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Exon deletion in the MSLN gene encoding MPF/mesothelin precursor protein during Laurasiatherian mammal evolution
1Department of Life Science (BK21 Program), Chung-Ang University, Seoul, Republic of Korea.
Abstract:
Mesothelin is a cell surface glycoprotein that is present in normal mesothelial cells and is highly expressed in several human cancers, including mesotheliomas and ovarian, pancreatic, and lung cancers. The human mesothelin gene (MSLN) encodes a precursor protein, which is processed into 2 mature polypeptides: the N-terminal soluble megakaryocyte-potentiating factor (MPF) and the C-terminal membrane-bound mesothelin which functions as a cell adhesion molecule. In this study, we report the identification and sequence comparison of the MSLN genes in various mammalian species. We found that multiple exon deletion occurred in the Laurasiatherian MSLN genes including 6 exons in the cow, pig, horse, cat, dog, and panda genes and 8 exons in the hedgehog gene. The genomic deletion did not change the open reading frame of the resulting Laurasiatherian MSLN genes, producing internally deleted precursor proteins. The modified precursor was still able to produce the intact cell surface mesothelin protein but would not confer the MPF activity. Genomic sequence comparison showed that a breakage and rejoining event of ancestral introns 2 and 8 was responsible for the deletion. The present findings support that exon deletion is one of the molecular mechanisms underlying gene evolution in mammalian genomes.
Insights
Gene evolution in mammals involves exon deletion, as seen in the mesothelin (MSLN) gene. Laurasiatherian species show internal deletions in MSLN, impacting protein function but preserving cell surface mesothelin.
Area of Science:
- Genomics
- Molecular Evolution
- Mammalian Genetics
Background:
- Mesothelin (MSLN) is a cell surface glycoprotein highly expressed in cancers like mesothelioma and ovarian, pancreatic, and lung cancers.
- The MSLN gene encodes a precursor protein processed into soluble megakaryocyte-potentiating factor (MPF) and cell adhesion molecule mesothelin.
Purpose of the Study:
- To identify and compare the MSLN genes across various mammalian species.
- To investigate the evolutionary mechanisms behind MSLN gene variations in mammals.
Main Methods:
- Comparative genomic sequence analysis of the MSLN gene in diverse mammalian species.
- Identification of exon deletions and their impact on gene structure and protein products.
Main Results:
- Multiple exon deletions were identified in Laurasiatherian MSLN genes (e.g., cow, pig, cat, dog, panda, hedgehog).
- These deletions maintained the open reading frame, producing internally deleted precursor proteins.
- The modified precursor yielded intact cell surface mesothelin but lacked MPF activity.
Conclusions:
- Exon deletion, specifically involving ancestral introns 2 and 8, is a mechanism in mammalian gene evolution.
- The findings suggest a role for exon deletion in modifying protein function during mammalian genome evolution.
