Using gene-history and expression analyses to assess the involvement of LGI genes in human disorders
Using gene-history and expression analyses to assess the involvement of LGI genes in human disorders
复制标题
DOI：
10.1093/molbev/msi214
复制
发表时间：
2005-11-01
影响因子：
10.7
通讯作者：
Begemann, G
中科院分区：
文献类型：
--
作者：
Gu, WL;Gibert, Y;Begemann, G
富含亮氨酸的胶质瘤失活1基因LGI1的突变，通过未知的机制导致常染色体显性遗传的颞叶外侧癫痫。LGI1是哺乳动物富含亮氨酸重复序列基因的一个亚家族，由四个成员(LGI1-LGI4)组成。本研究采用比较发育和分子进化的方法研究了LGI基因家族的进化及其不同基因成员的功能重要性。我们的系统发育研究表明，LGI基因在脊椎动物谱系中进化得很早。对所有五个斑马鱼LGI基因的遗传和表达分析表明，lgi1和lgi2基因存在重复，每个基因都产生了两个平行的基因拷贝，大部分表达模式不重叠。此外，所有脊椎动物的LGI1同源基因都经历了高度的纯化选择，这证明了该基因在神经发育或功能中的重要作用。这里使用的结合表达和选择数据的方法典型地表明，在特征不佳的基因家族中，进化和表达分析的框架可以识别那些在功能上最重要的基因，因此是人类疾病的主要候选基因。
Mutations in the leucine-rich, glioma-inactivated 1 gene, LGI1, cause autosomal-dominant lateral temporal lobe epilepsy via unknown mechanisms. LGI1 belongs to a subfamily of leucine-rich repeat genes comprising four members (LGI1-LGI4) in mammals. In this study, both comparative developmental as well as molecular evolutionary methods were applied to investigate the evolution of the LGI gene family and, subsequently, of the functional importance of its different gene members. Our phylogenetic studies suggest that LGI genes evolved early in the vertebrate lineage. Genetic and expression analyses of all five zebrafish lgi genes revealed duplications of lgi1 and lgi2, each resulting in two paralogous gene copies with mostly nonoverlapping expression patterns. Furthermore, all vertebrate LGI1 orthologs experience high levels of purifying selection that argue for an essential role of this gene in neural development or function. The approach of combining expression and selection data used here exemplarily demonstrates that in poorly characterized gene families a framework of evolutionary and expression analyses can identify those genes that are functionally most important and are therefore prime candidates for human disorders.