Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1
Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1
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DOI：
10.1101/gr.6.11.1029
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发表时间：
1996-11-01
期刊：
影响因子：
7
通讯作者：
King, MC
中科院分区：
文献类型：
--
作者：
Smith, TM;Lee, MK;King, MC
乳腺癌易感性基因 BRCA1 中已鉴定出 100 多种不同的与疾病相关的突变。遗传性 BRCA1 突变患者的肿瘤中超过 90% 的野生型等位基因缺失表明肿瘤抑制功能。体细胞突变的低发生率表明散发性肿瘤中的 BRCA1 失活是通过替代机制发生的，例如间质染色体缺失或转录减少。为了确定 BRCA1 基因组区域可能导致染色体不稳定的特征以及潜在的转录调控元件，通过对从人类 17 号染色体特异性文库中鉴定的四个粘粒进行随机测序，获得了包含 BRCA1 的 117,143 bp DNA 序列。 BRCA1 的 24 个外显子跨越 81 kb 区域，该区域具有异常高密度的 Alo 重复 DNA (41.5%)，但其他重复序列的密度相对较低 (4.8%)，BRCA1 内含子长度范围为 403 bp 至 9.2 kb，并包含基因内微卫星标记 D17S1323、D17S1322 和D17S855，分别定位于内含子 12、19 和 20。除了 BRCA1 之外，重叠群还包含两个完整的基因：Rho7（GTP 结合蛋白 rho 家族的成员）和 VAT1（胆碱能突触小泡的丰富膜蛋白）。 1A1-3B B-box 蛋白假基因和 IFP 35（干扰素诱导的亮氨酸拉链蛋白）的部分序列位于重叠群内。 L21核糖体蛋白假基因嵌入BRCA1内含子13中。染色体上基因的顺序是：着丝粒-IFP 35-VAT1-Rho7-BRCA1-1A1-3B-端粒。
Over 100 distinct disease-associated mutations have been identified in the breast-ovarian cancer susceptibility gene BRCA1. Loss of the wild-type allele in >90% of tumors from patients with inherited BRCA1 mutations indicates tumor suppressive function. The low incidence of somatic mutations suggests that BRCA1 inactivation in sporadic tumors occurs by alternative mechanisms, such as interstitial chromosomal deletion or reduced transcription. To identify possible features of the BRCA1 genomic region that may contribute to chromosomal instability as well as potential transcriptional regulatory elements, a 117,143-bp DNA sequence encompassing BRCA1 was obtained by random sequencing of four cosmids identified from a human chromosome 17 specific library. The 24 exons of BRCA1 span an 81-kb region that has an unusually high density of Alo repetitive DNA (41.5%), but relatively low density (4.8%) of other repetitive sequences, BRCA1 intron lengths range in size from 403 bp to 9.2 kb and contain the intragenic microsatellite markers D17S1323, D17S1322, and D17S855, which localize to introns 12, 19, and 20, respectively. In addition to BRCA1 the contig contains two complete genes: Rho7, a member of the rho family of GTP binding proteins, and VAT1, an abundant membrane protein of cholinergic synaptic vesicles. Partial sequences of the 1A1-3B B-box protein pseudogene and IFP 35, an interferon induced leucine zipper protein, reside within the contig. An L21 ribosomal protein pseudogene is embedded in BRCA1 intron 13. The order of genes on the chromosome is: centromere-IFP 35-VAT1-Rho7-BRCA1-1A1-3B- telomere.