Technologies developed by Pääbo to sequence Neanderthal DNA are being widely used in many clinical laboratory settings, including to study infectious disease outbreaks
Pääbo is considered to be the founder of paleogenetics. This field of science studies the past through examination of preserved genetic material found in remains of ancient organisms. It was his development of pioneering technologies that allowed for the genomic sequencing of Neanderthal DNA.
“[Pääbo’s] work has revolutionized our understanding of the evolutionary history of modern humans,” said German electrochemist Martin Stratmann, PhD, President of the Max Planck Society for the Advancement of Science (MPG), in a press release. “Svante Pääbo, for example, demonstrated that Neanderthals and other extinct hominids made a significant contribution to the ancestry of modern humans.”
“The thing that’s amazing to me is that you now have some ability to go back in time and actually follow genetic history and genetic changes over time,” Svante Pääbo, PhD (above), director of the Max Planck Institute for Evolutionary Anthropology, stated in a news conference, Reuters reported. “It’s a possibility to begin to actually look on evolution in real time, if you like.” Development of modern clinical laboratory techniques for identifying and tracking disease outbreaks have already evolved due to these findings. (Photo copyright: Max Planck Institute for Evolutionary Anthropology.)
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Comparing Neanderthal DNA to That of Modern Humans
Back in the mid-1990s, Pääbo and a team of researchers decoded relatively short fragments of mitochondrial DNA of a Neanderthal male. They discovered through their analysis that the DNA from the Neanderthal varied considerably from the genome of contemporary humans. This validated the belief that modern humans are not direct descendants of the Neanderthals.
Pääbo’s research team found nearly all (99.9%) of the Neanderthal DNA they studied to be heavily colonized by bacteria and fungi. That required them to create solutions for assembling the short components of mitochondrial DNA like a huge puzzle.
To accomplish this, the team had to:
Work under clean room conditions to prevent the accidental introduction of their own DNA into their experiments.
Establish more efficient extraction methods to enhance the output of Neanderthal DNA.
Generate complex computer programs that could compare the ancient DNA fragments with reference genomes of both humans and chimpanzees.
“Neanderthals are the closest relatives of humans today” said Pääbo in the press release. “Comparisons of their genomes with those of modern humans and with those of apes enable us to determine when genetic changes occurred in our ancestors. In the future, it could also be clarified why modern humans eventually developed a complex culture and technology that enabled them to colonize almost the entire world.”
Pääbo’s team succeeded in reconstructing their first version of the Neanderthal genome in 2010. Their comparisons between the genomes of Neanderthal and modern humans proved that the two groups had produced common offspring about 50,000 years ago and that this genetic contribution did influence human evolution.
The genome of modern non-African people still contains about 2% Neanderthal DNA.
“We have found around 30,000 positions in which the genomes of almost all modern humans differ from those of Neanderthals and great apes,” Pääbo added. “They answer what makes anatomically modern humans ‘modern’ in the genetic sense as well. Some of these genetic changes may be the key to understanding what distinguishes the cognitive abilities of today’s humans from those of now extinct hominids.”
Those with Neanderthal DNA More Susceptible to Severe COVID-19 Infection
Pääbo’s research also found that Neanderthal DNA may have affected the immune systems of modern people. During the COVID-19 pandemic, his work verified that individuals who carry a gene variant inherited from Neanderthals are more prone to severe forms of the illness than those who do not have that gene variant.
“We can make an average gauge of the number of the extra deaths we have had in the pandemic due to the contribution from the Neanderthals,” Pääbo said in a 2022 lecture, Reuters reported. “It is quite substantial, it’s more than one million extra individuals who have died due to this Neanderthal variant that they carry.”
Pääbo’s research team continues to develop new methods for reconstructing DNA fragments that are even more biodegraded, and which present in smaller amounts. Their ultimate goal is to investigate even older DNA and genetic material that is scarce due to climate conditions.
The DNA technologies pioneered by Pääbo to sequence Neanderthal DNA are being used widely in many clinical laboratory and research settings today. They include forensic science and the ability to collect DNA from human remains hundreds of years old to identify infectious disease outbreaks and study how today’s human genome has adopted new mutations.
DNA analysis of early plague victims pinpoints Black Death’s start on Silk Road trading communities in mountain region of what is now modern-day Kyrgyzstan in Central Asia
Microbiologists and clinical laboratory scientists will likely find it fascinating that an international team of scientists may have solved one of history’s greatest mysteries—the origin of the bubonic plague that ravaged Afro-Eurasia in the mid fourteenth century. Also known as the Black Death, the plague killed 60% of the population of Europe, Asia, and North Africa between 1346-1353 and, until now, the original source of this disease has largely gone unsolved.
