Downloaded from genome.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Insight/Outlook A New Function Evolved from Gene Fusion Manyuan Long1 Department of Ecology and Evolution, The University of Chicago, Chicago, Illinois 60637, USA What constitutes genetic difference changes consistent with origin of new scription, and cell-cycle progression among organisms? How do new gene functions: High protein substitution (Sancho et al. 1998; Thomson et al. functions originate in nature? Since the rates and drastic changes in gene struc- 1998; Xiao et al. 1998). In Saccharomyces early days of molecular biology, we have ture. Drosophila is not the only organism cerevisiae, the UEV protein controls elon- known that homologous genes between whose genome has been found to origi- gation of polyubiquitin chains when as- species differ in DNA and protein se- nate new protein-coding genes differen- sociated with ubiquitin-conjugating en- quence. Noncoding regions have also tiating one species from another. Other zymes (E2; Hoffman and Pickart 1999). been evolving with repetitive sequences, organisms, including plants and mam- The UEV genes in divergent organisms transposable elements, and other ele- mals, also have newly originated genes. have maintained a very conserved struc- ments continuously reshaping genomes For example, the Mus musculus genome ture in its common domain (C domain). of organisms. As more genomes of hu- contains multiple copies of the new However, there exists an additional do- mans and other organisms are exam- gene SP100-rs, which is absent in its sib- main (B domain) in one isoform of the ined, it also becomes clear that species ling species Mus caroli (Weichenhan et human gene that does not exist in other differ not only in these two genomic pa- al. 1998), though little detail of its evo- organisms and, thus, creates a new, chi- rameters but also in the number and lution and function is known. In potato, merical gene structure. How did this kinds of genes. a new cytochrome c1 originated a mito- new structure originate, and where does Genes are subject to a life and death chondrial targeting function (Long et al. the B domain come from? process: New genes have originated con- 1996). Retrosequences may have con- From the first glimpse, this human tinuously throughout evolution. For ex- tributed to the origin of new vertebrate gene is reminiscent of the chimerical ample, Drosophila melanogaster contains regulatory elements or new parts of ver- structure of two Drosophila young genes. 87 cuticle protein genes, while Cae- tebrate coding regions (Brosius 1999). In The first example is jingwei, which is norhabditis elegans contains no such these cases, recombination of protein composed of a major domain and an ad- genes in its genome (Rubin et al. 2000). modules and gene duplication played ditional N-terminal domain (Long and If this is thought to be comparing too- essential roles in creating the initial gene Langley 1993). Recent work implies that divergent organisms, take a look at re- structures, and natural selection partici- the mosaic structure of jingwei was cre- cently divergent sibling species. Dro- pated in the subsequent evolution. ated by insertion of the retrosequence of sophila teisseiri and Drosophila yakuba Although insights from young chi- the alcohol dehydrogenase gene into a contain a gene called jingwei (Long and merical genes in Drosophila have enor- previously existing gene, recruiting a Langley 1993; Wang et al. 2000), which mously changed our views of new gene portion of the N-terminal domain (Long originated only 2.5 million years ago. D. evolution, good data from humans or et al. 1999; Wang et al. 2000). The sec- melanogaster itself has a unique gene mammals have been lacking. This is a ond example is Sdic, which was created Sdic, which expresses particularly in the significant hurdle for understanding by a deletion in two adjacent genes at sperm tail and does not exist in even its new gene evolution in the genetic sys- the DNA level (Nurminsky et al. 1998). closest relative species (Nurminsky et al. tems of the human and its primate rela- However, the human UEV gene seems to 1998). tives. In this issue, Thompson et al. have taken a different evolutionary route New genes often give rise to new (2000) present a clear example of how to acquire its additional B domain (Fig. 1). biological functions driven by adaptive new genes with novel functions can In the genomic databases of D. Darwinian selection (Long and Langley originate in humans and other mam- melananogster and C. elegans, two small 1993; Chen et al. 1997; Begun 1997; mals, including the molecular process DNA fragments unrelated to the UEV Nurminsky et al. 1998). New genes may and derived biological function. A closer gene in these species were found to be even have controlled the origination of look at the origination of this new gene, significantly similar to the B domain of new species, for example, Odysseus, a ho- Kua-UEV, offers insights into the general the human UEV gene. Further analysis meobox duplicate gene in Drosophila problem of human gene origination. showed that these are seven exons en- (Ting et al. 1998). Such new genes UEV is a conserved gene, distributed coding a 319–amino acid protein in C. are associated with two conspicuous across all major eukaryotic lineages elegans and five exons encoding a 326– ranging from animals to fungi, plants, amino acid protein in D. melanogaster. 