Two of the traits that set modern humans apart from non-human primates are taller stature and a higher basal metabolic rate. Publishing in the Cell Press journal Cell Genomics on May 21, researchers have identified a genetic variant that contributed to the co-evolution of these traits. This mutation seems to help people grow taller—especially when they consume a lot of meat.
"The dietary shift from a primarily plant-based diet to increased meat consumption marks a major milestone in human evolution," say co-corresponding authors Jin Li and He Huang of Fudan University. "Previous studies have suggested that this shift influenced many traits and phenotypes in anatomically modern humans. It is therefore not surprising that height may also have been affected."
The researchers used the UK Biobank, a resource of biological samples and genomic data from 500,000 people, to identify genetic correlations between height and basal metabolic rate and found more than 6,000 potential causal variants. After narrowing down the likely functional impacts of these variants, including their effect on protein sequences and gene expression, a specific regulatory variant of ACSF3 emerged as particularly promising. Further experimentation revealed that the variant, called rs34590044-A, elevates ACSF3 expression in the liver of modern humans compared to other apes.
"In anatomically modern humans, basal metabolic rate and stature exhibit notable evolutionary divergence compared to non-human apes," says author Shaohua Fan of Fudan University in Shanghai, China. "Although both traits, particularly height, have been extensively investigated, the evolutionary mechanisms driving these changes remain comparatively underexplored. That's why we decided to focus on these two traits together."
To further validate these findings and determine how they relate to modern human traits, the team conducted detailed functional analyses of the variant and its effects on ACSF3 expression using both cellular and mouse models. Although the mechanism by which ACSF3 acts on the body is not fully understood, it appears to be localized to mitochondria, which the authors say explains its effects on metabolism. Increased expression of ACSF3 also appears to promote the formation of bone, which could contribute to increased height.
In a mouse model fed with the essential amino acids that are characteristic of meat-based diets, the researchers also noticed that when ACSF3 was overexpressed, the "meat" diet led to both increased body length and a higher basal metabolic rate.
The team notes that the ongoing study of global populations using a combination of approaches—including multiomics, experimental technologies, computational algorithms, and diverse collections of ancient DNA—is important for enhancing our understanding of complex evolutionary processes.
"This research reveals the intricate interplay between the genetic, environmental, and demographic factors that have contributed to the emergence and evolution of anatomically modern humans," Fan says. "It also has important implications understanding susceptibility and resistance in contemporary metabolic disorders like type 2 diabetes, obesity, and metabolic syndrome."
The researchers expect that many more traits may have co-evolved through similar mechanisms. They plan to continue investigating the genetic basis of metabolic homeostasis in human evolution, with the aim of determining how human ancestors adapted to diverse diets throughout evolutionary history.
