEs fre- Rubin 1984), which are alternately spliced to produce two quently invade novel host genomes through horizontal proteins (Laski et al. 1986; Rio et al. 1986). Removal of all transfer (Gilbert et al. 2010; Thomas et al. 2010). The mu- three introns produces a transcript encoding an 87-kDa trans- tational and selective mechanisms that fuel the evolution of posase enzyme, which is required for transposition (Laski small RNA-mediated TE regulation, however, remain poorly et al. 1986; Rio et al. 1986). By contrast, transcripts that re- understood. tain the intron between exons 2 and 3 (intervening sequence A stunning example of horizontal transfer and the sub- 3, IVS3) encode a 66-kDa protein with no transposase activity sequent evolution of TE regulation is provided by the invasion (Laski et al. 1986; Rio et al. 1986). of the Drosophila melanogaster genome by P elements in the P transposase catalyzes the mobilization of P elements mid-20th century. These DNA transposons rapidly spread through a nonreplicative “cut and paste” mechanism, in through natural populations of D. melanogaster, with repres- which they excise from one genomic location and insert into sion evolving almost concurrently with invasion (Kidwell another (Engels et al. 1990). Full-length elements transpose 1983; Anxolabéhère et al. 1988). Until recently, the molecu- autonomously because they encode this enzyme. Internally- lar mechanism(s) that underlie P-element repression baffled deleted elements do not encode the transposase; however, Drosophila geneticists. Although early studies demonstrated these nonautonomous elements can be mobilized in trans that P elements are partially regulated by self-encoded re- if transposase is furnished by a full-length element else- pressor proteins, this autoregulation does not explain the where in the genome (O’Hare and Rubin 1983). Multiple very strong germline repression exhibited by many wild- sequences at the 59 and 39 ends of P elements are required derived strains (Robertson and Engels 1989; Misra and Rio for their mobilization. In particular, a 10-bp consensus sequence 1990; Gloor et al. 1993; Misra et al. 1993; Jensen et al. 2008). at either end of the element is bound by P transposase (Figure The recent discovery of the Piwi-interacting RNA (piRNA) path- 1B) (Kaufman et al. 1989; Beall and Rio 1997) and is required way, a conserved silencing mechanism that controls germ- for efficient transposition (Mullins et al. 1989). line TE activity in both metazoans and ciliates (reviewed in P-element transposition occurs predominantly in the Aravin et al. 2007; Mani and Juliano 2013), provided the germline, with estimated transposition rates ranging from critical missing piece to the puzzle: the activity of P elements 1021 to 1023 (new insertions/element/genome) (Eggleston in D. melanogaster is also regulated by piRNAs (Brennecke et al. 1988; Robertson et al. 1988; Berg and Spradling 1991; et al. 2008; Jensen et al. 2008; Khurana et al. 2011). Kimura and Kidwell 1994). By contrast, P-element activity is This review integrates 40 years of research on the invasion rare in somatic tissues, where estimated excision rates are and regulation of P elements in D. melanogaster genomes, with more than two orders of magnitude lower than in germline recent insights into piRNA-mediated silencing that have cells (Engels 1979a). Germline-specific transposition is reg- emerged over the last decade. I describe both repressor pro- ulated by alternative splicing of the P-transposase messenger tein and piRNA-mediated regulation, and relate these mech- RNA (mRNA). While fully-spliced, transposase-encoding anisms to the genetic architecture of repression that is transcripts predominate in the germline, somatic tran- observed among wild-derived strains. I further integrate scripts generally retain IVS3 and encode the 66-kDa pro- empirical observations of repression in natural populations tein (Laski
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