title: Gene expression responses of threespine stickleback to salinity: implications for salt-sensitive hypertension.
abstract: Despite recent success with genome-wide association studies (GWAS), identifying hypertension (HTN)-susceptibility loci in the general population remains difficult. Here, we present a novel strategy to address this challenge by studying salinity adaptation in the threespine stickleback, a fish species with diverse salt-handling ecotypes. We acclimated native freshwater (FW) and anadromous saltwater (SW) threespine sticklebacks to fresh, brackish, and sea water for 30 days, and applied RNA sequencing to determine the gene expression in fish kidneys. We identified 1844 salt-responsive genes that were differentially expressed between FW sticklebacks acclimated to different salinities and/or between SW and FW sticklebacks acclimated to full-strength sea water. Significant overlap between stickleback salt-responsive genes and human genes implicated in HTN was detected (P < 10(-7), hypergeometric test), suggesting a possible similarity in genetic mechanisms of salt handling between threespine sticklebacks and humans. The overlapping genes included a newly discovered HTN gene-MAP3K15, whose expression in FW stickleback kidneys decreases with salinity. These also included genes located in the GWAS loci such as AGTRAP-PLOD1 and CYP1A1-ULK3, which contain multiple potentially causative genes contributing to HTN susceptibility that need to be prioritized for study. Taken together, we show that stickleback salt-responsive genes provide valuable information facilitating the identification of human HTN genes. Thus, threespine sticklebacks may be used as a model, complementary to existing animal models, in human HTN research.
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University College Station, TX, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University College Station, TX, USA.
authors.forename: Ence
authors.initials: E
authors.lastname: Yang
authors.affiliation: Interdisciplinary Program in Genetics, Texas A&M University College Station, TX, USA.
authors.forename: Kerri J
authors.initials: KJ
authors.lastname: Smith
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University College Station, TX, USA ; Department of Automation, Xiamen University Xiamen, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Department of Automation, Xiamen University Xiamen, China.
authors.forename: Guoli
authors.initials: G
authors.lastname: Ji
authors.affiliation: Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Connon
authors.affiliation: Department of Wildlife, Fish, and Conservation Biology, University of California Davis, CA, USA.
authors.forename: Nann A
authors.initials: NA
authors.lastname: Fangue
authors.affiliation: Department of Veterinary Integrative Biosciences, Texas A&M University College Station, TX, USA ; Interdisciplinary Program in Genetics, Texas A&M University College Station, TX, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Cai
keywords: differential expression; gene-environment interaction; mRNA sequencing; salt handling; salt-responsive gene