The diversity of retrotransposons and the properties of their reverse transcriptases

Abstract

A number of abundant mobile genetic elements called retrotransposons reverse transcribe RNA to generate DNA for insertion into eukaryotic genomes. Four major classes of retrotransposons are described here. First, the long-terminal-repeat (LTR) retrotransposons have similar structures and mechanisms to those of the vertebrate retroviruses. Genes that may enable these retrotransposons to leave a cell have been acquired by these elements in a number of animal and plant lineages. Second, the tyrosine recombinase retrotransposons are similar to the LTR retrotransposons except that they have substituted a recombinase for the integrase and recombine into the host chromosomes. Third, the non-LTR retrotransposons use a cleaved chromosomal target site generated by an encoded endonuclease to prime reverse transcription. Finally, the Penelope-like retrotransposons are not well understood but appear to also use cleaved DNA or the ends of chromosomes as primer for reverse transcription. Described in the second part of this review are the enzymatic properties of the reverse transcriptases (RTs) encoded by retrotransposons. The RTs of the LTR retrotransposons are highly divergent in sequence but have similar enzymatic activities to those of retroviruses. The RTs of the non-LTR retrotransposons have several unique properties reflecting their adaptation to a different mechanism of retrotransposition.

Introduction

Vertebrate retroviruses represent but one lineage of an ever-growing family of mobile genetic elements that utilize reverse transcriptase to generate a DNA copy from their RNA transcript. While a few of these other lineages, such as hepadnaviruses and caulimoviruses, are true viruses the largest number of lineages are classified as retrotransposable elements, or retrotransposons. The first retrotransposons to be identified were discovered because they caused mutations in two favorite model organisms: yeast, Saccharomyces cerevisiae, and the fruitfly, Drosophila melanogaster. The sequences of these elements revealed long-terminal repeats (LTRs) and open reading frames that encoded reverse transcriptase, RNase H, integrase, proteinase and gag-like proteins in an organization that was suggestive of retroviruses (Clare and Farabaugh, 1985, Mount and Rubin, 1985). Elegant experiments demonstrated that the yeast element made new copies by reverse transcription of their RNA transcripts (Boeke et al., 1985). These retrotransposons, however, did not encode a protein similar to retroviral envelope (env) genes and did not spread between individuals in a population. The retrotransposons were viewed as possible progenitors of the retroviruses, or alternatively as descendants of the retroviruses by loss of their envelope gene. Today the number of characterized retrotransposons has expanded dramatically and many new examples of elements with different putative env genes have been found. The wide diversity of retrotransposons compared to the limited diversity of vertebrate retroviruses suggests the ancestral forms were retrotransposons.

Without an env-like gene retrotransposons are unable to leave the environment of one cell for another cell, thus they must insert into the chromosomes of the germ cells to insure passage to the next generation. The inability to leave an organism also means that retrotransposons must be more circumspect than a virus in how often they replicate due to the potential damage caused by their insertion into the host genome. Any insertion that significantly reduces the fitness of the host will be lost from the population. Given this constraint, it is remarkable that large numbers of retrotransposon families using a variety of mechanisms to reverse transcribe and insert their genetic information into a genome have become highly successful in every lineage of eukaryotic organisms.

Even more remarkable than their diversity is the abundance of retrotransposons in most organisms. Indeed, the reason why many eukaryotic genomes are so enormous in size is because of the accumulation of retrotransposable elements. For example, retrotransposons constitute 42% of the human genome (Lander et al., 2001) and 75% of the maize genome (SanMiguel et al., 1998). Even these percentages are underestimates because the scrambling of DNA sequences by mutation, recombination and continued retrotransposon insertions make the oldest insertions impossible to recognize. Only those organisms that need to replicate their DNA quickly, or have found recombinational mechanisms to remove insertions, appear to be able to prevent the accumulation of elements over time (Charlesworth et al., 1994).

In the following sections we describe the major classes of retrotransposons that are known today emphasizing their structure, their phylogenetic relationship to each other and their mechanism of retrotransposition. Finally, for those retrotransposons where the reverse transcriptase have been studied, we compare the properties of their reverse transcriptases (RTs) with that of retroviral RTs.