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Origin and evolution of the genomic region for RAF1, MKRN2, PPARG, and SYN2 in human chromosome 3p25

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Shunnosuke Abe1, Shigeki Chiba2, Neena Mishra3, Masanori Doi4, Yasutaka Minamino5 and Todd A. Gray61-5 Laboratory of Molecular Cell Biology, Faculty of Agriculture, Ehime University, Matuyama 790-8566, Japan.. 6Genomics Institute, New York State Department of Health Wadsworth Center, NY 12180, USA

Genomic regions for RAF1 and its downstream flanking regions were studied in two fish, yellowtail (AB110017) and Chum salmon (AB110018), and in chicken, and compared with human chromosome 3p25.  In human, SYN2, PPARG, and MKRN2 are all 3f and on the opposite strand of RAF1, with MKRN2 producing overlapping, antisense transcripts with RAF1.   In chicken and fish, however, we identified novel transcripts that are antisense to their RAF1 homologs.  While we are still characterizing these novel transcripts, they do not appear to be protein-coding. In Atlantic salmon, a complete PPARG gene was found in the opposite strand of RAF1 flanking region, and a synapsin gene was located its upstream region. In antisense region of RAF1 in Atlantic salmon, a pseudogene of the transposase ssTN11 was located in the opposite strand of RAF1 downstream . The evolutionary conservation of antisense transcripts to RAF1 suggests that this feature might be important for RAF1 regulation.  Interestingly, we have also identified antisense transcripts in the two major RAF paralogs in human, ARAF (X chromosome) and BRAF (chromosome 7). From analyses on synteny, we were able to postulate a phylogenetic relationship of 3p25, 6p21.31, 7q34, 22q12-13, and Xp11.4 in human to the fish genes. We concluded that the characteristic arrangement of SYN2, PPARG, MKRN2, and RAF1 in human chromosome 3p25, and the anti-RAF1 gene, were already present in early evolution of vertebrates, and MKRN2 gene came to overlap RAF1 during evolution of mammals. Evolution of synapsin and PPAR families also appeared to derive from the RAF1 downstream synteny.  The protein products of genes that localize to this region may be functionally linked by roles in differentiation, apoptosis, and proliferation. PPARG, BRAF, and RAF1, for example, have been implicated in carcinogenesis in mice or humans, while SYN1 and ARAF may be involved in some X-linked disorders.  Therefore, understanding the possible functional linkages behind their evolution is potentially important not only in fish, but in human physiology as well. In addition, considerable instability of genomic region between RAF1 and PPARG were also evident, and this may contribute to chromosomal aberrations often observed in certain kind of carcinogensis.

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