Wednesday, May 21, 2025

This gene variant contributed to the dietary and physiological evolution of modern humans

Cell Press

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.

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This work was supported by funding from the Human Phenome Data Center, the National Key R&D Program of China, the National Natural Science Foundation of China, the Noncommunicable Chronic Diseases-National Science and Technology Major Project, the 111 Project, and the Shanghai Municipal Science and Technology.

Cell Genomics, Zhang et al. “An ancient regulatory variant of ACSF3 influences the coevolution of increased human height and basal metabolic rate via metabolic homeostasis” https://www.cell.com/cell-genomics/fulltext/S2666-979X(25)00111-9

Cell Genomics (@CellGenomics), is a new gold open access journal from Cell Press publishing multidisciplinary research at the forefront of genetics and genomics. The journal aims to bring together diverse communities to advance genomics and its impact on biomedical science, precision medicine, and global and ecological health. Visit https://www.cell.com/cell-genomics/home. To receive Cell Press media alerts, please contact press@cell.com.

Journal

Cell Genomics

DOI

10.1016/j.xgen.2025.100855

Method of Research

Experimental study

Subject of Research

People

Article Title

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

Article Publication Date

21-May-2025

Toothache from eating something cold? Blame these ancient fish

New research on fossils shows that teeth first evolved as sensory tissue in the armored exoskeletons of ancient fish.

University of Chicago

Astrapsis tubules — image:
CT scan of the tooth-like-odontode structure from *Astrapsis*, an ancient jawless vertebrate fish. The tubules (shown in green) are filled with dentine, the same material that makes up the sensitive inner layer of modern teeth. In red is the vascular system which would have housed the nerves in life allowing for sensation to be transmitted.
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Credit: Yara Haridy

Anyone who has ever squirmed through a dental cleaning can tell you how sensitive teeth can be. This sensitivity gives important feedback about temperature, pressure—and yes, pain—as we bite and chew our food. However, the sensitive parts inside the hard enamel first evolved for something quite different.

New research from the University of Chicago shows that dentine, the inner layer of teeth that transmits sensory information to nerves inside the pulp, first evolved as sensory tissue in the armored exoskeletons of ancient fish.

Paleontologists have long believed that teeth evolved from the bumpy structures on this armor, but their purpose wasn’t clear. The new study, published this week in Nature, confirms that these structures in an early vertebrate fish from the Ordovician period about 465 million years ago contained dentine, and likely helped the creature sense conditions in the water around it.

The research also showed that structures considered to be teeth in fossils from the Cambrian period (485-540 million years ago) were similar to features in the armor of fossil invertebrates, as well as the sensory organs in the shells of modern arthropods like crabs and shrimp. These similarities imply that sensory organs in the armor of diverse animals evolved separately in both vertebrates and invertebrates to help them sense the larger world around them.

“When you think about an early animal like this, swimming around with armor on it, it needs to sense the world. This was a pretty intense predatory environment and being able to sense the properties of the water around them would have been very important,” said Neil Shubin, PhD, Robert R. Bensley Distinguished Service Professor of Organismal Biology and Anatomy at UChicago and senior author of the new study. “So, here we see that invertebrates with armor like horseshoe crabs need to sense the world too, and it just so happens they hit on the same solution.”

Night at the particle accelerator

Yara Haridy, PhD, a postdoctoral researcher in Shubin’s lab who led the study, wasn’t looking for the origins of teeth when she started the project. Instead, she was hoping to answer another longstanding paleontological question: What is the earliest vertebrate in the fossil record? Haridy asked museums around the country for fossil specimens from the Cambrian period (485-540 million years ago) so she could CT scan them, looking for telltale signs of vertebrate features.

One of those signs, at least in later fish, is the presence of dentine inside the bumps on external armor, called odontodes. Haridy collected hundreds of specimens, some just tiny fragments that could fit on the end of a toothpick. She then took them to Argonne National Laboratory for an all-night scanning session using the Advanced Photon Source, which captured extremely high-resolution CT images of the fossils. “It was a night at the particle accelerator; that was fun,” Haridy said.

