Structural /Functional Analysis of Mammalian Chromosomes

正在进行的人类基因组计划的一项中心活动是绘制哺乳动物基因组的图谱和测序。物理制图科的主要目标是构建哺乳动物染色体的综合和注释物理图，以促进相应DNA的测序，并利用所得信息研究重要的生物学问题。我们最初将注意力集中在约170兆碱基的人类7号染色体上。具体来说，我们已经构建了酵母人工染色体（YAC）和细菌人工染色体（BAC）为基础的物理地图，这一地区的人类基因组。染色体的系统测序已接近完成，正在与两个校外基因组中心（华盛顿大学和华盛顿大学）合作进行。与此同时，我们正在积极使用这些序列数据来构建其他脊椎动物基因组相应区域的物理图谱，以进行测序。后者包括与NIH校内测序中心（NISC）合作进行的多物种比较测序的大型项目。最后，有几个正在进行的项目旨在研究与人类遗传疾病相关的7号染色体区域。这些努力使我们鉴定出了Pendred综合征基因，这是一种导致脑海绵状畸形的基因，也是一种长期寻找的肿瘤抑制基因。这些发现为基因及其编码蛋白的结构和功能的生物学研究开辟了许多新的途径，包括开发这些遗传疾病的小鼠模型。与其他一些重要疾病有关的基因，包括腓骨肌萎缩症（CMT2D）、威廉姆斯综合征和自闭症，也在继续研究。

A central activity of the ongoing Human Genome Project is the mapping and sequencing of mammalian genomes. The major aims of the Physical Mapping Section are to construct integrated and annotated physical maps of mammalian chromosomes, to facilitate the sequencing of the corresponding DNA, and to utilize the resulting information for studying important biological problems. We initially focused our attention on the ~170-megabase human chromosome 7. Specifically, we have constructed yeast artificial chromosome (YAC)- and bacterial artificial chromosome (BAC)-based physical maps of this region of the human genome. The systematic sequencing of the chromosome is nearly complete, being performed in collaboration with two extramural genome centers (at Washington University and the University of Washington). In parallel, we are actively using this sequence data to construct physical maps of the corresponding regions of other vertebrate genomes, en route to their sequencing. The latter includes a large program of multi-species comparative sequencing being performed in collaboration with the NIH Intramural Sequencing Center (NISC). Finally, there are several ongoing projects aiming to study regions of chromosome 7 associated with human genetic disease. These efforts have resulted in our identification of the Pendred syndrome gene, a gene responsible for cerebral cavernous malformations, and a long sought-after tumor suppressor gene. These findings have opened up numerous new avenues of biological study relating to the structure and function of the genes and their encoded proteins, including the development of mouse models for these genetics disorders. Searches continue for the genes implicated in a number of other important diseases, including Charcot-Marie-Tooth syndrome (CMT2D), Williams syndrome, and autism.