Humanity has always been intrigued by its origins. Where do we come from, and how are we related to those who came before us? What makes us, Homo sapiens, different from other hominins?
Through his pioneering research, Svante Pääbo accomplished something seemingly impossible: sequencing the genome of the Neanderthal, an extinct relative of present-day humans. He also made the sensational discovery of a previously unknown hominin, Denisova. Importantly, Pääbo also found that gene transfer had occurred from these now extinct hominins to Homo sapiens following the migration out of Africa around 70,000 years ago. This ancient flow of genes to present-day humans has physiological relevance today, for example affecting how our immune system reacts to infections.
Pääbo’s seminal research gave rise to an entirely new scientific discipline; paleogenomics. By revealing genetic differences that distinguish all living humans from extinct hominins, his discoveries provide the basis for exploring what makes us uniquely human.
Where do we come from?
The question of our origin and what makes us unique has engaged humanity since ancient times. Paleontology and archeology are important for studies of human evolution. Research provided evidence that the anatomically modern human, Homo sapiens, first appeared in Africa approximately 300,000 years ago, while our closest known relatives, Neanderthals, developed outside Africa and populated Europe and Western Asia from around 400,000 years until 30,000 years ago, at which point they went extinct. About 70,000 years ago, groups of Homo sapiens migrated from Africa to the Middle East and, from there they spread to the rest of the world. Homo sapiens and Neanderthals thus coexisted in large parts of Eurasia for tens of thousands of years. But what do we know about our relationship with the extinct Neanderthals? Clues might be derived from genomic information. By the end of the 1990’s, almost the entire human genome had been sequenced. This was a considerable accomplishment, which allowed subsequent studies of the genetic relationship between different human populations. However, studies of the relationship between present-day humans and the extinct Neanderthals would require the sequencing of genomic DNA recovered from archaic specimens.
A seemingly impossible task
Early in his career, Svante Pääbo became fascinated by the possibility of utilizing modern genetic methods to study the DNA of Neanderthals. However, he soon realized the extreme technical challenges, because with time DNA becomes chemically modified and degrades into short fragments. After thousands of years, only trace amounts of DNA are left, and what remains is massively contaminated with DNA from bacteria and contemporary humans (Figure 1). As a postdoctoral student with Allan Wilson, a pioneer in the field of evolutionary biology, Pääbo started to develop methods to study DNA from Neanderthals, an endeavor that lasted several decades.
In 1990, Pääbo was recruited to University of Munich, where, as a newly appointed Professor, he continued his work on archaic DNA. He decided to analyze DNA from Neanderthal mitochondria – organelles in cells that contain their own DNA. The mitochondrial genome is small and contains only a fraction of the genetic information in the cell, but it is present in thousands of copies, increasing the chance of success. With his refined methods, Pääbo managed to sequence a region of mitochondrial DNA from a 40,000-year-old piece of bone. Thus, for the first time, we had access to a sequence from an extinct relative. Comparisons with contemporary humans and chimpanzees demonstrated that Neanderthals were genetically distinct.
Sequencing the Neanderthal genome
As analyses of the small mitochondrial genome gave only limited information, Pääbo now took on the enormous challenge of sequencing the Neanderthal nuclear genome. At this time, he was offered the chance to establish a Max Planck Institute in Leipzig, Germany. At the new Institute, Pääbo and his team steadily improved the methods to isolate and analyze DNA from archaic bone remains. The research team exploited new technical developments, which made sequencing of DNA highly efficient. Pääbo also engaged several critical collaborators with expertise on population genetics and advanced sequence analyses. His efforts were successful. Pääbo accomplished the seemingly impossible and could publish the first Neanderthal genome sequence in 2010. Comparative analyses demonstrated that the most recent common ancestor of Neanderthals and Homo sapiens lived around 800,000 years ago.
Pääbo and his co-workers could now investigate the relationship between Neanderthals and modern-day humans from different parts of the world. Comparative analyses showed that DNA sequences from Neanderthals were more similar to sequences from contemporary humans originating from Europe or Asia than to contemporary humans originating from Africa. This means that Neanderthals and Homo sapiens interbred during their millennia of coexistence. In modern day humans with European or Asian descent, approximately 1-4% of the genome originates from the Neanderthals