The impact of transposable elements on eukaryotic genomes: From genome size increase to genetic adaptation to stressful environments

Transposable elements (TEs) are present in roughly all genomes. These mobile DNA sequences are able to invade genomes and their impact on genome evolution is substantial. The mobility of TEs can induce the appearance of deleterious mutations, gene disruption and chromosome rearrangements, but transposition activity also has positive aspects and the mutational activities of TEs contribute to the genetic diversity of organisms. This short review aims to give a brief overview of the impact TEs may have on animal and plant genome structure and expression, and the relationship between TEs and the stress response of organisms, including insecticide resistance.     

Molecular domestication of mobile elements

Transposable elements are ubiquitous in all organisms and represent a dynamic component of their genomes, causing mutations and thereby genetic variation. Because of their independent and expansive replication strategy, these elements are called selfish and were thought to have no impact on the adaptive evolution of their host organisms. Although most TE-induced mutations seem to exert only negative effects on the fitness of their carrier, recent evidence indicates that in the course of evolution at least some TE-mediated changes have become established features of the host genome. For example, the insertion of TEs may provide novel cis-regulatory regions to preexisting host genes or TE-derived trans-acting factors may undergo a molecular transition into novel host genes through a process described as molecular domestication. The stationary P element related gene clusters of D. guanche, D. madeirensis and D. subobscura provide an excellent model system to study the evolutionary impact of TEs on genome evolution. Each cluster unit consists of a cis-regulating section composed of different insertion sequences followed by the first three exons of a P element that are coding for a 66 kDa ‘repressor-like’ protein. This revised version was published online in August 2006 with corrections to the Cover Date.     

The Evolutionary Potential of Phenotypic Mutations

Errors in protein synthesis, so-called phenotypic mutations, are orders-of-magnitude more frequent than genetic mutations. Here, we provide direct evidence that alternative protein forms and phenotypic variability derived from translational errors paved the path to genetic, evolutionary adaptations via gene duplication. We explored the evolutionary origins of Saccharomyces cerevisiae IDP3 - an NADP-dependent isocitrate dehydrogenase mediating fatty acids ß-oxidation in the peroxisome. Following the yeast whole genome duplication, IDP3 diverged from a cytosolic ancestral gene by acquisition of a C-terminal peroxisomal targeting signal. We discovered that the pre-duplicated cytosolic IDPs are partially localized to the peroxisome owing to +1 translational frameshifts that bypass the stop codon and unveil cryptic peroxisomal targeting signals within the 3’-UTR. Exploring putative cryptic signals in all 3’-UTRs of yeast genomes, we found that other enzymes related to NADPH production such as pyruvate carboxylase 1 (PYC1) might be prone to peroxisomal localization via cryptic signals. Using laboratory evolution we found that these translational frameshifts are rapidly imprinted via genetic single base deletions occurring within the very same gene location. Further, as exemplified here, the sequences that promote translational frameshifts are also more prone to genetic deletions. Thus, genotypes conferring higher phenotypic variability not only meet immediate challenges by unveiling cryptic 3’-UTR sequences, but also boost the potential for future genetic adaptations.     

Retrotransposons and the evolution of mammalian gene expression

Transposable elements, and retroviral-like elements in particular, are a rich potential source of genetic variation within a host's genome. Many mutations of endogenous genes in phylogenetically diverse organisms are due to insertion of elements that affect gene expression by altering the normal pattern of regulation. While few such associations are known to have been maintained over time, two recently elucidated examples suggest transposable elements may have a significant impact in evolution of gene expression. The first example, concerning the mouse sex-limited protein (Slp), clearly establishes that ancient retroviral enhancer sequences now confer hormonal dependence on the adjacent gene. The second example shows that within the human amylase gene family, salivary specific expression has arisen due to inserted sequences, deriving perhaps from a conjunction of two retrotransposable elements.     

基于复制-转录碰撞的突变和进化意义

复制和转录机器会同时使用相同的DNA区域作为模板,因此复制和转录不可避免地以头对头或追尾方式相互碰撞。头对头碰撞和追尾碰撞均会导致复制机器停留,从而造成DNA损伤和基因组不稳定。就基因组完整性而言,头对头碰撞比追尾碰撞的后果更严重。本文回顾总结了复制-转录冲突的解决机制和进化影响。相对于前导链,滞后链上非同义（氨基酸改变）突变的发生率更高,并且滞后链上基因的高频诱变取决于转录本和基因大小,因此,较快的适应性突变发生在滞后链上。头对头基因的高度转录增加了复制过程中响应压力的突变率。无论是头对头还是追尾模式,复制-转录冲突都可能是适应性进化的驱动力。     

