Ahituv Nadav, Prabhakar Shyam, Poulin Francis, Rubin Edward M, Couronne Olivier
Genomics Division, Lawrence Berkeley National Laboratory, CA 94720, USA.
Hum Mol Genet. 2005 Oct 15;14(20):3057-63. doi: 10.1093/hmg/ddi338. Epub 2005 Sep 9.
Our inability to associate distant regulatory elements with the genes they regulate has largely precluded their examination for sequence alterations contributing to human disease. One major obstacle is the large genomic space surrounding targeted genes in which such elements could potentially reside. In order to delineate gene regulatory boundaries, we used whole-genome human-mouse-chicken (HMC) and human-mouse-frog (HMF) multiple alignments to compile conserved blocks of synteny (CBSs), under the hypothesis that these blocks have been kept intact throughout evolution at least in part by the requirement of regulatory elements to stay linked to the genes they regulate. A total of 2116 and 1942 CBSs >200 kb were assembled for HMC and HMF, respectively, encompassing 1.53 and 0.86 Gb of human sequence. To support the existence of complex long-range regulatory domains within these CBSs, we analyzed the prevalence and distribution of chromosomal aberrations leading to position effects (disruption of a gene's regulatory environment), observing a clear bias not only for mapping onto CBS but also for longer CBS size. Our results provide an extensive data set characterizing the regulatory domains of genes and the conserved regulatory elements within them.
我们无法将远距离调控元件与其所调控的基因联系起来，这在很大程度上阻碍了对导致人类疾病的序列改变进行研究。一个主要障碍是目标基因周围存在大片基因组空间，这些元件可能就位于其中。为了划定基因调控边界，我们利用全基因组人类-小鼠-鸡（HMC）和人类-小鼠-蛙（HMF）多重比对来汇编保守的同线性块（CBSs），其假设是这些块在整个进化过程中至少部分地由于调控元件需要与其所调控的基因保持连锁而得以完整保留。分别为HMC和HMF组装了总共2116个和1942个大于200 kb的CBSs，涵盖1.53 Gb和0.86 Gb的人类序列。为了支持这些CBSs内存在复杂的长程调控域，我们分析了导致位置效应（基因调控环境破坏）的染色体畸变的发生率和分布，不仅观察到明显倾向于映射到CBS上，而且倾向于更长的CBS大小。我们的结果提供了一个广泛的数据集，用于表征基因的调控域及其内部保守的调控元件。
