Gu Wenli, Gibert Yann, Wirth Thierry, Elischer Andrea, Bloch Wilhelm, Meyer Axel, Steinlein Ortrud K, Begemann Gerrit
Institute of Human Genetics, Ludwig Maximilians University Munich, University Hospital, Munich, Germany.
Mol Biol Evol. 2005 Nov;22(11):2209-16. doi: 10.1093/molbev/msi214. Epub 2005 Jul 13.
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.
富含亮氨酸的胶质瘤失活1基因（LGI1）的突变通过未知机制导致常染色体显性遗传性外侧颞叶癫痫。LGI1属于富含亮氨酸重复序列基因的一个亚家族，在哺乳动物中有四个成员（LGI1 - LGI4）。在本研究中，我们应用了比较发育和分子进化方法来研究LGI基因家族的进化，以及随后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揭示了lgi1和lgi2的复制，每个基因都产生了两个旁系同源基因拷贝，其表达模式大多不重叠。此外，所有脊椎动物的LGI1直系同源基因都经历了高度的纯化选择，这表明该基因在神经发育或功能中起着至关重要的作用。这里使用的结合表达和选择数据的方法示例性地证明，在特征不明确的基因家族中，进化和表达分析框架可以识别出那些功能上最重要的基因，因此这些基因是人类疾病的主要候选基因。