Viral proteins acquired from a host converge to simplified domain architectures

The infection cycle of viruses creates many opportunities for the exchange of genetic material with the host. Many viruses integrate their sequences into the genome of their host for replication. These processes may lead to the virus acquisition of host sequences. Such sequences are prone to accumulation of mutations and deletions. However, in rare instances, sequences acquired from a host become beneficial for the virus. We searched for unexpected sequence similarity among the 900,000 viral proteins and all proteins from cellular organisms. Here, we focus on viruses that infect metazoa. The high-conservation analysis yielded 187 instances of highly similar viral-host sequences. Only a small number of them represent viruses that hijacked host sequences. The low-conservation sequence analysis utilizes the Pfam family collection. About 5% of the 12,000 statistical models archived in Pfam are composed of viral-metazoan proteins. In about half of Pfam families, we provide indirect support for the directionality from the host to the virus. The other families are either wrongly annotated or reflect an extensive sequence exchange between the viruses and their hosts. In about 75% of cross-taxa Pfam families, the viral proteins are significantly shorter than their metazoan counterparts. The tendency for shorter viral proteins relative to their related host proteins accounts for the acquisition of only a fragment of the host gene, the elimination of an internal domain and shortening of the linkers between domains. We conclude that, along viral evolution, the host-originated sequences accommodate simplified domain compositions. We postulate that the trimmed proteins act by interfering with the fundamental function of the host including intracellular signaling, post-translational modification, protein-protein interaction networks and cellular trafficking. We compiled a collection of hijacked protein sequences. These sequences are attractive targets for manipulation of viral infection.     

Over-representation of repeats in stress response genes: a strategy to increase versatility under stressful conditions?

The survival of individual organisms facing stress is enhanced by the induction of a set of changes. As the intensity, duration and nature of stress is highly variable, the optimal response to stress may be unpredictable. To face such an uncertain future, it may be advantageous for a clonal population to increase its phenotypic heterogeneity (bet-hedging), ensuring that at least a subset of cells would survive the current stress. With current techniques, assessing the extent of this variability experimentally remains a challenge. Here, we use a bioinformatic approach to compare stress response genes with the rest of the genome for the presence of various kinds of repeated sequences, elements known to increase variability during the transfer of genetic information (i.e. during replication, but also during gene expression). We investigated the potential for illegitimate and homologous recombination of 296 Escherichia coli genes related to repair, recombination and physiological adaptations to different stresses. Although long repeats capable of engaging in homologous recombination are almost absent in stress response genes, we observed a significant high number of short close repeats capable of inducing phenotypic variability by slipped-mispair during DNA, RNA or protein synthesis.     

Variability of the mitochondrial genome in mammals at the inter-species/intra-species boundary

Genomic variations represent the molecular basis of the biodiversity of living organisms on which selection operates to generate evolution. In eukaryotes, genomic variability can be experienced in both nuclear and organellar, i.e. mitochondrial and plastid (where present), genomes, which can follow completely different evolution pathways, as revealed by comparative genomics analyses. In Metazoa, for which a substantial number of complete genome sequences are available (nuclear, but mainly mitochondrial), we are just starting to grasp the selective pressures operating on some basic features of the genome as a whole. In this brief review, we discuss the variability of the mitochondrial metazoan genome, with particular reference to mitochondrial DNA in mammals. In light of the recent assumption that a small segment of mitochondrial DNA may be used, particularly in Metazoa, as a species marker, some data on mitochondrial gene variability at the inter-species/intra-species boundary are reported. Intra-species variability has been evaluated in four mammalian species, Homo sapiens, Bos taurus, Sus scrofa and Canis familiaris, whereas the relationship between intra- and inter-species variability has been investigated in Bos taurus and Bos indicus.     

Complex prokaryotic genome structure: rapid evolution of chromosome II

Although many bacteria with two chromosomes have been sequenced, the roles of such complex genome structuring are still unclear. To uncover levels of chromosome I (CI) and chromosome II (CII) sequence divergence, Mauve 2.2.0 was used to align the CI- and CII-specific sequences of bacteria with complex genome structuring in two sets of comparisons: the first set was conducted among the CI and CII of bacterial strains of the same species, while the second set was conducted among the CI and CII of species in Alphaproteobacteria that possess two chromosomes. The analyses revealed a rapid evolution of CII-specific DNA sequences compared with CI-specific sequences in a majority of organisms. In addition, levels of protein divergence between CI-specific and CII-specific genes were determined using phylogenetic analyses and confirmed the DNA alignment findings. Analysis of synonymous and nonsynonymous substitutions revealed that the structural and functional constraints on CI and CII genes are not significantly different. Also, horizontal gene transfer estimates in selected organisms demonstrated that CII in many species has acquired higher levels of horizontally transferred segments than CI. In summary, rapid evolution of CII may perform particular roles for organisms such as aiding in adapting to specialized niches.     

