Beijing time at 5:31 pm on October 3, Beijing time, the 2022 Nobel Prize in Physiology or Medicine was announced. Swedish scientist Svante Pääbo won the award for his “discovery in the extinct ancient human genome and human evolution ”. The 2022 Nobel Prize single prize is 10 million Swedish Kroner (approximately RMB 6.428 million).
Human beings are always interested in their origins. Where do we come from? What does we have to do with our predecessors? What makes us Homo sapiens different from other ancient humans?
Through his pioneering research, Svante Pääbo accomplished a seemingly impossible thing: sequencing the genome of today's extinct relatives, Neanderthal . He also discovered an ancient human that was unknown to others - Denisovan . Importantly, Pääbo also discovered that after humans left Africa about 70,000 years ago, genes were transferred from these now-extinct ancient humans to Homo sapiens. This ancient gene flow to today’s humans is physiologically associated, such as affecting the response of our immune system to infection. The pioneering research of
Pääbo has produced a whole new scientific discipline: paleogenomics. By revealing the genetic differences between all existing humans and extinct ancient humans, his discovery provides the basis for exploring what makes us unique humans.
Where do we come from?
The origin of human beings and what makes human beings unique has troubled us since ancient times. Paleontology and archaeology are important for the study of human evolution. The evidence provided by the study shows that modern Homo sapiens on anatomy first appeared in Africa about 300,000 years ago, while our known close relative Neanderthals developed outside Africa, living in Europe and West Asia about 400,000 to 30,000 years ago, after which they became extinct. About 70,000 years ago, the Homo sapiens migrated from Africa to , Middle East, and spread from there to the rest of the world. Therefore, Homo sapiens and Neanderthals coexisted for tens of thousands of years in most parts of Eurasia.
But how much do we know about our relationship with the extinct Neanderthals? Genome information can provide relevant clues. By the late 1990s, almost the entire human genome had been sequenced. This is a considerable achievement and provides conditions for subsequent study of genetic relations between different human populations. However, studying the relationship between modern humans and extinct Neanderthals requires sequencing of genomic DNA recovered from ancient specimens.
Seemingly impossible tasks
Early in her career, Svante Pääbo was fascinated by the possibility of using modern genetic methods to study Neanderthal DNA. However, he quickly realized the extreme technical challenges. Because over time, DNA will undergo chemical modification and degradation into short fragments. Thousands of years later, only trace amounts of DNA were left, and the rest was heavily contaminated by bacteria and contemporary human DNA (Figure 1). As a postdoctoral fellow at Allan Wilson, a pioneer in evolutionary biology, Pääbo began to study ways to understand Neanderthal DNA, which lasted for decades.
Figure 1 DNA is localized to two different regions in the cell. Nuclear DNA preserves most of the genetic information, while the smaller mitochondrial genome has thousands of copies. After a person dies, DNA will degenerate over time, and eventually only a very small amount remains. It can also be contaminated by bacteria and modern human DNA.
In 1990, Pääbo was admitted to the University of Munich, Germany. As a new professor, he continued to work in the research of ancient DNA. He decided to analyze the DNA of Neanderthal mitochondria , which is an organelle containing its own DNA in the cells. The mitochondrial genome is small and contains only a small portion of the genetic information in the cell, but it exists in thousands of copies, increasing the chances of success. Through this method, Pääbo successfully sequenced a mitochondrial DNA region in a 40,000-year-old bone.Therefore, we have obtained the sequence of this extinct relative for the first time. Comparisons with contemporary humans and chimpanzees show that Neanderthals are genetically different.
Sequencing the Neanderthal genome
Since analysis of small mitochondrial genomes can only provide limited information, Pääbo faces a huge challenge to sequencing the Neanderthal nuclear genome. At this time, he was given a job opportunity to establish the Max Planck Institute in Leipzig, Germany. In the new institute, Pääbo and the team steadily improve methods for isolating and analyzing DNA from remains of ancient bones. The research team used new technology development to make DNA sequencing very efficient. Pääbo also hired several key collaborators with expertise in population genetics and advanced sequence analysis. His efforts were successful. Pääbo completed what seemed impossible and published the first Neanderthal genome sequence in 2010. Comparative analysis shows that the recent common ancestors of Neanderthals and Homo sapiens lived about 800,000 years ago.
