Comparative genomics of the SOX9 region in human and Fugu rubripes:: Conservation of short regulatory sequence elements within large intergenic regions
Comparative genomics of the SOX9 region in human and Fugu rubripes:: Conservation of short regulatory sequence elements within large intergenic regions
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DOI：
10.1006/geno.2001.6648
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发表时间：
2001-11-01
期刊：
影响因子：
4.4
通讯作者：
Pfeifer, D
中科院分区：
文献类型：
--
作者：
Bagheri-Fam, S;Ferraz, C;Pfeifer, D
Campomelic 发育不良 (CD) 是一种伴有 XY 性别逆转的人类骨骼畸形综合征，由 SOX9 基因及其周围的杂合突变引起。 SOX9 具有扩展的 5' 控制区，如分散在 SOX9 附近 1 Mb 上的 CD 易位断点以及来自跨越人 SOX9 酵母人工染色体的转基因小鼠的表达数据所表明的。为了鉴定 SOX9 5' 控制区内的长程调控元件，我们分别比较了人类和红鳍东方鲀 SOX9 周围的 3.7 Mb 和 195 kb 序列。我们在人和 F. rubripes 序列中分别仅鉴定了 7 个和 5 个蛋白质编码基因。 F. rubripes 的四个基因已在人类中定位；全部都位于 17 号染色体上，但与红鳍鱼中的基因顺序相比，显示出广泛的染色体内基因改组。在这两个物种中，SOX9 与其直接侧翼基因之间的基因间距离非常大：在人类中，SOX9 两侧分别为 2 Mb 和 500 kb，在 F. rubripes 中，SOX9 两侧分别为 68 和 97 kb。基因间区域的比较序列分析揭示了五个保守元件，E1-E5，长达290kb的5'至人SOX9和长达18kb 5'至F. rubripes SOX9，以及三个这样的元件，E6-E8，3'至SOX9。在可用的情况下，小鼠序列证实了元素的保守性。从酵母人工染色体转基因数据来看，元件E3-E5是肢体和脊柱中SOX9表达的候选增强子，并且10个CD易位断点中的8个将这些元件与SOX9分开。
Campomelic dysplasia (CD), a human skeletal malformation syndrome with XY sex reversal, is caused by heterozygous mutations in and around the gene SOX9. SOX9 has an extended 5' control region, as indicated by CD translocation breakpoints scattered over 1 Mb proximal to SOX9 and by expression data from mice transgenic for human SOX9-spanning yeast artificial chromosomes. To identify long-range regulatory elements within the SOX9 5' control region, we compared similar to 3.7 Mb and 195 kb of sequence around human and Fugu rubripes SOX9, respectively. We identified only seven and five protein-coding genes in the human and F. rubripes sequences, respectively. Four of the F. rubripes genes have been mapped in humans; all reside on chromosome 17 but show extensive intrachromosomal gene shuffling compared with the gene order in F. rubripes. In both species, very large intergenic distances separate SOX9 from its directly flanking genes: 2 Mb and 500 kb on either side of SOX9 in humans, and 68 and 97 kb on either side of SOX9 in F. rubripes. Comparative sequence analysis of the intergenic regions revealed five conserved elements, E1-E5, up to 290 kb 5' to human SOX9 and up to 18 kb 5' to F. rubripes SOX9, and three such elements, E6-E8, 3' to SOX9. Where available, mouse sequences confirm conservation of the elements. From the yeast artificial chromosome transgenic data, elements E3-E5 are candidate enhancers for SOX9 expression in limb and vertebral column, and 8 of 10 CD translocation breakpoints separate these elements from SOX9.