Neanderthal Interbreeding: The DNA Modern Humans Still Carry

Neanderthal interbreeding refers to the mixing of Homo sapiens with Neanderthals, which left a lasting mark in the DNA of living people. In 2010 the first draft Neanderthal genome showed that everyone with ancestry outside Africa carries a small share of Neanderthal DNA, now estimated at roughly 1 to 2 percent. Most of this mixing happened around 50,000 to 45,000 years ago, as modern humans spread out of Africa, and some of the inherited genes still affect our health today.

Background: two kinds of humans

Neanderthals lived in Europe and western and central Asia from roughly 400,000 years ago until about 40,000 years ago. Their ancestors and the ancestors of modern humans separated more than half a million years ago, with Neanderthals evolving in Eurasia and Homo sapiens in Africa.

When modern humans left Africa in large numbers (see Out of Africa), they entered regions where Neanderthals already lived. For a long time, scientists debated whether the two groups had mixed. Fossils such as an apparently hybrid child from Lagar Velho in Portugal, described in 1999, were suggestive but inconclusive. Early studies of Neanderthal mitochondrial DNA, from 1997 onwards, found no trace of it in living people, which many took as evidence against interbreeding.

The 2010 genome

The breakthrough came from the laboratory of Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Leipzig. Working with tiny amounts of degraded DNA from three Neanderthal bones from Vindija Cave in Croatia, and dealing with heavy contamination from bacteria and modern human DNA, the team produced a draft sequence of the Neanderthal genome. It was published in the journal Science on 7 May 2010, with Richard E. Green as lead author.

Comparing the Neanderthal genome with those of living people, the team found that Neanderthals shared more genetic variants with people from Europe, China and Papua New Guinea than with people from sub-Saharan Africa. The best explanation was that the ancestors of non-Africans had interbred with Neanderthals after leaving Africa. The initial estimate was that 1 to 4 percent of non-African genomes came from Neanderthals; higher-quality genomes published in 2014 and 2017 refined this to roughly 1.5 to 2 percent.

In the same year, DNA from a finger bone from Denisova Cave in Siberia revealed another archaic group, the Denisovans, who also interbred with modern humans. The discovery of Denny, a girl with a Neanderthal mother and a Denisovan father, later showed that archaic groups also mixed with each other.

How Neanderthal DNA is detected

Scientists cannot simply look for “Neanderthal genes”, because Neanderthals and modern humans share the vast majority of their DNA. Instead, they look at the small number of positions where the two differ. One widely used test compares a Neanderthal genome with pairs of living people, such as a European and an African. If the Neanderthal matches the European significantly more often than the African, beyond what chance allows, it points to mixing in the ancestors of the European.

Later methods scan individual genomes for long stretches that closely match the Neanderthal sequence but are rare or absent in Africans. This makes it possible to map exactly which pieces of Neanderthal DNA each person carries. Large medical databases, linking genomes to health records, then allow researchers to test whether particular Neanderthal pieces are associated with traits or diseases.

When and where it happened

Neanderthal DNA in living people comes in fragments that have been broken up over generations. The length of these fragments acts as a clock: the older the mixing, the shorter the pieces. Ancient genomes have sharpened this clock.

A 45,000-year-old man from Ust’-Ishim in Siberia, sequenced in 2014, carried longer Neanderthal segments than people today, indicating mixing only some thousands of years before he lived. A jawbone from Peștera cu Oase in Romania, about 40,000 years old, had 6 to 9 percent Neanderthal DNA, with a Neanderthal ancestor just four to six generations back. Studies published in 2024 place the main period of mixing at roughly 50,000 to 45,000 years ago, possibly spread over several thousand years.

Because all non-Africans share this signal, the main mixing probably happened early, in or near the Middle East, before the ancestors of Europeans and Asians separated. Later, local mixing also took place, as the Oase individual shows. East Asians carry slightly more Neanderthal DNA than Europeans, possibly because of additional mixing or differences in how natural selection removed it.

Contact also flowed the other way. A Neanderthal from the Altai Mountains carried DNA from modern humans dating back more than 100,000 years, evidence of earlier encounters with Homo sapiens groups who had left Africa before the main dispersal.

The genes we still carry

Each living non-African carries only a small amount of Neanderthal DNA, but different people carry different pieces. Together, living humans preserve perhaps a fifth or more of the Neanderthal genome.

Some inherited variants seem to have been useful in Eurasian environments:

• Immunity: Neanderthal versions of several immune-system genes, including some that recognise bacteria and other pathogens, are common in Europeans and Asians.
• Skin and hair: genes related to keratin, a protein in skin and hair, and to skin pigmentation contain many Neanderthal variants.

Others are linked to disease risk. Studies of medical records have connected Neanderthal variants with conditions such as depression, blood clotting and skin lesions caused by sun exposure. In 2020 Hugo Zeberg and Svante Pääbo showed that a stretch of chromosome 3 inherited from Neanderthals is a major genetic risk factor for severe COVID-19; it is carried by roughly half of people in South Asia and about one in six Europeans. Another Neanderthal stretch, on chromosome 12, is associated with a lower risk.

Signs of incompatibility

Not all Neanderthal DNA was welcome. Large regions of the human genome, known as “Neanderthal deserts”, contain almost no Neanderthal DNA. These include the X chromosome and genes active in the testes, a pattern that suggests male hybrids may have had reduced fertility. Over generations, natural selection appears to have removed many Neanderthal variants that were harmful in modern human genetic backgrounds, which helps explain why the share is now so small.

Legacy

The discovery changed the picture of human evolution. Instead of a clean replacement of Neanderthals by modern humans, scientists now describe a process in which groups met, mixed and sometimes merged, even as Neanderthals as a population disappeared (see extinction of the Neanderthals). In 2022 Svante Pääbo received the Nobel Prize in Physiology or Medicine for his discoveries concerning the genomes of extinct hominins and human evolution.

Timeline

• More than 100,000 years ago: Early modern humans contribute DNA to Neanderthals in Asia.
• c. 50,000-45,000 years ago: Main period of interbreeding between Homo sapiens and Neanderthals.
• c. 45,000 years ago: The Ust’-Ishim man lives in Siberia.
• c. 40,000 years ago: The Oase individual, with a recent Neanderthal ancestor, lives in Romania; Neanderthals disappear.
• 7 May 2010: The draft Neanderthal genome is published in Science.
• 2015: The Oase genome is published.
• 2020: A Neanderthal-derived risk factor for severe COVID-19 is identified.
• 2022: Svante Pääbo receives the Nobel Prize in Physiology or Medicine.

Why it matters

Neanderthal interbreeding shows that Neanderthals did not entirely vanish: part of their genetic legacy lives on in billions of people. It has transformed how scientists think about human origins and has practical uses in medicine, helping to explain why some people respond differently to infections and diseases.