As they started seeing the images from the scans, one of the samples from a Cambrian fossil called Anatolepis looked like it showed the hallmarks of a vertebrate fish. It had a series of tubules, or pores underneath the odontodes, filled with material that bore the chemical signatures of dentine. If it truly was a vertebrate, this specimen would have extended the fossil record back by tens of millions of years.

“We were high fiving each other, like ‘oh my god, we finally did it,’” Haridy said. “That would have been the very first tooth-like structure in vertebrate tissues from the Cambrian. So, we were pretty excited when we saw the telltale signs of what looked like dentine.”

They had to confirm this, of course, so they began analyzing images of the other specimens Haridy scanned. This library of shells and skeletons included everything from other ancient fossils to modern crabs, snails, beetles, barnacles, sharks, and skates, plus miniature suckermouth catfish that Haridy raised herself in an aquarium.

Once they compared the possible vertebrate Anatolepis to a known arthropod fossil from the Milwaukee Public Museum, they realized that what looked like dentine-lined tubules of a vertebrate were more like the sensory organs on the shells of crabs, called sensilla. This means that Anatolepis, which was claimed to be a vertebrate in the pages of Nature in 1996, is an ancient invertebrate arthropod instead. The large tubules in another Ordovician vertebrate called Eriptychius were similar in structure to these sensilla, but did contain dentine.

“This shows us that ‘teeth’ can also be sensory even when they're not in the mouth,” Haridy said. “So, there's sensitive armor in these fish. There's sensitive armor in these arthropods. This explains the confusion with these early Cambrian animals. People thought that this was the earliest vertebrate, but it actually was an arthropod.”

Tooth-like structures scattered across the fossil record

Sharks, skates, and catfish also have tooth-like structures called denticles that make their skin feel like sandpaper. When Haridy studied the tissues of her catfish, she saw that the denticles were connected to nerves, just like a tooth would be. She said the similarities to teeth, the ancient odontodes of armored fish, and the sensilla of arthropods was striking.

“We think that the earliest vertebrates, these big, armored fish, had very similar structures, at least morphologically. They look the same in ancient and modern arthropods, because they're all making this mineralized layer that caps their soft tissue and helps them sense the environment,” she said.

There are two schools of thought about how these structures eventually became teeth. One, the “inside-out” hypothesis, says that teeth arose first, and were later adapted for exoskeletons. This paper would support the second, “outside-in” hypothesis, that says sensitive structures developed first on exoskeletons, and at some point, animals utilized the same genetic toolkit to produce sensitive teeth as well.

While they didn’t pin down the earliest vertebrate fish, Shubin said this discovery was more than worth the effort.

“For some of these fossils that were putative early vertebrates, we showed that they’re not. But that was a bit of misdirection,” Shubin said. “We didn’t find the earliest one, but in some ways, we found something way cooler.”

The study, “The Origin of Vertebrate Teeth and Evolution of Sensory Exoskeletons,” was supported by the National Science Foundation, the US Department of Energy, and the Brinson Family Foundation. Additional authors include Sam C.P. Norris, Matteo Fabbri, Neelima Sharma, Mark Rivers, Patrick La Riviere, and Phillip Vargas from the University of Chicago; Karma Nanglu and Javier Ortega-Hernández from Harvard University; and James F Miller from Missouri State University.

The Origin of Vertebrate Teeth and Evolution of Sensory Exoskeletons [VIDEO] |

Yara Haridy and Neil Shubin discuss their new study in Nature on the origins of sensitive teeth in vertebrates.

CT scan image of tooth like dermal denticles on a catshark. These tooth-like structures are connected to the nervous system, suggesting they create sensation.

Segmented confocal scan of the tooth-like-odontode structure from suckermouth catfish fish, showing nerves (in green) that allow transmission of sensory information from the tooth like odontode to the nervous system.

CT scan of the front of a skate, showing the hard, tooth-like denticles on its skin (shown in orange).

Credit

Yara Haridy