Dominant negative mutator mutations in the mutS gene of Escherichia coli.

The MutS protein of Escherichia coli is part of the dam-directed MutHLS mismatch repair pathway which rectifies replication errors and which prevents recombination between related sequences. In order to more fully understand the role of MutS in these processes, dominant negative mutS mutations on a multicopy plasmid were isolated by screening transformed wild-type cells for a mutator phenotype, using a Lac+ papillation assay. Thirty-eight hydroxylamine- and 22 N-methyl-N'-nitro-N-nitrosoguanidine-induced dominant mutations were isolated. Nine of these mutations altered the P-loop motif of the ATP-binding site, resulting in four amino acid substitutions. With one exception, the remaining sequenced mutations all caused substitution of amino acids conserved during evolution. The dominant mutations in the P-loop consensus caused severely reduced repair of heteroduplex DNA in vivo in a mutS mutant host strain. In a wild-type strain, the level of repair was decreased by the dominant mutations to between 12 to 90% of the control value, which is consistent with interference of wild-type MutS function by the mutant proteins. Increasing the wild-type mutS gene dosage resulted in a reversal of the mutator phenotype in about 60% of the mutant strains, indicating that the mutant and wild-type proteins compete. In addition, 20 mutant isolates showed phenotypic reversal by increasing the gene copies of either mutL or mutH. There was a direct correlation between the levels of recombination and mutagenesis in the mutant strains, suggesting that these phenotypes are due to the same function of MutS.     

Local Neutral Networks Help Maintain Inaccurately Replicating Ribozymes

The error threshold of replication limits the selectively maintainable genome size against recurrent deleterious mutations for most fitness landscapes. In the context of RNA replication a distinction between the genotypic and the phenotypic error threshold has been made; where the latter concerns the maintenance of secondary structure rather than sequence. RNA secondary structure is treated as a proxy for function. The phenotypic error threshold allows higher per digit mutation rates than its genotypic counterpart, and is known to increase with the frequency of neutral mutations in sequence space. Here we show that the degree of neutrality, i.e. the frequency of nearest-neighbour (one-step) neutral mutants is a remarkably accurate proxy for the overall frequency of such mutants in an experimentally verifiable formula for the phenotypic error threshold; this we achieve by the full numerical solution for the concentration of all sequences in mutation-selection balance up to length 16. We reinforce our previous result that currently known ribozymes could be selectively maintained by the accuracy known from the best available polymerase ribozymes. Furthermore, we show that in silico stabilizing selection can increase the mutational robustness of ribozymes due to the fact that they were produced by artificial directional selection in the first place. Our finding offers a better understanding of the error threshold and provides further insight into the plausibility of an ancient RNA world.     

Gene Conversion Drives Within Genic Sequences: Concerted Evolution of Ribosomal RNA Genes in Bacteria and Archaea

Multiple copies of a given ribosomal RNA gene family undergo concerted evolution such that sequences of all gene copies are virtually identical within a species although they diverge normally between species. In eukaryotes, gene conversion and unequal crossing over are the proposed mechanisms for concerted evolution of tandemly repeated sequences, whereas dispersed genes are homogenized by gene conversion. However, the homogenization mechanisms for multiple-copy, normally dispersed, prokaryotic rRNA genes are not well understood. Here we compared the sequences of multiple paralogous rRNA genes within a genome in 12 prokaryotic organisms that have multiple copies of the rRNA genes. Within a genome, putative sequence conversion tracts were found throughout the entire length of each individual rRNA genes and their immediate flanks. Individual conversion events convert only a short sequence tract, and the conversion partners can be any paralogous genes within the genome. Interestingly, the genic sequences undergo much slower divergence than their flanking sequences. Moreover, genomic context and operon organization do not affect rRNA gene homogenization. Thus, gene conversion underlies concerted evolution of bacterial rRNA genes, which normally occurs within genic sequences, and homogenization of flanking regions may result from co-conversion with the genic sequence. Received: 31 March 2000 / Accepted: 15 June 2000     

Genomic mutation rates: what high‐throughput methods can tell us

High‐throughput DNA analyses are increasingly being used to detect rare mutations in moderately sized genomes. These methods have yielded genome mutation rates that are markedly higher than those obtained using pre‐genomic strategies. Recent work in a variety of organisms has shown that mutation rate is strongly affected by sequence context and genome position. These observations suggest that high‐throughput DNA analyses will ultimately allow researchers to identify trans‐acting factors and cis sequences that underlie mutation rate variation. Such work should provide insights on how mutation rate variability can impact genome organization and disease progression.     