Figure 2 A. Pääbo DNA extracted from extinct ancient human bone specimens. He first obtained a fragment of bone from the German Neanderthals, where the Neanderthals named it. Later, he used a phalanx from the Denisovan Cave in the south of Siberia , where the Denisovans named it. B. Phylogenetic tree showing evolution and relationship between Homo sapiens and extinct ancient humans. Phylogenetic trees also illustrate the gene flow found by Pääbo.
Pääbo and colleagues can now investigate the relationship between Neanderthals and modern people from different parts of the world. Comparative analysis showed that Neanderthal DNA sequence was more similar to that of contemporaries from Europe or Asia, rather than contemporaries from Africa. This means that Neanderthals and Homo sapiens have crossed over thousands of years of coexistence. In modern humans with European or Asian descent, approximately 1-4% of the genomes are from Neanderthals (Figure 2).
A sensational discovery: Denisovans
In 2008, a fragment of a phalanx from 40,000 years ago was found in the Denisovan cave in southern Siberia. The bone contains very well-preserved DNA, and Pääbo's team sequenced it. The results caused a sensation: This DNA sequence is unique compared to all known DNA sequences of Neanderthal and modern humans. Pääbo discovered an ancient human that was previously unknown, named Denisova. Comparison of sequences with contemporaries from different parts of the world shows that gene flow has also occurred between the Denisovans and Homo sapiens. This relationship was first found in Melanesia and in other parts of Southeast Asia, where individuals carry up to 6% of Denisovan DNA. The discovery of
Pääbo has given people a new understanding of the history of human evolution. When Homo sapiens left Africa, at least two extinct ancient human populations lived in Eurasia. Neanderthals live in the western part of Eurasia, while Denisovans live in the eastern part of the continent. During Homo sapiens’ expansion and eastward migration outside Africa, they met and crossed not only with Neanderthals, but also with Denisovans (Figure 3).
Paleogenomics and its correlations
Through pioneering research, Pääbo has established a brand new discipline - Paleogenomics. After the initial discovery, his team has completed the analysis of several additional genome sequences of the extinct ancient humans. Pääbo's discovery has established a unique resource that has been widely used by the scientific community to better understand human evolution and migration. New powerful sequence analysis methods suggest that ancient ancient humans may also be mixed with African Homo sapiens. However, the genome of extinct ancient humans in Africa has not been sequenced as ancient DNA accelerates degradation in tropical climates.
thanks to Svante Pääbo's discovery, and now we have learned that ancient genetic sequences from extinct relatives of human beings affect the physiological functions of today's human beings.One example is the EPAS1 gene of the Denisovans, which gives the advantage of survival in high altitude areas and is common among Tibetans today. Another example is that Neanderthal genes affect our immune response to different types of infections.
Figure 3 Pääbo's discovery provides important information on how the world population is distributed when Homo sapiens migrated from Africa to other parts of the world. Neanderthals live in the western part of Eurasia, while Denisovans live in the eastern part. Mixed blood appears when Homo sapiens spread across the African continent, leaving traces in our DNA.
What makes human beings unique?
Homo sapiens are characterized by their unique ability to create complex cultures, advanced innovations and concrete art, as well as their ability to travel through open waters and migrate to all parts of the earth (Figure 4). Neanderthals also live in groups and have huge brains (Figure 4). They also use tools, but over hundreds of thousands of years, little progress has been made. The genetic differences between Homo sapiens and our extinct close relatives have been unknown and have been identified through Pääbo's pioneering work. A large number of ongoing research focuses on analyzing the functional implications of these differences, with the ultimate goal being to explain what makes us humans unique.
Figure 4 Pääbo's pioneering work provides the basis for explaining what makes us unique human beings.
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