Researchers studying the Y chromosome of a 49,000-year-old Neanderthal from Spain reveal that it’s unlike that of any humans today. Prehistoric female Homo sapiens may have been genetically incompatible with the male Neanderthals they mated with. The divergence in Y chromosomes may have led to the miscarriage of hybrid male fetuses, according to findings published in the American Journal of Human Genetics this week.

Because humans today carry traces of Neanderthal DNA, we know that Neanderthals mixed with anatomically modern humans who expanded out of Africa. However, "we’ve never observed the Neanderthal Y chromosome DNA in any human sample ever tested," Stanford’s Carlos Bustamante said in a statement. "That doesn’t prove it’s totally extinct, but it likely is."

Bustamante, together with a team led by Stanford’s Fernando Mendez, analyzed the Y-chromosome DNA of a Neanderthal male from El Sidrón, Spain. They also compared it to reference sequences of chimpanzee and modern human Y chromosomes. Although the Neanderthal Y chromosome (and the maternally inherited mtDNA) might have simply drifted out of the modern human gene pool, it’s also possible that genetic incompatibilities contributed to the loss.

The team found potentially damaging changes to four genes on the Neanderthal Y chromosome: PCDH11Y, TMSB4Y, USP9Y, and KDM5D. The first three are unique to the Neanderthal lineage, while the fourth is found in modern human sequences, and it codes for an enzyme that suppresses the invasiveness of some cancers. Male-specific antigens derived from KDM5D may elicit an immune response in pregnant women against the male fetuses they’re carrying – which could result in a miscarriage.

Additionally, the team also found that the Neanderthal Y chromosome from El Sidrón diverged from that of modern humans around 588,000 years ago. Their estimate of Y-chromosome divergence fits with previous work on the population divergence of Neanderthals and our human ancestors.

Neanderthal Y-chromosome genes likely disappeared from the human genome a long time ago, and it’s possible that incompatibilities at one or more of those genes kept these two Homo groups reproductively isolated. "The functional nature of the mutations we found suggests to us that the Y chromosome may have played a role in barriers to gene flow," Bustamante added. The team plans to conduct experiments to demonstrate this.