Somewhere in the intracellular tail of a hormone receptor, one amino acid was swapped for another. Proline became threonine. That’s the whole event, chemically speaking: a single position in a stretch of protein that doesn’t even fold into a stable shape. And yet, according to a new study in Current Biology,1 that swap is enough to make cells grow 6% faster when stimulated with growth hormone, enough to leave measurable traces in the bones and muscles of over a million people alive today, and enough to tie a straight line from a 400,000-year-old lineage to the shape of somebody’s jaw in 2026.
The team, led by Philipp Kanis and Hugo Zeberg, went looking for this because Neanderthals have always presented a puzzle of description without mechanism. We know what they looked like: heavier bones, bigger muscles, a barrel-shaped ribcage, browridges you could hang a hat on, and famously short-rooted teeth, a trait so recognizable that early anatomists coined the term taurodontism just to describe it. What nobody had was a genetic account of why. Robust build is easy to observe and hard to trace to a specific molecular cause, because so many things regulate growth at once.
So the researchers picked a specific, plausible culprit: the hypothalamic-pituitary-somatotropic axis, the signaling chain that runs from the brain to the pituitary gland to growth hormone itself, and asked whether Neanderthals carried any distinctive changes in the genes that build this system. They scanned eight genes across three high-coverage Neanderthal genomes, covering hormones like growth hormone and ghrelin as well as their receptors. Most of the axis came back unremarkable. But the growth hormone receptor, or GHR, stood out. All three Neanderthal genomes carried two amino acid substitutions absent from sub-Saharan African genomes, plus a large deletion removing an entire exon, a mutation earlier work had already flagged as ancient. Denisovans, the Neanderthals’ sister lineage, shared the deletion but not the two substitutions, suggesting the substitutions arose specifically along the Neanderthal branch.
Finding a variant is one thing. Showing it does something is another, and this is where the paper gets interesting: it doesn’t stop at genomics. The researchers pushed the Neanderthal receptor gene into a mouse cell line called Ba/F3, cells that are normally kept alive with a cytokine but can be switched over to depend entirely on growth hormone once they’re engineered to express a GHR. With the Neanderthal receptor installed, the cells didn’t bind growth hormone any more tightly than cells carrying the modern human version. What changed was what happened after binding. Cells with the Neanderthal receptor proliferated faster, ending up 39% more numerous after five days, and showed 22% higher levels of phosphorylated STAT5, the signaling protein that growth hormone receptors activate downstream. By systematically testing every possible combination of the two substitutions and the exon deletion, the team traced the entire effect to one single change: the proline-to-threonine swap. The other substitution and the deletion did nothing measurable on their own.
That’s a strange result if you think about it for a second. The intracellular region carrying this mutation is intrinsically disordered, meaning it doesn’t have a stable three-dimensional shape to begin with, and NMR analysis confirmed the mutation barely alters the local structure. The best lead the researchers have is a nearby tyrosine that gets phosphorylated more slowly in the Neanderthal version, which they suggest could mean the receptor stays “on” longer during its phosphorylation-dephosphorylation cycling, adding up to more signaling over time even without a structural change driving it. It’s a reasonable hypothesis, not a settled mechanism.