In their study published in the journal Nature, titled, “The Source of the Black Death in Fourteenth-Century Central Eurasia,” the authors outlined their investigation of cemeteries in the Chüy Valley of modern-day Kyrgyzstan. The tombstone inscriptions showed a disproportionally high number of burials dating between 1338 and 1339 with inscriptions stating “pestilence” as the cause of death.
Archeological evidence combined with ancient DNA analysis of early plague victims enabled scientists to pinpoint the Black Death’s origins in Kyrgyzstan. “We have basically located the origin in time and space, which is really remarkable,” geneticist Johannes Krause, PhD (above), Professor at the Max Planck Institute for Evolutionary Anthropology, who co-led the study, told The Guardian. “We found not only the ancestor of the Black Death, but the ancestor of the majority of the plague strains that are circulating in the world today.” These new research findings may help microbiologists and clinical pathologists gain new insights into how current strains of Yersinia pestis can be better diagnosed. (Photo copyright: Max Planck Institute.)
Big Bang of Plague
Using 30 skeletons that were excavated from these cemeteries in the late 1880s and moved to St. Petersburg, Russia, the scientists analyzed the DNA of ancient pathogens recovered from the remains of seven people. They discovered Yersinia pestis (Y. pestis) DNA in three burials from Kara-Djigach, which lies in the foothills of the Tian Shan mountains.
According to another article in Nature, the scientists showed that a pair of full Y. pestis genomes from their data were direct ancestors of strains linked to the Black Death, and that the Kara-Djigach strain was an ancestor of the vast majority of Y. pestis lineages circulating today.
“It was like a big bang of plague,” Krause stated at a press briefing, Nature reported.
The research team concluded that the Tian Shan region was the location where Y. pestis first spread from rodents to people, and that the local marmot colonies likely the prevalent rodent carriers of plague.
“We found that modern strains [of the plague] most closely related to the ancient strain are today found in plague reservoirs around the Tian Shan mountains, so very close to where the ancient strain was found. This points to an origin of Black Death’s ancestor in Central Asia,” Krause explained in a Max Planck Institute news release.
He told Nature that fleas likely passed the marmot-based infection on to humans, sparking a local Kyrgyzstan epidemic. The disease then spread along the Silk Road trade routes, eventually reaching Europe, where rats (and the fleas that they carried) spread the disease.
Understanding Context of Plague
Writing in The Conversation, Associate Professor of Medieval and Environmental History Philip Slavin, PhD, University of Stirling, who co-authored the study, explained that Kara-Djigach is unlikely to be “the specific source of the pandemic,” but rather that the “disaster started somewhere in the wider Tian Shan area, perhaps not too far from that site,” where marmot colonies were likely the source of the 1338-1339 outbreak.
Making a modern-day comparison, Krause told Nature, “It is like finding the place where all the strains come together, like with coronavirus where we have Alpha, Delta, Omicron all coming from this strain in Wuhan.”
Slavin maintains that understanding the “big evolutionary picture” is key when studying the phenomenon of emerging epidemic diseases.
“It is important to see how these diseases develop evolutionary and historically, and avoid treating different strains as isolated phenomena,” he wrote in The Conversation. “To understand how the diseases develop and get transmitted, it is also crucial to consider the environmental and socioeconomic contexts.”
Scientists have spent centuries debating the source of the Black Death that devastated the medieval world. The multidisciplinary process used by the Slavin/Krause-led team provides a lesson to clinical laboratory managers and pathologists on the important role they play when collaborating with colleagues from different fields on scientific investigations.
Of interest to clinical pathologists is the finding that sequencing the genomes of Humans and Neanderthals revealed a link between severity of COVID-19 infections and Neanderthal DNA
Genetic scientists from the University of California Santa Cruz have learned that just 7%—or less—of our DNA is unique to the human species, with the remainder of our genomes coming from other archaic species, such as Neanderthal and Denisovan.
Why should this matter to pathologists and clinical laboratories? Because a broader knowledge of how DNA evolves may help researchers and healthcare providers better understand how a modern family’s DNA can change over generations. In turn, these insights may lead to precision medicine tools for personalized diagnosis and treatment.
“We find that a low fraction, 1.5 to 7%, of the human genome is uniquely human, with the remainder comprising lineages shared with archaic hominins from either ILS [incomplete lineage sorting] or [genetic] admixture,” wrote the paper’s authors.
To complete their study, the researchers used DNA extracted from fossils of Neanderthals and Denisovans, as well as genetic information from 279 people from various locations around the world.
One goal was to determine what part of a modern human’s genome is truly unique. Though only a small percentage of our entire genome, those portions are important.