1E-MAIL [email protected]; FAX and protozoa. The UEV proteins in these This newly discovered gene, named Kua (773)702-9740. Article and publication are at www.genome.org/cgi/ organisms share multiple functions, for (derived from the word “Cua” in Cat- doi/10.1101/gr.165700 example, cell protection, c-FOS tran- alan, which means “tail” or “queue”) en- 10:1655–1657 ©2000 by Cold Spring Harbor Laboratory Press ISSN 1088-9051/00 $5.00; www.genome.org Genome Research 1655 www.genome.org Downloaded from genome.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Long genes are also encoded in an operon-like structure (Blumen- thal and Spieth 1996). Thus, an authentic gene fusion should possess a particular mechanism to override the nonsense codon used to stop translation of the N-terminal protein. For ex- ample, a mutation-like inser- tion in the stop codon would continue translation for a fused protein (Burns et al. 1990). However, the Kua-UEV human gene uses another, more sophis- ticated mechanism to solve the problem. Taking advantage of the more efficient splicing sys- tem in eukaryotes, Kua-UEV employs alternative splicing to skip the exon k6 of Kua that contains the Kua stop codon and exon A of UEV that con- tains a translation initiation codon. Given that many verte- brates genes often contain long UTR regions and an intergenic region, alternative splicing may Figure 1 The molecular process for Kua-UEV gene fusion. be an efficient mechanism to avoid the stop codon in up- codes a protein having features reminis- fore in various organisms. The classic ex- stream gene(s), as represented by the cent of fatty acid hydroxylase. Kua was amples are the fatty acid synthase gene Kua-UEV gene. These long stretches of also detected in other species (M. muscu- (McCarthy and Hardie 1984) and trypo- noncoding DNA may contain many lus, Trypanosoma cruzi, and Arabidopsis tophan synthethase gene in fungi stop codons, and the random peptides thaliana) but was not found in S. cerevi- (Burns et al. 1990). Other noted cases translated from such DNAs may not be siae genome sequences. include HisA and HisF in the histidine able to provide useful folds. Thus, one What is the linkage relationship be- pathway (Lang et al. 2000), glutamyl- can predict that, in the future, it would tween Kua and UEV?InD. melanogaster, and prolyl-tRNA synthetase genes (Ber- not be unusual to find gene fusion prod- Kua and the UEV gene are separated by thonneau and Mirande 2000), the ucts using this existing cellular mecha- 2.5 million bases in chromosome 1, young fusion gene Sp100-rs in M. mus- nism, rather than waiting for a mutation while in C. elegans these genes are lo- culus (Weichenhan et al. 1998), and the in the stop codon. cated on two different chromosomes. old fused genes of ubiquitin and ribo- What is the evolutionary advantage Thus, the genes Kua and UEV are simply somal proteins in diverged organisms of gene fusion? Conspicuously, cova- different loci. However, in the human like yeast and human (Kirschner and lently connected proteins would ensure genome these two loci are adjacent by Stratakis 2000). In bacteria and archaea, coregulation of gene expression of re- several kilobases, and a portion of RNA gene fusion was genomically surveyed lated functions. The covalently linked transcripts from the two genes is fused in a number of species whose genomes proteins can ensure stoichiometric pro- into a single RNA. This fused transcript have been sequenced (Snel et al. 2000). duction of the component peptides (Mc- structure may result from a relatively However, the human Kua-UEV gene fu- Carthy and Hardie 1984). Gene fusion weak terminating signal for Kua gene sion provides a revealing case regarding also confers other advantages for par- transcription. A similar mechanism is re- several important aspects of new protein ticular proteins. For example, the multi- sponsible for generating read-through origin. functionality of fatty acid synthase pre- transcripts of the L1 element and its First, a fused transcript is not a syn- vents dissociation at low protein con- downstream cellular gene sequences onym for a fused protein. Distinct pro- centration (McCarthy and Hardie 1984).