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Genetics

Family ties

Roughly 46,000 years ago, modern human beings ventured into the heart of Europe and interbred with Neanderthals

Different angles of a lower molar from a Homo sapiens with Neanderthal ancestors, found in the Bacho Kiro cave in Bulgaria

Rosen Spasov, MPI-EVA Leipzig

A cave at the foot of the Balkan Mountains near Dryanovo, a town of 8,000 inhabitants in central Bulgaria, is home to one of the oldest records of the presence of modern human beings in Europe. Four bone fragments and a lower molar tooth excavated in the Bacho Kiro cave between 2015 and 2018 belong to three Homo sapiens who lived between 45,900 and 42,500 years ago. After analyzing the genomes of these fossils, a group led by Swedish paleogeneticist Svante Pääbo, from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, discovered that these modern humans were hybrids. They are actually a cross between Homo sapiens and their closest evolutionarily relatives, the now extinct Neanderthals (Homo neanderthalensis), archaic human beings that emerged somewhere in Europe or Asia between 700,000 and 500,000 years ago and had a stockier body, a more protruding face, and a shorter, more elongated skull than today’s human populations.

From 400,000 to 40,000 years ago, small groups of Neanderthals spread across a region that today encompasses Europe, West Asia, and the Middle East. Since the Neanderthal genome was sequenced in 2010, genetic data has repeatedly suggested that on some of the occasions they met, H. sapiens and Neanderthals reproduced and had fertile descendants. As a result, current human populations without exclusively African ancestry (there is no evidence that Neanderthals lived in Africa) still have stretches of Neanderthal DNA in their genome. Experts claim that this small contribution has influenced certain characteristics of modern human beings. Several studies have already associated Neanderthal genes with advantageous traits, such as a stronger immune system, which may have allowed H. sapiens to survive new pathogens and spread across the planet, as well as disadvantageous traits, including a greater risk of certain diseases, such as diabetes or depression.

The three oldest Homo sapiens in the Bacho Kiro cave had a Neanderthal ancestor in their not-too-distant past—within five or six generations—according to an article published in the journal Nature on April 7 by Pääbo, a world-renowned expert on ancient DNA, and his team. As a consequence, 3.4–3.8% of these individuals’ genomes were Neanderthal, a proportion greater than is found today in human beings without African descent (1.8–2.6%). “We do have, now, some of the oldest human genomes out there,” paleogeneticist Mateja Hajdinjak, lead author of the paper and currently a researcher at the Francis Crick Institute in the UK, told Nature.

On the same day, another group from Max Planck, led by German paleogeneticist Johannes Krause, recalculated the age of another fossil of H. sapiens with Neanderthal ancestry in the journal Nature Ecology & Evolution. The almost complete skull of a woman, known as Zlatý kůň (golden horse, in Czech), was found in a cave near Prague, Czech Republic, in the early 1950s, almost 1,500 kilometers northwest of Bacho Kiro. Krause and his colleagues were unable to precisely date the skull using the carbon-14 method, so they extracted some DNA. By analyzing sections of Neanderthal DNA, the group estimated that Zlatý kůň, who had a Neanderthal ancestor within 80 previous generations (almost 2,000 years), is at least 45,000 years old.

Marek Jantac Zlatý kůň, a skull found in the Czech Republic in the 1950s, belonged to a female modern human being with Neanderthal ancestry. Its age has now been estimated at over 45,000 yearsMarek Jantac

Such old fossils of modern humans are rarely found outside of Africa, where the species originated. With the publication of these results, however, the total number of H. sapiens fossils over 40,000 years old and with Neanderthal ancestry jumped from two to six in a single day. As well as the specimens from Bacho Kiro and Zlatý kůň, there are two others: a 45,000-year-old femur found in 2008 in the village of Ust’-Ishim, western Siberia, and a mandible called Oase 1, aged 37,000 to 42,000 years, found in a cave in southwestern Romania in 2003. The Ust’-Ishim man, as the former has become known, had a Neanderthal ancestor within 8,000–13,000 years of his birth (i.e., between 53,000 and 58,000 years ago), while Oase 1, which had 9% Neanderthal DNA, descended from a cross within less than six generations.

“The discovery that modern humans from the Upper Pleistocene systematically present evidence of recent Neanderthal ancestry suggests that this type of cross-breeding was not an exception, but the rule,” wrote paleogeneticist Carles Lalueza-Fox, from the Institute of Evolutionary Biology in Barcelona, Spain, in a commentary on the two papers in Nature Ecology & Evolution. Interestingly, genes from Neanderthals have been found in H. sapiens, but not vice versa, says the Spanish researcher. “It is possible that modern humans could tolerate hybrids, but Neanderthals could not. Or that mixed individuals were socially rejected by groups of Neanderthals,” Lalueza-Fox theorizes.

