MBE Advance Access originally published online on December 20, 2005
Molecular Biology and Evolution 2006 23(3):479-481; doi:10.1093/molbev/msj076
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Letter |
The Contribution of LTR Retrotransposon Sequences to Gene Evolution in Mus musculus
Department of Genetics, University of Georgia
E-mail: john.mcdonald{at}biology.gatech.edu.
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Abstract |
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 TOP Abstract BackgroundLRS Are Components of...Many LRS Are Located...LRS Are Preferentially...Summary and ConclusionsReferences |
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Approximately 1.5% of mouse genes (Mus musculus) contain long terminal repeat retrotransposon sequences (LRS). Consistent with earlier findings in Caenorhabditis elegans, Drosophila melanogaster, and Homo sapiens, LRS are more likely to be associated with newly evolved genes. Evidence is presented that LRS are often recruited as novel exons or as spliced additions to existing exons. These novel gene configurations may be expressed initially as alternative transcripts providing an opportunity for the evolution of new gene function.
Key Words: LTR retrotransposon • gene evolution • Mus musculus • mouse
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Background |
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TOPAbstractBackgroundLRS Are Components of...Many LRS Are Located...LRS Are Preferentially...Summary and ConclusionsReferences |
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Once considered parasitic sequences of little or no functional significance (Doolittle and Sapienza 1980
; Orgel and Crick 1980; Charlesworth, Sniegowski, and Stephan 1994), transposable elements (TE) are now widely recognized as significant contributors to gene evolution (McDonald 1993; Brosius 1999; Kidwell and Lisch 2001; Bowen et al. 2003; Makalowski 2003; Kazazian 2004). It has recently been reported that retrotransposon sequences contribute to 
4% of protein-coding regions (Nekrutenko and Li 2001), 27% of untranslated regions (van de Lagemaat et al. 2003), and 25% of promoter regions (Jordan et al. 2003) of human genes. We recently reported that long terminal repeat retrotransposon sequences (LRS) (defined as full-length elements or fragments of full-length elements) are present within the regulatory region and/or the transcription boundaries of 0.6% of Caenorhabditis elegans genes (Ganko et al. 2003) and 1.8% of Drosophila genes. (Ganko et al. 2006). Here we report on the contribution of LRS to transcribed regions of genes in the sequenced genome of the mouse (Mus musculus). |
LRS Are Components of Many Mouse Genes |
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TOPAbstractBackgroundLRS Are Components of...Many LRS Are Located...LRS Are Preferentially...Summary and ConclusionsReferences |
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Recently, 21 families of long terminal repeat (LTR) retrotransposons have been identified in the mouse genome, including 13 not previously described (McCarthy and McDonald 2004
). Genes with at least one fully sequenced mRNA from the mouse Unigene database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=unigene) were Blasted against consensus sequences representing each of these 21 families of mouse LTR retrotransposons. Of the 18,374 Unigenes examined, 267 (1.5%) were found to contain LRS. It has been reported that 0.9% of genes in humans contain LRS (Nekrutenko and Li 2001). The higher number of mouse genes containing LRS may, in part, be due to the greater number of transpositionally active LTR retrotransposons in the mouse genome (Smit 1999; Waterston et al. 2002; Deininger et al. 2003).
As a rule, genes involved in basic cellular functions are relatively conserved across taxa, while more recently evolved, specialized genes are taxa specific (e.g., van de Lagemaat et al. 2003; Castillo-Davis et al. 2004). To determine if mouse LRS are more likely to be associated with newly evolved genes, we queried the ortholog information provided by the Homologene data set (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=homologene). Homologenes are genes associated with functions that are generally conserved among even phylogenetically diverse groups of species (Wheeler et al. 2003). Of the 18,374 Unigenes examined, 11,341 had a homolog assigned by the Homologene data set, 88 (0.8%) of these contained an LRS. Thus, LRS are associated with homologenes about half as frequently as they are with all mouse genes.
