Department of Genetics, University Paris Descartes and INSERM U-781, Necker-Enfants Malades APHP, Paris, France.
Ann N Y Acad Sci. 2010 Dec;1214:34-46. doi: 10.1111/j.1749-6632.2010.05878.x.
One of the key discoveries of vertebrate genome sequencing projects has been the identification of highly conserved noncoding elements (CNEs). Some characteristics of CNEs include their high frequency in mammalian genomes, their potential regulatory role in gene expression, and their enrichment in gene deserts nearby master developmental genes. The abnormal development of neural crest cells (NCCs) leads to a broad spectrum of congenital malformation(s), termed neurocristopathies, and/or tumor predisposition. Here we review recent findings that disruptions of CNEs, within or at long distance from the coding sequences of key genes involved in NCC development, result in neurocristopathies via the alteration of tissue- or stage-specific long-distance regulation of gene expression. While most studies on human genetic disorders have focused on protein-coding sequences, these examples suggest that investigation of genomic alterations of CNEs will provide a broader understanding of the molecular etiology of both rare and common human congenital malformations.
脊椎动物基因组测序项目的一个重要发现是高度保守的非编码元件（CNEs）的鉴定。CNEs 的一些特征包括它们在哺乳动物基因组中的高频出现、它们在基因表达中的潜在调节作用，以及它们在附近主发育基因的基因沙漠中的富集。神经嵴细胞（NCCs）的异常发育导致广泛的先天性畸形（s），称为神经嵴病变，和/或肿瘤易感性。在这里，我们回顾了最近的发现，即 CNEs 的破坏，无论是在参与 NCC 发育的关键基因的编码序列内还是远处，都会通过改变组织或特定阶段的基因表达的长距离调控，导致神经嵴病变。虽然大多数关于人类遗传疾病的研究都集中在蛋白质编码序列上，但这些例子表明，对 CNEs 的基因组改变的研究将提供对罕见和常见人类先天性畸形的分子病因的更广泛理解。
