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MBE Advance Access published online on July 13, 2005
Molecular Biology and Evolution, doi:10.1093/molbev/msi214
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© The Author 2005. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Accepted July 7, 2005

Research Article

Using Gene-History and Expression Analyses to Assess the Involvement of LGI Genes in Human Disorders

Wenli Gu 1 *, Yann Gibert 2 *, Thierry Wirth 2, Andrea Elischer 3, Wilhelm Bloch 3, Axel Meyer 2, Ortrud K Steinlein 1*, and Gerrit Begemann 2

1 Institute of Human Genetics, Ludwig Maximilians University Munich, University Hospital, Munich, Germany
2 Lehrstuhl Zoologie/Evolutionsbiologie, Department of Biology, University of Konstanz, Konstanz, Germany
3 Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Cologne, Germany

* To whom correspondence should be addressed.
Ortrud K Steinlein, E-mail: Ortrud.Steinlein{at}med.uni-muenchen.de


  Abstract

Mutations in the leucine-rich, glioma-inactivated 1 gene, LGI1, cause autosomal-dominant lateral temporal lobe epilepsy (ADLTE) via unknown mechanisms. LGI1 belongs to a subfamily of leucine-rich repeat genes comprised of 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 lgi1and lgi2, each resulting in two paralogous gene copies with mostly non-overlapping 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.

Keywords: LGI1; zebrafish; epilepsy; phylogeny; expression pattern; purifying selection.

*These authors contributed equally to this work.


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