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Host–Transposon Interactions: Conflict, Cooperation, and Cooption Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Host–transposon interactions: conflict, cooperation, and cooption Rachel L Cosby, Ni-Chen Chang, and Cédric Feschotte Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA Transposable elements (TEs) are mobile DNA sequences (i.e., the germline), the newly integrated TE copy becomes that colonize genomes and threaten genome integrity. inheritable and may spread vertically within the popula- As a result, several mechanisms appear to have emerged tion. TEs also spread horizontally between species at an during eukaryotic evolution to suppress TE activity. How- appreciable frequency, which is crucial to their evolution- ever, TEs are ubiquitous and account for a prominent frac- ary persistence by allowing the colonization of new ge- tion of most eukaryotic genomes. We argue that the nomes (Gilbert and Feschotte 2018). evolutionary success of TEs cannot be explained solely As for any heritable mutational event, natural selection by evasion from host control mechanisms. Rather, some and genetic drift dictate the fate of a new TE insertion in TEs have evolved commensal and even mutualistic strat- the population. Because of their sheer length (∼100– egies that mitigate the cost of their propagation. These co- 10,000 bp) and propensity to carry regulatory elements evolutionary processes promote the emergence of (i.e., promoters, splice sites, and poly-A signals), TE inser- complex cellular activities, which in turn pave the way tions are particularly prone to disrupt gene function. For for cooption of TE sequences for organismal function. instance, ∼10% and ∼50% of spontaneous mutant pheno- types isolated in laboratory strains of mice and flies, re- spectively, are caused by de novo TE insertions within Transposable elements (TEs) are mobile repetitive DNA the coding or noncoding portion of genes (Eickbush and sequences that comprise a substantial fraction of eukary- Furano 2002; Gagnier et al. 2019). An equally sizeable frac- otic genomes (Bourque et al. 2018). For instance, TEs and tion of maize mutants arose from transposition events their remnants account for more than half the nuclear (Neuffer et al. 1997). In humans, at least 120 Mendelian DNA content of maize, zebrafish, and humans and ap- diseases have been attributed to de novo TE insertions proximately a third of the nuclear DNA content of Droso- (Hancks and Kazazian 2016). These observations, together phila melanogaster and Caenorhabditis elegans (The with more direct measurement of fitness effects in Droso- C. elegans Sequencing Consortium 1998; Schnable et al. phila caged populations (e.g., Pasyukova 2004), indicate 2009; de Koning et al. 2011; Howe et al. 2013; Hoskins that TE mobilization is highly mutagenic and represents et al. 2015). The evolutionary success of TEs lies in their a significant source of genome instability in a wide range ability to replicate independently of and faster than the of organisms. host genome (Doolittle and Sapienza 1980; Orgel and Even TEs that are no longer mobile still pose a threat to Crick 1980). TEs are classified into two broad groups organismal fitness. The repetitive nature of TE families based on their molecular transposition intermediate: provides a substrate for ectopic recombination events Class I elements (retrotransposons) mobilize via an RNA that can lead to chromosomal rearrangements, often intermediate, while class II elements (DNA transposons) with deleterious consequences (Montgomery et al. 1991; mobilize via a DNA intermediate. Retrotransposons in- Ade et al. 2013; Bennetzen and Wang 2014; Hancks and clude endogenous retroviruses (ERVs) and related long ter- Kazazian 2016). TE-encoded products (RNA, cDNA, and minal repeat (LTR) retrotransposons as well as non-LTR proteins), even with compromised functionalities, can retrotransposons (Wicker et al. 2007; Bourque et al. be toxic, and their accumulation to aberrant amounts 2018). DNA transposons include “cut and paste” DNA are associated with and increasingly recognized as directly transposons as well as non-“cut and paste” elements contributing to various disease states, including cancer, (Wicker et al. 2007; Bourque et al. 2018). If transposition senescence, and chronic inflammation (Lee et al. 2012a; occurs in cells that contribute to the next generation Tubio et al. 2014; Burns 2017; Tang et al. 2017; Bourque et al. 2018; Dubnau 2018; Schauer et al. 2018; De Cecco et al. 2019). [Keywords: gene regulation; genomics; KRAB zinc finger; fetrotransposons; transposable elements; piRNA] Correspondence author: [email protected] © 2019 Cosby et al. This article, published in Genes & Development,is Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.327312. available under a Creative Commons License (Attribution-NonCommer- 119. Freely available online through the Genes & Development Open Ac- cial 4.0 International), as described at http://creativecommons.org/licens- cess option. es/by-nc/4.0/. 