“We can tell those regions of the genome are highly enriched for genes that have to do with neural development and brain function,” Richard Green, PhD, Associate Professor of Biomolecular Engineering at the University of California Santa Cruz and co-author of the paper, told the Associated Press (AP).
In addition to highlighting what makes modern humans unique as a species, the study also suggests, “That we’re actually a very young species. Not that long ago, we shared the planet with other human lineages,” said Joshua Akey, PhD, Professor of Ecology and Evolutionary Biology and the Lewis-Sigler Institute for Integrative Genomics at Princeton University. Akey co-authored the Science Advances research paper.
Human/Neanderthal Genetic Overlap
The genetic research being conducted at the University of California Santa Cruz is just the most recent in a flurry of studies over the past decade investigating the Neanderthal genome. Most of these studies point to the vast similarities between humans and Neanderthals, but also to how similar humans are to each other.
“Humans have more than three billion letter pairs of DNA in their genome: It turns out less than 2% of that spells out around 20,000 specific genes, or sets of instructions that code for the proteins that make our tissues,” wrote zooarcheologist Anna Goldfield, PhD (above), Adjunct Instructor Cosumnes River College in Sacramento, Calif., and at the University of California, Davis, in Sapiens. “All humans share the same basic set of genes (we all have a gene for earwax consistency, for example), but there are subtle variations in the DNA spelling of those genes from individual to individual that result in slightly different proteins (sticky earwax versus dry earwax) … Overall, any given human being is about 99.9% similar, genetically, to any other human being,” she added. It is those variations that could lead to precision medicine treatments, personalized drug therapies, and clinical laboratory tests that inform physicians about relevant genetic variations. (Photo copyright: Boston University.)
Practically Everyone Has Neanderthal DNA
Understanding that humans and Neanderthals are 93-98.5% similar genetically may—or may not—come as a surprise. In delving into those similarities and differences researchers are making interesting and potentially important discoveries.
For example, researchers have studied a gene that occurs in both modern humans and Neanderthal fossils that has to do with how the body responds to carcinogenic hydrocarbons, such as smoke from burning wood. Neanderthals were far more sensitive to the carcinogens, but also had more genetic variants, such as single-nucleotide polymorphisms, that could neutralize their effects.
Most modern humans carry some Neanderthal DNA. For some time, scientists thought that Africans likely did not carry Neanderthal DNA, since ancient people tended to migrate out of Africa and met Neanderthals in Europe. More recent research, however, shows that migration patterns were more complex than previously thought, and that the ancient people migrated back to Africa bringing Neanderthal DNA with them.
“Our results show this history was much more interesting and there were many waves of dispersal out of Africa, some of which led to admixture between modern humans and Neanderthals that we see in the genomes of all living individuals today,” Akey told CNN.
Neanderthal DNA and COVID-19
Researchers have found that having Neanderthal DNA may affect the health of modern people who carry it. Perception of pain, immune system function, and even hair color and sleeping patterns have been associated with having Neanderthal DNA.
Scientists have even found a potential link between severe COVID-19 infection and Neanderthal DNA, CNN reported.
The researchers added, “It turns out that this gene variant was inherited by modern humans from the Neanderthals when they interbred some 60,000 years ago. Today, the people who inherited this gene variant are three times more likely to need artificial ventilation if they are infected by the novel coronavirus SARS-CoV-2.”
Of course, these links and associations are preliminary science. John Capra, PhD, Research Associate Professor of Biological Sciences and Associate Professor of Biomedical Informatics at the University of California, San Francisco says, “We can’t blame Neanderthals for COVID. That’s a damaging response, and that’s why I want to emphasize so much [that] the social and environmental factors are the real things that people should be worrying about,” he told CNN.
“That said,” he continued, “as a geneticist, I think it is important to know the evolutionary history of the genetic variants we find that do have effects on traits. The effects of Neanderthal DNA traits are detectable, but they’re modest.”
Nevertheless, genetic scientists agree that understanding the genetic roots of disorders could lead to breakthroughs that result in new types of clinical laboratory tests designed to guide precision medicine treatments.
Latest-generation DNA sequencing technology helped scientists achieve this feat
This spring, a particularly interesting milestone on the road to genetic medicine was achieved. The genome of Neanderthal man has been sequenced at the 1X level. It is a remarkable accomplishment by scientists from both the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and 454 Life Sciences Inc. , a division of Roche Holdings.
The final Neanderthal draft sequence is made up of three billion bases of Neanderthal DNA. This represents an estimated two-thirds of the entire genome. A research team has been assembled to evaluate and analyze the Neanderthal genome. Their findings may be published by the end of the year.