The evolution of sex-biased genes and sex-biased gene expression

Differences between males and females in the optimal phenotype that is favoured by selection can be resolved by the evolution of differential gene expression in the two sexes. Microarray experiments have shown that such sex-biased gene expression is widespread across organisms and genomes. Sex-biased genes show unusually rapid sequence evolution, are often labile in their pattern of expression, and are non-randomly distributed in the genome. Here we discuss the characteristics and expression of sex-biased genes, and the selective forces that shape this previously unappreciated source of phenotypic diversity. Sex-biased gene expression has implications beyond just evolutionary biology, including for medical genetics.     

Evolution of the mitochondrial genome of Metazoa as exemplified by comparison of congeneric species

The mitochondrial genome (mtDNA) of Metazoa is a good model system for evolutionary genomic studies and the availability of more than 1000 sequences provides an almost unique opportunity to decode the mechanisms of genome evolution over a large phylogenetic range. In this paper, we review several structural features of the metazoan mtDNA, such as gene content, genome size, genome architecture and the new parameter of gene strand asymmetry in a phylogenetic framework. The data reviewed here show that: (1) the plasticity of Metazoa mtDNA is higher than previously thought and mainly due to variation in number and location of tRNA genes; (2) an exceptional trend towards stabilization of genomic features occurred in deuterostomes and was exacerbated in vertebrates, where gene content, genome architecture and gene strand asymmetry are almost invariant. Only tunicates exhibit a very high degree of genome variability comparable to that found outside deuterostomes. In order to analyse the genomic evolutionary process at short evolutionary distances, we have also compared mtDNAs of species belonging to the same genus: the variability observed in congeneric species significantly recapitulates the evolutionary dynamics observed at higher taxonomic ranks, especially for taxa showing high levels of genome plasticity and/or fast nucleotide substitution rates. Thus, the analysis of congeneric species promises to be a valuable approach for the assessment of the mtDNA evolutionary trend in poorly or not yet sampled metazoan groups.     

Eucaryotic genome evolution through the spontaneous duplication of large chromosomal segments

There is growing evidence that duplications have played a major role in eucaryotic genome evolution. Sequencing data revealed the presence of large duplicated regions in the genomes of many eucaryotic organisms, and comparative studies have suggested that duplication of large DNA segments has been a continuing process during evolution. However, little experimental data have been produced regarding this issue. Using a gene dosage assay for growth recovery in Saccharomyces cerevisiae, we demonstrate that a majority of the revertant strains (58%) resulted from the spontaneous duplication of large DNA segments, either intra- or interchromosomally, ranging from 41 to 655 kb in size. These events result in the concomitant duplication of dozens of genes and in some cases in the formation of chimeric open reading frames at the junction of the duplicated blocks. The types of sequences at the breakpoints as well as their superposition with the replication map suggest that spontaneous large segmental duplications result from replication accidents. Aneuploidization events or suppressor mutations that do not involve large-scale rearrangements accounted for the rest of the reversion events (in 26 and 16% of the strains, respectively).     

Pinaceae show elevated rates of gene turnover that are robust to incomplete gene annotation

Gene duplications and gene losses are major determinants of genome evolution and phenotypic diversity. The frequency of gene turnover (gene gains and gene losses combined) is known to vary between organisms. Comparative genomic analyses of gene families can highlight such variation; however, estimates of gene turnover may be biased when using highly fragmented genome assemblies resulting in poor gene annotations. Here, we address potential biases introduced by gene annotation errors in estimates of gene turnover frequencies in a dataset including both well‐annotated angiosperm genomes and the incomplete gene sets of four Pinaceae, including two pine species, Norway spruce and Douglas‐fir. We show that Pinaceae experienced higher gene turnover rates than angiosperm lineages lacking recent whole‐genome duplications. This finding is robust to both known major issues in Pinaceae gene sets: missing gene models and erroneous annotation of pseudogenes. A separate analysis limited to the four Pinaceae gene sets pointed to an accelerated gene turnover rate in pines compared with Norway spruce and Douglas‐fir. Our results indicate that gene turnover significantly contributes to genome variation and possibly to speciation in Pinaceae, particularly in pines. Moreover, these findings indicate that reliable estimates of gene turnover frequencies can be discerned in incomplete and potentially inaccurate gene sets. Because gymnosperms are known to exhibit low overall substitution rates compared with angiosperms, our results suggest that the rate of single‐base pair mutations is uncoupled from the rate of large DNA duplications and deletions associated with gene turnover in Pinaceae.