1098 GENES & DEVELOPMENT 33:1098–1116 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/19; www.genesdev.org Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Host–transposon interactions The manifold capacity of TEs to compromise genome tinguish TEs from host sequences. Another predicted hall- integrity and interfere with normal cellular function sug- mark of a TE defense system is that it should be able to gests that uncontrolled TE amplification can have cata- adapt to control new or variant TEs that evade repression, strophic consequences for both organisms and TEs, as triggering an arms race between TEs and components of their fitness is inextricably linked. Thus, like any parasitic the pathway. Below, we discuss two pathways that appear system, natural selection will eliminate TEs with exces- to possess these attributes: piwi-interacting small RNAs sive activity and overly deleterious effects on their host. (piRNAs) and Kruppel-associated box-containing zinc fin- It will also select for the emergence of host-encoded ger proteins (KRAB-ZFPs). mechanisms that suppress or dampen TE activity. If a de- fense mechanism completely blocks a given TE family, it piRNA-mediated TE silencing will in turn place selective pressure on these elements to evolve a counterdefense or escape mechanism to avoid ex- piRNAs are small RNAs found in most metazoans that are tinction, pressuring the host to evolve further mecha- typically produced from long precursor transcripts derived nisms to compensate. Such genetic conflict is often from specialized loci called piRNA clusters (for review, see framed in terms of an arms race (Hurst and Werren Ernst et al. 2017; Ozata et al. 2019). Once expressed, pri- 2001; Burt and Trivers 2006; Werren 2011; McLaughlin marily in the gonads but also in the soma of some organ- and Malik 2017; Ozata et al. 2019), which builds on the isms, piRNA precursors are processed into mature Red Queen model for host–pathogen interactions (Van piRNAs, which then complex with PIWI clade Argonaute Valen 1973). Alternatively, the arms race could be avoided proteins. These ribonucleoprotein (RNP) complexes rec- if TEs mitigate the conflict with their host either through ognize complementary target mRNAs in the cytoplasm self-control or by providing a benefit offsetting their cost. or nascent RNAs in the nucleus, triggering a cascade of Such strategies would reduce pressure on the host to biochemical processes that ultimately reduces target evolve systems to counteract TEs, promoting equilibrium RNA expression via posttranscriptional or transcriptional rather than precipitating an arms race. mechanisms, respectively (Fig. 1A; Ozata et al. 2019). In the first part of this review, we examine the evidence piRNAs produced from TE loci act as potent trans-repres- for and against the arms race model of host–TE interac- sors of related TEs located throughout the genome (Ozata tions. We posit that the extent to which TEs outcompete et al. 2019). In some organisms, piRNA-mediated TE re- their host is constrained by their dependence on organis- pression appears necessary to preserve the integrity of mal fitness, which favors TEs that evolve strategies that the germline. This is best documented in D. melanogaster, circumvent or attenuate, rather than block, host defenses. where the loss of piRNAs normally repressing certain TEs We then explore alternative models, including self-reg- (P element and I element) leads to rampant transposition ulatory mechanisms and mutualistic interactions, that re- and hybrid dysgenesis, which is characterized by extensive duce the cost of TE activity. We speculate that cooperative DNA damage, gonadal atrophy, and sterility (Kidwell et al. strategies may be more widespread than currently appreci- 1977; Bucheton et al. 1984; Brennecke et al. 2008; Wang ated and pave the way for cooption of TE sequences for et al. 2018). Increased piRNA production against P ele- host function. ments in aging flies rescues fertility, further underlining the importance of the piRNA pathway in maintaining germline integrity (Khurana et al. 2011). In mice, elimina- Arms races tion of PIWI proteins also results in massive accumulation of retrotransposon transcripts in sperm and oocytes (Car- Consistent with a need to prevent the deleterious effects of mell et al. 2007; Kuramochi-Miyagawa et al. 2008; De rampant transposition, a variety of host-encoded
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