The idea that H. sapiens lived alongside Neanderthals is not new. Before the recent DNA studies, we already had archaeological evidence of their coexistence in the Middle East and Europe. Remains of both species were found in caves in Israel and Jordan. Other fossils, such as that of a child found in the Abrigo de Lagar Velho rock-shelter in Portugal, had mixed traces of H. sapiens and Neanderthals. “Current genetic data give us a glimpse of a complex pattern of H. sapiens migrations to Europe, where they arrived around 45,000 years ago,” says bioanthropologist Mercedes Okumura, head of the Laboratory of Human Evolutionary Studies at the University of São Paulo (USP).

Tracing the hominid family tree and understanding how each species relates to others of the same genus is not a simple task. Ancient fossils are rare, and when found, it is difficult to extract genetic material from them. Recent findings suggest that H. sapiens emerged in North Africa about 300,000 years ago, but only later did it venture to other continents. The fossils indicate that at least three main routes were taken out of the continent: the first just over 100,000 years ago to the Middle East (where they encountered the Neanderthals), the second between 70,000 and 50,000 years ago to South Asia, and the third, roughly 60,000 years ago, to northern Asia and Europe, where they again encountered groups of H. neanderthalensis. “It is possible that during these migrations, some human populations had more contact with Neanderthals than others. That would explain why only some skeletons show evidence of cross-breeding,” explains Okumura.

Tsenka Tsanova, MPI-EVA Leipzig Archaeologists in the Bacho Kiro cave in Bulgaria excavate a layer in which four fossilized Homo sapiens bones were found, dated at between 45,900 and 42,500 years oldTsenka Tsanova, MPI-EVA Leipzig

The occurrence of several waves of migration also explains why only some of the oldest H. sapiens who lived outside Africa are related to today’s human beings. The data indicate that the individuals from Bacho Kiro, the Ust’-Ishim man, and Oase 1 all share genetic similarities with current populations in East Asia and the Americas, but not with those in Europe. This suggests that they are representatives of a population that initially spread across Europe and Asia and then disappeared from Europe. The Zlatý kůň fossil, on the other hand, does not share any genetic characteristics with present-day populations. It belonged to a group of H. sapiens that interacted with Neanderthals and then went extinct.

In recent years, archaeological and genetic studios have helped dispel the long-held notion that Neanderthals were more primitive and less skilled than H. sapiens. A little taller, stronger, and with a slightly larger brain, they hunted large animals, produced sophisticated tools (spears, axes, blades, and hooks) and made string by braiding vegetable fibers (they may even have made clothes). Evidence found in caves indicates that they knew how to use medicinal plants, produced symbolic representations (paintings on walls and structures using stalagmites), and buried their dead. All before modern humans had even left Africa.

Although most of what we know about Neanderthals is discovered outside Brazil, Brazilian researchers have contributed to studies into what our close relatives might have been like. As soon as the Neanderthal genome was published in 2010, research by a group led by geneticists Francisco Salzano (1928–2018) and Maria Cátira Bortolini at the Federal University of Rio Grande do Sul (UFRGS) suggested that from a genetic point of view, Neanderthals were not so different from H. sapiens.

Geneticist Tábita Hünemeier, at the time a doctoral student at UFRGS and now a researcher at USP, compared the characteristics of the HACNS1 gene region, associated with manual dexterity and the ability to walk on two legs, in modern humans and Neanderthals. This part of the genome, most expressed in the feet and hands, is attributed to the ability of H. sapiens to grip objects between their thumb and forefinger, which is essential to precise movements. According to the results, published in the American Journal of Physical Anthropology in 2010, this section is identical in both modern and archaic human beings, a sign that they had the potential to achieve a similar level of dexterity. “The version present in both groups must have been selected before the emergence of the Homo genus,” Says Hünemeier.

Pacal Goetgheluck / Science Photo Libraray / Fotoarena The H. neanderthalensis skull (left) is larger and more elongated than that of the H. sapiens (right)Pacal Goetgheluck / Science Photo Libraray / Fotoarena

Now a researcher at the Federal University of Bahia (UFBA), Vanessa Paixão-Cortes, at the time also a doctoral student in the UFRGS group, decided to test the common hypothesis that Neanderthals were less intelligent than H. sapiens. She analyzed 162 genes that in primates are associated with brain formation—and in some ways with intelligence. Fifty-one of the genes were unique to the genus Homo, with 93 mutations. Data were not available for 25 of these mutations in Neanderthals. The rest, however, were identical to modern humans, according to the result published in American Journal of Human Biology in 2013. “Taking genetic background into account, we found no difference that would allow us to say that one of species was more intelligent than the other,” says Paixão-Cortes.

