MBE Advance Access first published online on February 29, 2008
This version published online on March 10, 2008
Molecular Biology and Evolution, doi:10.1093/molbev/msn056
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Research Article |
Adaptive Evolution of Hepcidin Genes in Antarctic Notothenioid Fishes
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* Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, P.R. China
Department of Animal Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
College of Marine Sciences and Shanghai International Marine Bio-resources Research Center, Shanghai Fisheries University, Shanghai 200090, China
Author for correspondence: Liangbiao Chen, Mailing Address: Institute of Genetics and Developmental Biology, the Chinese Academy of Sciences, Beijing 100101, P.R. China; Phone: +86-10-62554807; Fax: +86-10-62554807; E-mail: lbchen{at}genetics.ac.cn (L.Chen)
Received for publication December 30, 2007. Revision received February 13, 2008. Accepted for publication February 21, 2008.
Hepcidin is a small bioactive peptide with dual roles as an antimicrobial peptide and as the principal hormonal regulator of iron homeostasis in human and mouse. Hepcidin homologs of very similar structures are found in lower vertebrates, all comprise 
20-25 amino acids with eight highly conserved cysteines forming four intramolecular disulfide bonds, giving hepcidin a hairpin structure. Hepcidins are particularly diverse in teleost fishes, which may be related to the diversity of aquatic environments with varying degree of pathogen challenge, oxygenation, and iron concentration, factors known to alter hepcidin expression in mammals. We characterized the diversity of hepcidin genes of the Antarctic notothenioid fishes that are endemic to the world's coldest and most oxygen-rich marine water. Notothenioid fishes have at least four hepcidin variants, in two distinctive structural types. Type I hepcidins comprise three distinct variants that are homologs of the widespread 8-cysteine hepcidins. Type II is a novel 4-cysteine variant and therefore only two possible disulfide bonds, highly expressed in hematopoietic tissues. Analyses of dN/dS substitution rate ratios and Likelihood Ratio Test under site-specific models detected significant signal of positive Darwinian selection on the mature hepcidin coding sequence, suggesting adaptive evolution of notothenioid hepcidins. Genomic PCR and Southern hybridization showed that the novel type II hepcidin occurs exclusively in lineages of the Antarctic notothenioid radiation but not in the basal non-Antarctic taxa, and lineage-specific positive selection was detected on the branch leading to the type II hepcidin clade under Branch-site models, suggesting adaptive evolution of the reduced-cysteine variant in response to the polar environment. We also isolated a structurally distinct 4-cysteine hepcidin from an Antarctic eelpout that is unrelated to the notothenioids but inhabits the same freezing water. Neighbor-Joining analyses of teleost hepcidins showed the eelpout 4-cysteine variant arose independently from the notothenioid version, which lends support to adaptive evolution of reduced cysteine hepcidin variants on cold selection. The NJ tree also showed taxonomic-specific expansions of hepcidin variants, indicating duplication and diversification of hepcidin genes play important roles in evolutionary response to diverse ecological conditions.
Key Words: hepcidin • iron regulation • cold adaptation • positive selection • gene duplication
1 Equal contribution to this work
Author names have been updated.
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  Z. Chen, C.-H. C. Cheng, J. Zhang, L. Cao, L. Chen, L. Zhou, Y. Jin, H. Ye, C. Deng, Z. Dai, et al. Transcriptomic and genomic evolution under constant cold in Antarctic notothenioid fish PNAS, September 2, 2008; 105(35): 12944 - 12949. [Abstract] [Full Text] [PDF]
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