Structure and function of chromosome band boundaries of warm-blooded vertebrates

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The genomes of warm-blooded vertebrates, including humans, are composed of long-range mosaic structures of G+C% (GC%), which are thought to be related to chromosome bands. We previously reported an example of a boundary of megabase-sized GC% mosaic domains at the junction area between MHC classes II and III,proposing it to be a possible chromosome band boundary. We then found in the domain boundary a sequence very similar to pseudoautosomal boundary (PAB) sequences of human sex chromosomes. We designated it "PABL" and found many PABLs in the human genome. Band boundaries have been predicted to contain a switch point for DNA replication timing during S phase. To identify the replication swich point, we determined the precise DNA replication timing for MHC classes II and III,focusing on the junction area. The replication timing changed precisely in the boundary region with 2-hours difference between both sides, showing this region to be a chromosome band boundary. Replication fork movement appears to terminate(pause) or significantly slow down in the switch region, which contains dense Alu clusters and polypurine/polypyrimidine tracts. Three scaffold-associated regions (SARs/MARs) were found in and around the switch region. The human counterpart of the mouse mammary tumor gene Int3 was found near the GC% border. We designated this class III gene as NOTCH4. The comparison of the predicted amino acid sequence with those of other known Notch homologues revealed four subfamilies for mammalian Notch. In the human NOTCH4, we found (CTG)n repeats showing variable number tandem repeat (VNTR) polymorphism for different HLA haplotypes. We show also that ten genes mapped on 6p21.3, including NOTCH4, have counterparts structurally and functionally similar to those mostly mapped on 9q33-q34, indicating segmental chromosome duplication during evolution. Similarity of genes on chromosome 1,6,9 and 19 was also found.