Downloaded from genome. cshlporg on June 20, 2011-Published by Cold Spring Harbor Laboratory Press Kaessmann material for the emergence of new fusion genes, allowing ancestral potential offered by DNA-based gene fusion events for the more gene functions to be preserved. Thus, chimeric genes often arise recent evolution of animals. However, a number of highly modular from juxtaposed pieces of duplicate gene copies through fission ancient genes, sharing exons encoding specific protein domains, and fusion processes( Fig 2A). For example, the dispersion and also attest to the functional importance of DNA-based exon shuf- shuffling of numerous segmental gene copies in hominoids fling(i.e, the exchange/fusion of individual exons) for early meta- through various recombination and translocation events has led evolution(Patthy 1999) to the formation of many mosaic gene structures, some of which Retroduplication is a mechanism that could be ex have become transcribed(Bailey et al. 2002; She et al. 2004; lend itself well for the process of gene fusion, given that it readily Marques-Bonet et al. 2009a). Among these transcribed chimeras, moves gene sequences to new locations in the genome. Indeed here are several genes with known functions (e. g, USP6, also a number of functionally relevant fusion events involving retro- known as Tre2, oncogene with testis expression; Paulding et al. genes have been described. For example, retrocopies were shown 2003)or genes that have further expanded and show signatures of to frequently have inserted into an intron of a host gene and to positive selection(e.g, RANBP2; Ciccarelli et al. 2005), suggesting have become transcribed in the form of a fusion transcript to that they evolved new beneficial functions. Juxtaposition of partial gether with host gene exons(Vinckenbosch et al. 2006; Kaessma segmental duplicates also seems to rather frequently have led to the et al. 2009). Often, these retrocopies are transcribed with only emergence of young functional genes in fruit flies, more often so 5-untranslated exons of the host gene, as alternative splice vari- than the apparently often redundant complete gene duplications ants, thus profiting from promoters from the host gene(also see Zhou et al. 2008). These observations illustrate the evolutionary above), while leaving host gene functions unaltered. However, functional coding s quence fusions of host genes and retro- genes have occurred as well. A classical example is the testis-expressed jingwei ggw) gene in Drosophila(Long and langley scribed. This gene emerged through a se- Partial duplication Partial dup ication ries of events based on the fusion of part a which provided the regulatory elements with a retrocopy of the Alcohol dehy. drogenase gene. Biochemical and evolu- tionary analysis further revealed that the igw-encoded protein evolved a new func tional role in hormone and pheromone metabolism under the influence of posi re Darwinian selection(Zhang et al. 2004). Functionally important retrogene host gene-coding fusions have also oc. 上 curred in mammals. Retrocopies from the cyclophilin A(CYPA) gene(also known a Evolution of splicing signais and transcriptional readthrough PPIA)which encodes a protein that po- tently binds retroviral capsids, were shown == to have integrated into the 3 end of the antiviral defense gene TRIM5 in a New World monkey, replacing and functionally substituting the exons encoding the origi- nal capsid-binding domain from TRIM5 AAA (Sayah et al. 200-4). Remarkably, a highly similar event was independently fixed in the old world monkey lineage(Brennan Reverse transcripton and integration et al. 2008), which illustrates the high selective benefit associated with the crea. TRIMS-CYPA gene fusions present striking nd taken Figure 2. Origin of new chimeric gene or transcript structures. (A) DNA-based (genomic)gene fu, gether, provide yet another fascinating ex- ample of convergent evolution in the field or transcription termination/polyadenylation sites).(B) Transcription-mediated gene fusion. Now fusion. Novel of new gene origination. with respect to anscript structures may arise from intergenic splicing after evolution of novel splicing signals the fusion of retrogenes with preexisting chimeric retrogenes(see also fig. 1).