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

温血脊椎动物染色体带边界的结构和功能

基本信息

批准号：
07454207
负责人：
IKEMURA Toshimichi
金额：
$ 3.01万
依托单位：
NATIONAL INSTITUTE OF GENETICS
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

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.

包括人类在内的温血脊椎动物的基因组由 G+C% (GC%) 的长程嵌合结构组成，这被认为与染色体带有关。我们之前报道了MHC II类和III类交界处兆碱基大小的GC％镶嵌结构域边界的例子，认为它是可能的染色体带边界。然后我们在域边界中发现了一个与人类性染色体的伪常染色体边界（PAB）序列非常相似的序列。我们将其命名为“PABL”，并在人类基因组中发现了许多PABL。据预测，条带边界包含 S 期 DNA 复制计时的转换点。为了确定复制切换点，我们确定了 MHC II 类和 III 类的精确 DNA 复制时间，重点关注连接区域。复制时间在边界区域精确变化，两侧相差2小时，表明该区域是染色体带边界。复制叉运动似乎在转换区域终止（暂停）或显着减慢，该区域包含密集的 Alu 簇和多聚嘌呤/多聚嘧啶束。在开关区域内和周围发现了三个支架相关区域（SAR/MAR）。在 GC% 边界附近发现了小鼠乳腺肿瘤基因 Int3 的人类对应物。我们将这个III类基因命名为NOTCH4。将预测的氨基酸序列与其他已知的Notch同源物的氨基酸序列进行比较，揭示了哺乳动物Notch的四个亚科。在人类 NOTCH4 中，我们发现 (CTG)n 重复序列显示不同 HLA 单倍型的可变数量串联重复序列 (VNTR) 多态性。我们还表明，定位在 6p21.3 上的 10 个基因（包括 NOTCH4）在结构和功能上与大多数定位在 9q33-q34 上的基因相似，表明进化过程中存在片段性染色体重复。还发现了 1、6、9 和 19 号染色体上基因的相似性。