In a study published in Science in February this year, Brazilian neuroscientist Alysson Muotri and his team at the University of California, San Diego, in the USA, came to a different conclusion. They used a gene editing technique to create mini-brains (miniature organs that simulate the brain) containing a Neanderthal gene in place of its human equivalent. The mini-brains with the archaic gene developed more quickly than those with the modern human version, but they ended up smaller, possibly because they had a slower neuron proliferation rate and greater cell death. They also had fewer of the proteins associated with the connections (synapses) between neurons, indicating a simpler and less effective network for transmitting information. “Our hypothesis is that the neural networks of the human brain have become much more complex over the course of evolution,” explained Muotri in the article “Neanderthal brain in a laboratory,” published on the Pesquisa FAPESP website.

Another study by the group from Rio Grande do Sul helped to dispel the myth that Neanderthals always had red hair and light eyes. The study included three Neanderthal women whose fossils were found in Croatia, and analyzed variations of 67 genes linked to skin, eye, and hair pigmentation in modern and archaic human beings. The results, published in the American Journal of Human Biology in 2012, showed that one of the Neanderthals was a redhead with fair skin and the others had darker skin and brown hair. They all had brown eyes (see Pesquisa FAPESP issue no. 193).

Beyond the questions about similarities and intelligence, it is increasingly evident that the small Neanderthal contribution—2%, on average—to the H. sapiens genome influenced some characteristics of modern human beings. In 2017, a group led by geneticist Joshua Akey, then at the University of Washington in Seattle, USA, found that our Neanderthal heritage is not silent. According to the study, published in the journal Cell, at least 25% of the Neanderthal genes introduced into the human genome are active in the human body, to varying degrees.

In recent years, dozens of studies have linked Neanderthal genes to the manifestation of advantageous traits, as well as a greater risk of developing certain diseases. Neanderthal genes have been associated with the ability of modern human beings to live at high altitudes, greater fertility in women, and a lower risk of bleeding during pregnancy. They have also been linked, however, to a greater likelihood of developing diabetes, schizophrenia, depression, and lupus, and even to a propensity to feel more pain. Recently, Pääbo and Hugo Zeberg, a colleague from Karolinska Institutet in Sweden, found that people that have inherited a region of chromosome 3 from Neanderthals are at greater risk of dying from COVID-19, while those with a Neanderthal section of chromosome 12 are slightly less likely to get sick if they are infected by the virus.

The biggest contribution, however, seems to have been to the strength of the immune system. In a 2018 paper published in Cell, biologists David Enard of the University of Arizona and Dmitri Petrov of Stanford University, both in the USA, showed that several genes inherited from Neanderthals provide protection against viruses, a fact that may have been instrumental in the survival of modern humans after they left Africa. As Akey and his colleagues highlighted in 2017, although Neanderthals went extinct some 40,000 years ago, much of their DNA remains alive in modern humans, shaping our biology.

Scientific articles
HAJDINJAK, M. et al. Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry. Nature. Apr. 7, 2021.
PRÜFER, K. et al. A genome sequence from a modern human skull over 45,000 years old from Zlatý kůň in Czechia. Nature Ecology & Evolution. Apr. 7, 2021.
Hünemeier, T. et al. Brief communication: Population data support the adaptive nature of HACNS1 sapiens/neandertal-chimpanzee differences in a limb expression domain. American Journal of Physical Anthropology. Vol. 143, no. 3, pp. 478–81. Nov. 2010.
PAIXÃO-CORTES, V. et al. The cognitive ability of extinct hominins: bringing down the hierarchy using genomic evidences. American Journal of Human Biology. Vol. 25, no. 5, pp. 702–5. 2013.
TRUJILLO, C. A. et al. Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment. Science. Feb. 12, 2021.
CERQUEIRA, C. C. S. et al. Predicting Homo pigmentation phenotype through genomic data: from Neanderthal to James Watson. American Journal of Human Biology. Vol. 24, no. 5, pp. 705–9. Sept.–Oct. 2012.
MCCOY, R. C. et al. Impacts of Neanderthal-introgressed sequences on the landscape of human gene expression. Cell. Vol. 168, no. 5, pp. 916–27. Feb. 27, 2017.
ENARD, D. & PETROV, D. A. Evidence that RNA Viruses Drove Adaptive Introgression between Neanderthals and Modern Humans. Cell. Vol. 175, no. 2, pp. 360–71. Oct. 4, 2018.

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