(Green, blue, red large boxes) Exons, (red exons, it is finally noteworthy that this (dotted lines)splicing of ancestral gene structures, (green lines)intergenic splicing that results in new plants(Wang et al. 2006; Zhuet al. 2009) chimeric transcripts while the functions and phenotypic 1318 Genomematerial for the emergence of new fusion genes, allowing ancestral gene functions to be preserved. Thus, chimeric genes often arise from juxtaposed pieces of duplicate gene copies through fission and fusion processes (Fig. 2A). For example, the dispersion and shuffling of numerous segmental gene copies in hominoids through various recombination and translocation events has led to the formation of many mosaic gene structures, some of which have become transcribed (Bailey et al. 2002; She et al. 2004; Marques-Bonet et al. 2009a). Among these transcribed chimeras, there are several genes with known functions (e.g., USP6, also known as Tre2, oncogene with testis expression; Paulding et al. 2003) or genes that have further expanded and show signatures of positive selection (e.g., RANBP2; Ciccarelli et al. 2005), suggesting that they evolved new beneficial functions. Juxtaposition of partial segmental duplicates also seems to rather frequently have led to the emergence of young functional genes in fruit flies, more often so than the apparently often redundant complete gene duplications (Zhou et al. 2008). These observations illustrate the evolutionary potential offered by DNA-based gene fusion events for the more recent evolution of animals. However, a number of highly modular ancient genes, sharing exons encoding specific protein domains, also attest to the functional importance of DNA-based exon shuf￾fling (i.e., the exchange/fusion of individual exons) for early meta￾zoan evolution (Patthy 1999). Retroduplication is a mechanism that could be expected to lend itself well for the process of gene fusion, given that it readily moves gene sequences to new locations in the genome. Indeed, a number of functionally relevant fusion events involving retro￾genes have been described. For example, retrocopies were shown to frequently have inserted into an intron of a host gene and to have become transcribed in the form of a fusion transcript to￾gether with host gene exons (Vinckenbosch et al. 2006; Kaessmann et al. 2009). Often, these retrocopies are transcribed with only 59-untranslated exons of the host gene, as alternative splice vari￾ants, thus profiting from promoters from the host gene (also see above), while leaving host gene functions unaltered. However, functional coding se￾quence fusions of host genes and retro￾genes have occurred as well. A classical example is the testis-expressed jingwei (jgw) gene in Drosophila (Long and Langley 1993), the first young fusion gene de￾scribed. This gene emerged through a se￾ries of events based on the fusion of parts of a segmental duplicate gene copy (ynd, which provided the regulatory elements) with a retrocopy of the Alcohol dehy￾drogenase gene. Biochemical and evolu￾tionary analysis further revealed that the jgw-encoded protein evolved a new func￾tional role in hormone and pheromone metabolism under the influence of posi￾tive Darwinian selection (Zhang et al. 2004). Functionally important retrogene– host gene-coding fusions have also oc￾curred in mammals. Retrocopies from the cyclophilin A (CYPA) gene (also known as PPIA) which encodes a protein that po￾tently binds retroviral capsids, were shown to have integrated into the 39 end of the antiviral defense gene TRIM5 in a New World monkey, replacing and functionally substituting the exons encoding the origi￾nal capsid-binding domain from TRIM5 (Sayah et al. 2004). Remarkably, a highly similar event was independently fixed in the Old World monkey lineage (Brennan et al. 2008), which illustrates the high selective benefit associated with the crea￾tion of this type of chimeric gene. Thus, the TRIM5-CYPA gene fusions present striking cases of domain shuffling and, taken to￾gether, provide yet another fascinating ex￾ample of convergent evolution in the field of new gene origination. With respect to the fusion of retrogenes with preexisting exons, it is finally noteworthy that this process seems to be rather prevalent in plants (Wang et al. 2006; Zhu et al. 2009). While the functions and phenotypic Figure 2. Origin of new chimeric gene or transcript structures. (A) DNA-based (genomic) gene fu￾sion. Partial duplication (and hence fission) of ancestral source genes precedes juxtaposition of partial duplicates and subsequent fusion (presumably mediated by the evolution of novel splicing signals and/ or transcription termination/polyadenylation sites). (B) Transcription-mediated gene fusion. Novel transcript structures may arise from intergenic splicing after evolution of novel splicing signals and transcriptional readthrough from the upstream gene. New chimeric mRNAs may sometimes be reversed transcribed to yield new chimeric retrogenes (see also Fig. 1). (Green, blue, red large boxes) Exons, (red right-angled arrows) transcriptional start sites (TSSs), (black connecting lines) constitutive splicing, (dotted lines) splicing of ancestral gene structures, (green lines) intergenic splicing that results in new chimeric transcripts. Kaessmann 1318 Genome Research www.genome.org Downloaded from genome.cshlp.org on June 20, 2011 - Published by Cold Spring Harbor Laboratory Press