How ancient attraction shaped the human genome

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The human genome is a complex record of migration, evolution, and ancestry written over thousands of millennia. Now, new genomic research by members of Sarah Tishkoff’s lab at the University of Pennsylvania reveals that prehistoric mating preferences between humans and Neanderthals may explain one of the enduring puzzles of human genetics: why modern people have small amounts of Neanderthal DNA almost everywhere in their genome except on the X chromosome.

“Along our X chromosomes, we have these missing swaths of Neanderthal DNA we call ‘Neanderthal deserts,’” says Alexander Platt, a senior research scientist in the Tishkoff Lab. “For years, we just assumed these deserts existed because certain Neanderthal genes were biologically ‘toxic’ to humans—as tends to be the case when species diverge—so we thought the genes may have caused health problems and were likely purged by natural selection.”

Now, Tishkoff and her team have discovered a more social explanation.

In a paper published in Science, their analysis of Neanderthal and modern human genomes suggests that long-standing mating preferences—rather than genetic incompatibility—shaped which Neanderthal DNA sequences persisted in modern humans and which were gradually lost. Their findings reveal the role social interactions in sculpting the human genome, challenging the idea that human evolution was driven solely by survival of the fittest.

“We found a pattern indicating a sex bias: gene flow occurred predominantly between Neanderthal males and anatomically modern human females,” says Platt, co-first author of the paper, resulting in the loss of Neanderthal DNA X chromosomes of modern humans.

“Roughly 600,000 years ago, the ancestors of anatomically modern humans and their closest-related species, the Neanderthals, diverged, forming two distinct groups, says Tishkoff, the David and Lyn Silfen University Professor in Genetics and Biology in the Perelman School of Medicine and School of Arts & Sciences. “Our ancestors evolved in Africa, while the ancestors of Neanderthals evolved in and adapted to life in Eurasia. But that separation was far from permanent.”

Over hundreds of millennia, she adds, human populations migrated into Neanderthal territories and back again, and when these groups met, they mated, swapping segments of DNA.

To determine whether Neanderthal X chromosomes contain alleles from humans, the team identified modern human DNA preserved in three Neanderthals—Altai, Chagyrskaya, and Vindija—and compared this dataset against one of diverse African genomes, a control group who had historically never encountered a Neanderthal.

“What we found was a striking imbalance,” says Daniel Harris, a research associate in the Tishkoff lab and co-first author. “While modern humans lack Neanderthal X chromosomes, Neanderthals had a 62% excess of modern human DNA on their X chromosomes compared to their other chromosomes.”

This mirrorlike reversal was their answer. If the two species were biologically incompatible, modern human DNA should have been missing from Neanderthal X chromosomes as well. But because the team found an abundance of human DNA in Neanderthal X chromosomes, they were able to rule out reproductive incompatibility or toxic gene interactions as the barrier.

The remaining explanation, the team argues, lies in sex-biased interbreeding.

Because females carry two X chromosomes and males carry only one, mating direction matters. If Neanderthal males partnered more often with modern human females, fewer Neanderthal X chromosomes would enter the human gene pool, and more human X chromosomes would enter Neanderthal populations.

Mathematical models confirmed that this bias could reproduce the observed genetic patterns. Other possibilities, such as sex-biased migration, could theoretically produce similar results—but only through complex, shifting scenarios that varied across time and geography.

“Mating preferences provided the simplest explanation,” Platt says.

With the “who” and “how” of these ancient trysts established, the team is now turning their attention to the “why,” investigating whether similar genetic comparisons—specifically the ratio of diversity between X chromosomes and autosomes—can reveal the gender dynamics of Neanderthal society, such as whether females stayed with their birth families while males migrated to new groups.

By mapping these ancient interactions, the lab hopes to further illuminate the complex social lives of human’s closest evolutionary cousins.

Sarah Tishkoff is the David and Lyn Silfen University Professor in Genetics and Biology, and a Penn Integrates Knowledge University Professor with appointments in the Department of Genetics and Department of Medicine in the Perelman School of Medicine and in Department of Biology in the School of Arts & Sciences at the University of Pennsylvania.

Daniel Harris is a research associate in the Perelman School of Medicine at Penn.

Alexander Platt is a senior research scientist in Penn’s Perelman School of Medicine.

This work was supported by the National Institutes of Health (Grants 1R35GM134957 and R01AR076241) and the American Diabetes Association (Grant 1-19-VSN-02).