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Peer-reviewedCC BY-NCScience Advances

Cis-regulatory inactivation of vitamin D signaling confers extreme calcium tolerance in Jialing fish

  • Nan Zhang1
  • Yongsen Zhou1
  • Jianbin Feng1
  • Tianhao Yang1
  • Huilin Liu1
  • Yongsheng Zhang1
  • Lingyun Chen1
  • Weiyang Xiao2
  • Tai Wang3
  • Aaron J. W Hsueh1,4
  • Jianzhen Li1,5
5 affiliations
  1. 1College of Life Sciences, Northwest Normal University, Lanzhou 730000, China.
  2. 2Jiuzhaigou Administration Bureau, Jiuzhaigou 623407, China.
  3. 3Gansu Key Laboratory of Cold Water Fishes Germplasm Resources and Genetics Breeding, Gansu Fishers Research Institute, Lanzhou 730000, China.
  4. 4Department of Obstetrics and Gynecology, Stanford University, Stanford, CA 94305, USA.
  5. 5Gansu Pharmaceutical Group, Lanzhou 730000, China.
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Abstract

The turquoise karst lakes of China’s Jiuzhaigou Nature Reserve harbor among the highest natural calcium concentrations known in freshwater, around threefold higher than adjacent rivers. Yet the Jialing fish ( Schizopygopsis kialingensis ) thrives there with serum calcium levels indistinguishable from river-dwelling conspecifics. We show that this calcium tolerance arose through evolutionary loss of vitamin D signaling. Lake and river populations diverged ∼410,000 years ago. Gill transcriptomics revealed >90% suppression of vitamin D receptor b ( vdrb ) and 99% reduction of its downstream calcium transporter calb2a in lake fish. Zebrafish knockout of either gene enhanced survival under hypercalcemia. We traced this suppression to specific mutations in a vdrb enhancer that reduce its activity. These findings reveal that regulatory dismantling of a canonical endocrine pathway can drive vertebrate adaptation to extreme environments, providing a clear example of how cis-regulatory evolution can drive ecological adaptation.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026cisregulatory,
  title = {{Cis-regulatory inactivation of vitamin D signaling confers extreme calcium tolerance in Jialing fish}},
  author = {Nan Zhang and Yongsen Zhou and Jianbin Feng and Tianhao Yang and Huilin Liu and Yongsheng Zhang and Lingyun Chen and Weiyang Xiao and Tai Wang and Aaron J. W Hsueh and Jianzhen Li},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeg8398},
  url = {https://www.science.org/doi/10.1126/sciadv.aeg8398},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Cis-regulatory inactivation of vitamin D signaling confers extreme calcium tolerance in Jialing fish
AU  - Nan Zhang
AU  - Yongsen Zhou
AU  - Jianbin Feng
AU  - Tianhao Yang
AU  - Huilin Liu
AU  - Yongsheng Zhang
AU  - Lingyun Chen
AU  - Weiyang Xiao
AU  - Tai Wang
AU  - Aaron J. W Hsueh
AU  - Jianzhen Li
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aeg8398
UR  - https://www.science.org/doi/10.1126/sciadv.aeg8398
AB  - The turquoise karst lakes of China’s Jiuzhaigou Nature Reserve harbor among the highest natural calcium concentrations known in freshwater, around threefold higher than adjacent rivers. Yet the Jialing fish ( Schizopygopsis kialingensis ) thrives there with serum calcium levels indistinguishable from river-dwelling conspecifics. We show that this calcium tolerance arose through evolutionary loss of vitamin D signaling. Lake and river populations diverged ∼410,000 years ago. Gill transcriptomics revealed >90% suppression of vitamin D receptor b ( vdrb ) and 99% reduction of its downstream calcium transporter calb2a in lake fish. Zebrafish knockout of either gene enhanced survival under hypercalcemia. We traced this suppression to specific mutations in a vdrb enhancer that reduce its activity. These findings reveal that regulatory dismantling of a canonical endocrine pathway can drive vertebrate adaptation to extreme environments, providing a clear example of how cis-regulatory evolution can drive ecological adaptation.
SN  - 2375-2548
ER  -