@misc{oai:ir.soken.ac.jp:00000901,
 author = {菅谷, 公彦 and スガヤ, キミヒコ and SUGAYA, Kimihiko},
 month = {2016-02-17, 2016-02-17},
 note = {Genomes of higher vertebrates are composed of long-range mosaic structures of GC% , which are related to chromosome bands. Several groups, including ours , showed chromosomal G bands to be mainly composed of AT-rich sequences and T bands (an evidently heat-stable subgroup of R bands), of GC-rich sequences: ordinary R bands are heterogeneous and appear to be intermediate. Gene dens ity, DNA replication timing, repeat sequence density and other chromosome behaviors such as recombination are related to chromosomal bands and to the long-range GC% mosaic structures. <br />  Human MHC spans about a 4 megabase (Mb) segment of the short arm of chromosome 6 (6p21. 3), and the region is composed of classes I (about 2 Mb), III ( 1 Mb) and II (1 Mb) from telomere to centromere. Genes in classes I and II encode polymorphic antigens involved in genetic control of immune response: Class III, which is one of the regions most densely packed with genes in the human genome, encode proteins of diverse functions mostly unrelated to immune response. Susceptibility to a large number of diseases, including autoimmune disorders, is thought related to genes in the MHC. However, in many cases, it is not clear whether the susceptibility is due to known genes or to those not yet identified. <br />  Previous studies of our group showed the human MHC to be a long-range mosaic of GC%. Contiguous classes I and III correspond to an evidently GC-rich domain and class II, to a domain with reduced GC%. Thus , borders of Mb-level GC% mosaic domains had been as signed within under-characterized 450 kb harboring the junction of classes II and III. To precisely locate the domain border and find new genes, chromosome walking to completely cover this 450-kb area were carried out by isolating cosmid, λ phage and YAC contigs. During characterization of the 450 kb, especially of the region near the border of the Mb-level GC% mosaic domains , three human MHC class III genes were found; the gene for receptor of advanced glycos ylation end products of proteins (RAGE, a member of immunoglobulin superfamily molecules believed to be related to diabetes complication), PBX2 homeobox gene (designated HOX12 by me and suspected to be a proto-oncogene), and human counterpart of mouse mammary tumor gene int-3, designated as NOTCH3 . Human RAGE and PBX2 sequences were previously determined sequencing their cDNA clones , but the gene structures and map locations had not been known. The contiguous RAGE and PBX2 (HOX12) genes were completely sequenced in this work, and a single copy number of these genes in the human genome was shown by Southern blot analysis. <br />  Integration of the mouse mammary tumor virus (MMTV) into the int-3 locus promotes the transcription of flanking mouse cellular int-3 sequence that shares s ignificant homology with the intracellular domain of Drosophila neurogenic Notch gene. The human sequences found in the present work contained not only the intracellular domain part present in the int-3 sequence but also the extracellular part present in typical Notch-family genes, showing the sequence found in this study to correspond to the human counterpart of an uninterrupted form of the transmembrane protein gene predicted for the mouse int-3 locus. The placental CDNA clones of the human NOTCH3 were is olated and sequenced. By constructing phylogenetic tree based on their sequences, four subfamilies for mammalian Notch genes were found. <br /> Near a GC% transition of the long-range mosaic structures, being centromeric of NOTCH3, there were a 20 kb of dense Alu cluster and a 30 kb of dense LINE- 1 cluster, as well as pseudoautosomal boundary-like sequence (PABL) found by Fukagawa in our group. Summary of the organization of the walked 450 kb is as follows; [Class II; AT-rich side] HLA-DRA - 140kb - PABL - 30 kb of LINE- 1 cluster - 20 kb of Alucluster -NOTCH3 - PBX2 - RAGE - 90 kb - TNX (the tenascin X gene) - 70 kb - CYP21 [Class III; GC-rich side]. <br />  I have also found the gross similarity of genes on 6p2 1.3 and those on 9q33-q34. The human gene most closely related to NOTCH3 is TAN1 being precisely mapped on 9q34. 3, that to PBX2 is PBX3 roughly mapped on 9q3 3-34, and that to TNX is HXB (the tenascin C gene) on 9q32-q34. By searching human Genome Data Base (GDB), not only the three genes discovered by our group but also several others on 6p2 1 . 3 were found to have counterparts mostly mapped on 9q33-q34. This gross similarity should have been brought on by duplication of a wide range of the genome and thus gives a realis tic know ledge concerning evolutionary processes to built up the present human genome. The similarity is also useful for finding undiscovered genes , especially candidate genes respons ible for genetic diseas es., application/pdf, 総研大甲第140号},
 title = {ヒトＭＨＣクラスII近傍のクラスIII領域に見い出した特徴的ゲノム構造と新遺伝子類に関する研究},
 year = {}
}