The Neanderthal Altai, Vi3315, and Vi3319 have a very special genetic mutation, the CYP21A2 rs6467 (C;T) variant. This mutation causes a form of nonclassic Congenital Adrenal Hyperplasia (NCAH). In simple terms: it weakened their ability to make cortisol, the body’s main stress hormone. This one genetic quirk may have had an outsized role in shaping Neanderthals and humanity.
Neanderthals were already highly interbred, but NCAH put even more pressure on their numbers. Children who inherited two bad copies of this mutation usually didn’t survive past birth, which would have kept populations small and fragile. That, in turn, created strong evolutionary pressure to adapt to NCAH.
Today we often credit Neanderthal DNA with boosting the human immune system. NCAH likely played the key part because by disrupting the HPA axis, it pushed selection to favor genetic tweaks that strengthened immune response to compensate.
Estrogen increases cortisol-binding globulin which reduces the effectiveness of the little cortisol that NCAH would produce. Neanderthals collected genetics that reduced estrogen signaling such as reduced serotonin which also improves reproduction. Another change that reduced estrogen makes it so today we can have caffeine even late in the day. The poor cortisol response, low serotonin response, and low estrogen is the formula for higher intelligence with enhancement abilities to detect unexpected events. Many genetic variants related to intelligence we see today directly balance out weaker estrogen signaling.
Low cortisol also means frequent hypoglycemia (blood sugar crashes). To cope, somewhere between 130-70,000 years ago Neanderthals leaned into starchy foods such as grains which were also calorie dense. This dietary shift was a game-changer: more calories, more stable survival, and eventually, less need to rely on cannibalism (yes, the bones and teeth marks don’t lie).
Neanderthals began to interbreed around 50–43,000 years ago. Neanderthal mitochondrial DNA faded out (probably due to lower female fertility), but male Neanderthal genes mixed in successfully. While much of the DNA was lost or spread out, the most valuable roughly 2–4% of the DNA, everything around the HPA Axis was kept together and can be found in many humans today.
The last glacial period (the Younger Dryas) forced Neanderthal influenced groups southward in what is today Europe. This sudden rise in population encouraged farming which led to permanent settlements in places like Mesopotamia. Agricultural societies then spread and with them, the Neanderthal derived genetic quirks that helped shape modern humanity.