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{"project":"2_test","denotations":[{"id":"15207008-12777526-9666000","span":{"begin":397,"end":399},"obj":"12777526"},{"id":"15207008-12808028-9666001","span":{"begin":1186,"end":1188},"obj":"12808028"},{"id":"15207008-12481130-9666002","span":{"begin":2472,"end":2474},"obj":"12481130"},{"id":"15207008-12142439-9666003","span":{"begin":2559,"end":2561},"obj":"12142439"},{"id":"15207008-12481130-9666004","span":{"begin":4899,"end":4901},"obj":"12481130"}],"text":"Evolution of the chromosomal segments containing the TACC genes\nThe phylogenetic tree of the FGFR genes closely resembles that of the vertebrate TACC1-3 genes. Recently, detailed analyses of the chromosomal regions containing the FGFR gene family in humans, mouse and the arthopod D. melanogaster have revealed the conservation of paralogous chromosomal segments between these organisms (Fig. 2, [13], Table 1 [see Additional file 1]). This has provided further support that an ancient chromosomal segment was duplicated twice during vertebrate evolution, with the first duplication that gave rise to the human chromosome 4p16/5q32-ter and human chromosome 8p/10q23-ter ancestors occurring in the early stages after the invertebrate divergence. This suggests that the ancestral FGFR-TACC gene pair most probably arose prior to the initial duplication and subsequent divergence of these paralogous chromosomal segments, estimated to have occurred 687 ± 155.7 MYA. This has raised the suggestion that a fourth TACC gene in vertebrates would reside in the same chromosomal region as FGFR4. Indeed this hypothesis has been used in support for the RHAMM gene as a member of the TACC family [10]. Human RHAMM maps to chromosome 5q32 in a region bounded by GPX3 and NKX2E. These loci separate two clusters of genes on human chromosome 5 that are paralogous with 4p16. Interestingly, these three clusters are located on different chromosomes in mouse and rat (Fig. 2), further suggesting that this cluster of genes was transposed into this region after the primate/rodent divergence.\nFigure 2 Linear organization of gene clusters centering upon the chromosomal loci of the FGFR genes in humans. Paralogous genes present in at least two of the four loci are shown, with the exception of the region between GPX3 and NKX2E on chromosome 5, which appears to represent a series of intervening genes inserted after duplication of the 4p16/5q32-35 clusters, and genes mentioned in Fig. 3. Corresponding syntenic mouse chromosomal regions (mm*) are indicated. Takifugu rubripes scaffolds are shown (TR*) that contain more than one homologous gene from these clusters. Further details on the location of paralogous genes can be found in [see Additional file 1]. Because the conservation of gene order can also provide clues to the evolution of gene regulation, we next attempted to trace the evolution of these paralogous segments by examining the genome of the tunicate C. intestinalis [11] and the most \"primitive\" compact vertebrate genome sequenced to date, T. rubripes [14]. Although not fully assembled, examination of the genome of T. rubripes confirmed the presence of chromosomal segments paralogous to those found in higher vertebrates (Fig. 2). For instance, the orthologues of GPRK2L and RGS12 are found on T. rubripes scaffold 290 (emb|CAAB01000290.1), and within 300 kb of each other in human 4p16. The T. rubripes orthologues of FGFR3, LETM1 and WHSC1 are located on the same 166 kb genomic scaffold 251 (emb|CAAB01000166.1). Significantly, the three human orthologues of these genes are also located within 300 kb of each other on 4p16. Furthermore, TACC3 and FGFRL map to the overlapping scaffolds 1184/4669 (emb|CAAB01004668). Similarly, elements of these gene clusters, extending from HMP19 to GPRK6 in human chromosome 5q34-ter are also found in the pufferfish, with the T. rubripes orthologues of NSD1, FGFR4 and a RAB-like gene mapping on scaffold 407 (emb|CAAB01000407). However, there is no evidence for a gene corresponding to a TACC4 gene in any of these clusters.\nAs noted above, phylogenetic analysis of the TACC sequences indicate that there are two TACC1 related genes in the pufferfish. trTACC1B is located on the 180 kb scaffold 191 (emb|CAAB01000191.1), which also contains the orthologues of several genes located in human chromosome 8p21-11. Thus, this scaffold represents the more \"developed\" TACC1 chromosomal segment that is evident in higher vertebrates. On the other hand, the trTACC1A gene is located in the 396 kb scaffold 12 (emb|CAAB010012.1). This scaffold also contains the T. rubripes orthologues of MSX1, STX18, D4S234E and the predicted gene LOC118711, in addition to sequences with homology to LOXL, EVC, LOC159291, and the LDB family. Thus, scaffold 12 contains genes found in the regions of human chromosome 4 and 10 that also contain the loci for TACC3 and TACC2, respectively, and may therefore more closely resemble the genomic organization resulting from the initial duplication of the ancestral paralogous chromosomal segment.\nConserved paralogous clusters may result from the initial clustering of the genes in a relatively small ancestral genomic contig. Some evidence for the existence of \"protoclusters\" that could correspond to the paralogous chromosomal segments noted in higher vertebrates is present in the genome of the urochordate C. intestinalis [11]. For instance, the orthologues of FGFR, and WHSC1, carboxypeptidase Z and FLJ25359 cluster within an 85 kb region of the C. intestinalis genome and the human orthologues are still maintained in paralogous segments of 4p16, 8p and 10q (Fig. 3, [see Additional file 1]). However, it should be noted that no clusters of genes from the vertebrate paralogous segments are locate close to the TACC or RHAMM genes of C. intestinalis, indicating that the formation of the much larger paralogous segments encompassing the FGFR-TACC genes formed later in evolutionary time, or conversely have been subject to extensive rearrangement in tunicates. In combination with the examination of the T. rubripes genome, this also provides additional evidence that either the second round of duplication of the chromosomal segment that contained the FGFR3/4 ancestor did not include a TACC gene, or that such a gene was lost very early in vertebrate evolution, prior to the divergence of the Gnanthostome lineages. However, the final resolution of the initial evolution of these paralogous segment will await the sequencing of the amphioxus and lamprey genomes, which only have one FGFR gene, and therefore should only contain one copy of the other corresponding genes in this conserved segment.\nFigure 3 Formation of protoclusters in Takifugu rubripes and Ciona intestinalis: (A): Structure of the genomic scaffolds containing the Takifugu rubripes trTACC1A and trTACC1B genes. Scaffold 12, the site for the trTACC1A gene contains genes found with either homologues or orthologues on the distal long arm of human chromosome 10 and 4p16. This scaffold, therefore, has some of the characteristics of the predicted immediate ancestor of the TACC1/TACC2 chromosomal segment. trTACC1B is found on scaffold 191, which contains orthologues of genes found in the proximal short arm of human chromosome 8. (B): Ciona intestinalis clusters containing genes found in paralogous segments on human 8, 4p16, 10q and 5q.\nFigure 4 Genomic structure of the TACC genes. Conserved regions known to bind protein factors in all human TACC proteins are shown. The SDP repeat of human TACC1-3 is known to bind GAS41 ([3,15] and data not shown). The TACC domain binds ch-TOG and members of the Aurora kinases in all species examined to date. This motif is characteristically encoded by the 3' exons of the TACC genes. The size of the largest isoform for each gene is shown."}

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PMC:441373 / 14596-21930 JSON TXT