Volume 30, No 5, May 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 5, May 2020: 408-420

ORIGINAL ARTICLES

Accelerated evolution of an Lhx2 enhancer shapes mammalian social hierarchies

Yuting Wang^1,2,† , Guangyi Dai^1,† , Zhili Gu^1,† , Guopeng Liu^1,2,† , Ke Tang³ , Yi-Hsuan Pan⁴ , Yujie Chen⁵ , Xin Lin^1,2 , Nan Wu⁴ , Haoshan Chen^2,6 , Su Feng^2,7 , Shou Qiu^2,6 , Hongduo Sun^1,2 , Qian Li¹ , Chuan Xu¹ , Yanan Mao^2,8 , Yong Edward Zhang^2,8,9 , Philipp Khaitovich^1,9 , Yan-Ling Wang¹⁰ , Qunxiu Liu¹¹ , Jing-Dong Jackie Han¹ , Zhen Shao¹ , Gang Wei¹ , Chun Xu⁶ , Naihe Jing⁷ , Haipeng Li^1,9,*

¹CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Yueyang Road 320, 200031 Shanghai, China;
²University of Chinese Academy of Sciences, Beijing, China
³Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, Guangzhou 510405 Guangdong, China
⁴Key Laboratory of Brain Functional Genomics of Ministry of Education, School of Life Science, East China Normal University, 200062 Shanghai, China;
⁵Bio-Med Big Data Center, CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Yueyang Road 320, 200031 Shanghai, China;
⁶Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Yueyang Road 320, 200031 Shanghai, China;
⁷State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Yueyang Road 320, 200031 Shanghai, China;
⁸Key Laboratory of Zoological Systematics and Evolution & State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China;
⁹Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, 650223 Kunming, China;
¹⁰State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101 Beijing, China
¹¹Shanghai Zoological Park, 200335 Shanghai, China
^†These authors contributed equally
Correspondence: Haipeng Li(lihaipeng@picb.ac.cn)

Social hierarchies emerged during evolution, and social rank influences behavior and health of individuals. However, the evolutionary mechanisms of social hierarchy are still unknown in amniotes. Here we developed a new method and performed a genome-wide screening for identifying regions with accelerated evolution in the ancestral lineage of placental mammals, where mammalian social hierarchies might have initially evolved. Then functional analyses were conducted for the most accelerated region designated as placental-accelerated sequence 1 (PAS1, P = 3.15 × 10−18). Multiple pieces of evidence show that PAS1 is an enhancer of the transcription factor gene Lhx2 involved in brain development. PAS1s isolated from various amniotes showed different cis-regulatory activity in vitro, and affected the expression of Lhx2 differently in the nervous system of mouse embryos. PAS1 knock-out mice lack social stratification. PAS1 knock-in mouse models demonstrate that PAS1s determine the social dominance and subordinate of adult mice, and that social ranks could even be turned over by mutated PAS1. All homozygous mutant mice had normal huddled sleeping behavior, motor coordination and strength. Therefore, PAS1-Lhx2 modulates social hierarchies and is essential for establishing social stratification in amniotes, and positive Darwinian selection on PAS1 plays pivotal roles in the occurrence of mammalian social hierarchies.

https://doi.org/10.1038/s41422-020-0308-7

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