2. Academic Validation
  3. An ancient regulatory variant of ACSF3 influences the coevolution of increased human height and basal metabolic rate via metabolic homeostasis

An ancient regulatory variant of ACSF3 influences the coevolution of increased human height and basal metabolic rate via metabolic homeostasis

  • Cell Genom. 2025 Jun 11;5(6):100855. doi: 10.1016/j.xgen.2025.100855.
Yufeng Zhang 1,  Jie Wang 1,  Chuanyou Yi 1,  Yue Su 1,  Zi Yin 1,  Shuxian Zhang 1,  Li Jin 1,  Mark Stoneking 2,  Jian Yang 3,  Ke Wang 1,  He Huang 4,  Jin Li 5,  Shaohua Fan 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetics and Development of Complex Phenotypes, Lab for Evolutionary Synthesis, Shanghai Key Laboratory of Metabolic Remodeling and Health, Human Phenome Institute, Zhongshan Hospital and School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 2 Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany and Biométrie et Biologie Évolutive, UMR 5558, CNRS & Université de Lyon, Lyon, France.
  • 3 Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou 310024, China.
  • 4 State Key Laboratory of Genetics and Development of Complex Phenotypes, Lab for Evolutionary Synthesis, Shanghai Key Laboratory of Metabolic Remodeling and Health, Human Phenome Institute, Zhongshan Hospital and School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: he_huang@fudan.edu.cn.
  • 5 State Key Laboratory of Genetics and Development of Complex Phenotypes, Lab for Evolutionary Synthesis, Shanghai Key Laboratory of Metabolic Remodeling and Health, Human Phenome Institute, Zhongshan Hospital and School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: li_jin_lifescience@fudan.edu.cn.
  • 6 State Key Laboratory of Genetics and Development of Complex Phenotypes, Lab for Evolutionary Synthesis, Shanghai Key Laboratory of Metabolic Remodeling and Health, Human Phenome Institute, Zhongshan Hospital and School of Life Sciences, Fudan University, Shanghai 200438, China. Electronic address: shaohua_fan@fudan.edu.cn.
PMID: 40403731 DOI: 10.1016/j.xgen.2025.100855
Abstract

Anatomically modern humans (AMHs) exhibit a significant increase in basal metabolic rate (BMR) and height compared to non-human apes. This study investigates the genetic basis underlying these traits. Our analyses reveal a strong genetic correlation between height and BMR. A regulatory mutation, rs34590044-A, was found to be associated with the increased height and BMR in AMHs. rs34590044-A upregulates the expression of ACSF3 by increasing its enhancer activity, leading to increased body length and BMR in mice fed essential Amino acids which are characteristic of meat-based diets. In the British population, rs34590044-A has been under positive selection over the past 20,000 years, with a particularly strong signal in the last 5,000 years, as also evidenced by ancient DNA analysis. These results suggest that the emergence of rs34590044-A may have facilitated the adaptation to a meat-enriched diet in AMHs, with increased height and BMR as consequences of this dietary shift.

Keywords

basal metabolic rate; evolution; height; human-specific mutation; macronutrient metabolism.

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