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Many LRS Are Located in Mouse Exons |
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TOPAbstractBackgroundLRS Are Components of...Many LRS Are Located...LRS Are Preferentially...Summary and ConclusionsReferences |
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Our results indicate LRS are located within the coding regions of many mouse genes. Such associations are believed to have arisen directly by insertion of an LRS into an existing exon or indirectly by exon recruitment of an LRS from an adjacent intron or untranslated leader region (ULR) (Nekrutenko and Li 2001
). To estimate the number of LRS located within the coding regions of mouse genes, a database of mouse exonic sequences was obtained from Ensembl (http://www.ensembl.org/Multi/martview). If the predicted transcripts or proteins display significant similarity to species-specific Swiss-Prot, RefSeq, or TrEMBL entries, Ensembl classifies them as "known" otherwise they are classified as "novel" genes. At the time of this analysis (September 2004), the Ensembl database was composed of 25,307 mouse genes. Of these, 20,166 were subclassified as known and 5,141 as novel genes. Many of the novel genes in the Ensembl database are unannotated. Thus, as a precaution against overestimating the contribution of LRS to mouse gene evolution, we limited analysis to well-annotated genes (Ensembl known genes). The 20,166 annotated (known) genes in the Ensembl data set contain 186,823 exons. A total of 239 of these genes are associated with LRS located in 263 exons. Ten of these exons have two independently inserted LRS, and one has three (i.e., 275 associations). We found 22 of these 275 associations (22/275 or 8.0%) were composed of 
95% LRS. Exons composed almost exclusively of LRS are considered to have been recruited as novel exons from LRS located in adjacent introns or ULRs (e.g., Nekrutenko and Li 2001). Of the remaining LRS associated with exons, 55 (55/275 or 20.0%) were located at the 5' or 3' exon boundaries. LRS located at exon boundaries are considered to have been added to preexisting exons due to the presence of appropriate splice acceptor or donor sites (e.g., Nekrutenko and Li 2001). The remaining 198 (72.0%) LRS associated with exons, including the 11 exons containing more than one LRS, are located within the body of the exon. The origins of these LRS are more difficult to reconstruct, but some are likely to represent insertions into preexisting exons.
The addition of LRS to preexisting exons may be expected to disrupt gene function and be eliminated by natural selection. One possible hypothesis to explain the maintenance of relatively high number of LRS associated with exons is they are tolerated by natural selection at loci encoding multiple alternative transcripts. Under such a scenario, an inserted sequence would, due to the presence of appropriate splice acceptor/donor sites, be associated with generation of one or more novel alternative transcripts while the native transcript maintains the original gene function. Over evolutionary time, a novel transcript containing the LRS may evolve to encode a function favored by natural selection and thus be selectively maintained in conjunction with, or in place of, the original transcript. Under this hypothesis, alternative transcripts generated by TE insertions may provide an opportunity for the evolution of new gene functions in a manner similar to what has been proposed for gene duplications (Ohno 1970). Consistent with this view, we found that those mouse genes confirmed to encode alternative transcripts rarely contained LRS in all transcripts (table 1).
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LRS Are Preferentially Associated with Genes Encoding Metabolic Functions |
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TOPAbstractBackgroundLRS Are Components of...Many LRS Are Located...LRS Are Preferentially...Summary and ConclusionsReferences |
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Functional information from the Gene Ontology (GO) Consortium (http://www.geneontology.org/) was used to investigate possible functional trends among genes associated with LRS. GO networks are composed of three main functional classifications: molecular function, cellular component, and biological process. A number of subclasses are listed under each of these classifications. Based on the observed frequency of all experimentally verified genes in the Unigene database that group under each of the GO classifications, we computed the number of LRS-associated genes expected to group under each GO classification. This expected number was compared with the observed number to identify significant differences within the subclasses of each main classification. Only subclasses within the "biological process" classification demonstrated a significant difference between observed and expected numbers of associations (chi square = 30.05, df = 6, P
0.025).
The results presented in table 2 show mouse genes grouped under the biological process classification that encode physiological functions associated with LRS more frequently (251 observed, 0.68 success probability, 307 trials, P 0.025), while genes encoding cellular processes are associated with LRS less frequently (39 observed, 0.24 success probability, 307 trials, P 0.025) than expected. Significant deviations from expected numbers were also observed in two additional subclasses of physiological function. Genes associated with LRS that encode cell growth and maintenance functions are less frequent, while LRS-associated genes encoding metabolic functions were more frequent than expected.
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Summary and Conclusions |
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TOPAbstractBackgroundLRS Are Components of...Many LRS Are Located...LRS Are Preferentially...Summary and ConclusionsReferences |
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Consistent with earlier studies of Homo sapiens (Nekrutenko and Li 2001
), Drosophila (Ganko et al. 2006), and C. elegans (Ganko et al. 2003) genomes, we found LRS are contained within the coding regions of a significant proportion of mouse genes. Also consistent with earlier findings (Waterston et al. 2002; van de Lagemaat et al. 2003), our results indicate LRS may be preferentially associated with more recently evolved genes. The mechanisms by which LRS have been incorporated into genes over evolutionary time are likely to be varied and complex. However, our results suggest the recruitment of LRS as novel or spliced additions to existing exons is likely a primary mechanism. We propose that these novel gene configurations may be expressed initially as alternative transcripts, providing an opportunity for the evolution of new gene functions. |
Footnotes |
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1 Present address: Department of Biology, University of North Carolina.
2 Present address: School of Biology, Georgia Institute of Technology.
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References |
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