DeSilva U, Massa H, Trask B J, Green E D
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Genome Res. 1999 May;9(5):428-36.
Williams syndrome (WS) is a complex developmental disorder resulting from the deletion of a large (approximately 1.5-2 Mb) segment of human chromosome 7q11.23. Physical mapping studies have revealed that this deleted region, which contains a number of known genes, is flanked by several large, nearly identical blocks of DNA. The presence of such highly related DNA segments in close physical proximity to one another has hampered efforts to elucidate the precise long-range organization of this segment of chromosome 7. To gain insight about the structure and evolutionary origins of this important and complex genomic region, we have constructed a fully contiguous bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC) contig map encompassing the corresponding region on mouse chromosome 5. In contrast to the difficulties encountered in constructing a clone-based physical map of the human WS region, the BAC/PAC-based map of the mouse WS region was straightforward to construct, with no evidence of large duplicated segments, such as those encountered in the human WS region. To confirm this difference, representative human and mouse BACs were used as probes for performing fluorescence in situ hybridization (FISH) to metaphase and interphase chromosomes. Human BACs derived from the nonunique portion of the WS region hybridized to multiple, closely spaced regions on human chromosome 7q11.23. In contrast, corresponding mouse BACs hybridized to a single site on mouse chromosome 5. Furthermore, FISH analysis revealed the presence of duplicated segments within the WS region of various nonhuman primates (chimpanzee, gorilla, orangutan, and gibbon). Hybridization was also noted at the genomic locations corresponding to human chromosome 7p22 and 7q22 in human, chimpanzee, and gorilla, but not in the other animal species examined. Together, these results indicate that the WS region is associated with large, duplicated blocks of DNA on human chromosome 7q11.23 as well as the corresponding genomic regions of other nonhuman primates. However, such duplications are not present in the mouse.
威廉姆斯综合征（WS）是一种复杂的发育障碍，由人类染色体7q11.23上一个大的（约1.5 - 2兆碱基）片段缺失所致。物理图谱研究表明，这个缺失区域包含多个已知基因，其两侧是几个大的、几乎相同的DNA片段。这些高度相关的DNA片段在物理位置上彼此紧邻，阻碍了人们阐明7号染色体这一片段精确的长程组织结构的努力。为了深入了解这个重要且复杂的基因组区域的结构和进化起源，我们构建了一个完全连续的细菌人工染色体（BAC）和P1衍生人工染色体（PAC）重叠群图谱，该图谱涵盖了小鼠5号染色体上的相应区域。与构建人类WS区域基于克隆的物理图谱时遇到的困难不同，小鼠WS区域基于BAC/PAC的图谱构建起来很直接，没有证据表明存在像人类WS区域那样的大的重复片段。为了证实这种差异，使用代表性的人类和小鼠BAC作为探针，对中期和间期染色体进行荧光原位杂交（FISH）。源自WS区域非唯一部分的人类BAC与人类染色体7q11.23上多个紧密间隔的区域杂交。相比之下，相应的小鼠BAC与小鼠5号染色体上的单个位点杂交。此外，FISH分析揭示了各种非人类灵长类动物（黑猩猩、大猩猩、猩猩和长臂猿）的WS区域内存在重复片段。在人类、黑猩猩和大猩猩中，在与人类染色体7p22和7q22对应的基因组位置也观察到杂交，但在其他所检测的动物物种中未观察到。总之，这些结果表明，WS区域与人类染色体7q11.23上大的、重复的DNA片段以及其他非人类灵长类动物的相应基因组区域相关。然而，这种重复在小鼠中不存在。
