Discoveries gleaned from ancient human DNA

Four research articles published in Nature track the genetic traces and geographic origins of human diseases over time. The analyzes provide detailed images of prehistoric human diversity and migration, while offering an explanation for the increased genetic risk of multiple sclerosis (MS).

By analyzing data from the world’s largest dataset to date of 5,000 ancient human genomes from Europe and Western Asia (Eurasia), new research has uncovered prehistoric human gene pools from Western Eurasia with unprecedented details.

The results are presented in four articles published in the same issue of Nature by an international team of researchers led by experts from the University of Copenhagen and contributions from around 175 researchers from universities and museums from the UK, USA, Germany, Australia, Sweden , Denmark, Norway, France, Poland, Switzerland, Armenia and Ukraine. , Russia, Kazakhstan and Italy. The numerous researchers represent a wide range of scientific disciplines, including archaeology, evolutionary biology, medicine, ancient DNA research, infectious disease research and epidemiology.

The research findings presented in the Nature The articles are based on analyzes of a subset of the 5,000 genomes and include:

• The broad genetic implications of a culturally determined barrier, which until about 4,000 years ago extended across Europe, from the Black Sea in the south to the Baltic Sea in the north.
• Mapping how risk genes for several diseases, including type 2 diabetes and Alzheimer’s disease, were dispersed across Eurasia following major migratory events more than 5,000 years ago.
• New scientific evidence of ancient migrations explains why the prevalence of multiple sclerosis is twice as high in Scandinavia as in southern Europe.
• Mapping two almost complete population changes in Denmark, over the course of a single millennium.

The 5,000 Ancient Human Genomes Project

The unprecedented dataset of 5,000 ancient human genomes was reconstructed using analysis of bones and teeth made available through a scientific partnership with museums and universities in Europe and Western Asia. The sequencing effort was carried out using the power of Illumina technology.

The age of the specimens ranges from the Mesolithic and Neolithic to the Middle Ages, including the Bronze Age, the Iron Age and the Viking period. The oldest genome in the dataset comes from an individual who lived around 34,000 years ago.

“The initial goal of the Ancient Human Genomes Project was to reconstruct 1,000 ancient human genomes from Eurasia into a new precision tool for research into brain disorders,” explain the three professors from the University of Copenhagen who came up with the idea in 2018 of DNA. dataset, and initially described the project concept: Eske Willerslev, expert in ancient DNA analysis, jointly at the University of Cambridge, and project director; Thomas Werge, expert on the genetic factors behind mental disorders and director of the Institute of Biological Psychiatry serving mental health services in the Capital Region of Denmark; and Rasmus Nielsen, expert in statistical and computational analyzes of ancient DNA, jointly at the University of California, Berkeley, USA

The goal was to produce a unique set of ancient genomic data to study the traces and genetic evolutionary history of brain disorders as far back as possible in order to gain new medical and biological understanding of these disorders. This was to be accomplished by comparing information from ancient DNA profiles with data from several other scientific disciplines.

Among the brain disorders initially identified by the three professors as candidates for this study were neurological diseases such as Parkinson’s disease, Alzheimer’s disease and multiple sclerosis, as well as mental disorders such as ADHD and schizophrenia.

In 2018, the three professors then contacted the Lundbeck Foundation, a major Danish research foundation, for funding to compile the special DNA data set. They received a five-year research grant totaling 60 million DKK (around 8 million euros) for the project, which was to be coordinated at the University of Copenhagen via a newly established center, later named Lundbeck Foundation GeoGenetics Center.

“The reason we gave such a large research grant to this project, as the Lundbeck Foundation did in 2018, was that if it all worked, it would represent an innovative way to better understand how the genetic architecture underlying “Underlying brain disorders have evolved over time. And brain disorders are our specific focus area,” says Jan Egebjerg, director of research at the Lundbeck Foundation.

The Lundbeck Foundation also supports the iPYSCH consortium, one of the world’s largest studies into the genetic and environmental causes of mental disorders such as autism, ADHD, schizophrenia, bipolar disorder and depression, where the focus There is also a focus on developing genetic risk profiles for these disorders. as precise as possible.

The results reported in Naturewere supported by comparison of the ancient genomic dataset with anonymized genetic data from the large Danish consortium iPYSCH and DNA profiles of 400,000 current individuals registered in the UK Biobank.

Many challenges

The principle of the project was experimental, says Professor Werge. “We wanted to collect ancient human specimens to see what we could learn from them, for example to try to understand some of the environmental context of the evolution of diseases and disorders. In my opinion, the fact that the project took a dimension as vast and complex of the proportions which Nature I wanted it to be described in four articles is very unique.

Professor Willerslev comments that compiling the full DNA data posed major logistical challenges. “We needed access to archaeological specimens of human teeth and bones that we knew were scattered across museums and other institutions across the Eurasian region, which required many collaborative agreements. But once ‘they were put in place, things really took off: the data “The dataset was booming and now exceeds 5,000 ancient human genomes. The size of the dataset significantly improved both the usability and accuracy of the results. “

Professor Nielsen was responsible for planning the statistical and bioinformatics analyzes of information gleaned from ancient teeth and bones in the laboratories of the University of Copenhagen. And he was dealing with a huge volume of data, in which the DNA was often severely degraded.

“No one had analyzed so many ancient genomes before. We now had to figure out how to handle such large volumes of data. The problem was that raw data is very difficult to work with because you end up with lots of short DNA sequences with many errors., and then these sequences must be correctly mapped to the correct position in the human genome. Additionally, there is the problem of contamination by all the microorganisms present on ancient teeth and bones.

“Imagine you have a puzzle made up of millions of pieces mixed with four other incomplete puzzle sets, and then you put it all in the dishwasher for an hour. Putting it all together afterwards is not an easy task. One keys to our success in Ultimately, we collaborated with Dr Olivier Delanau from the University of Lausanne, who developed algorithms to overcome this problem,” explains Professor Nielsen.

International interest

Rumors that a large set of ancient human genome data was being compiled quickly circulated in scientific circles. And since 2022, interest has been very high, say Professors Werge, Willerslev and Nielsen. “We are constantly fielding requests from researchers around the world, especially those studying diseases, who typically request access to explore the ancient DNA dataset.”

The fourth Nature The papers demonstrate that the large dataset of 5,000 genomes serves as a precision tool capable of providing new insights into diseases when combined with analyzes of current human DNA data and input from several others areas of research.

According to Professor Willerslev, this in itself is extremely surprising. “There is no doubt that an ancient genomic data set of this size will have applications in many different contexts within disease research. As new scientific discoveries derived from the 5,000 data set “When genomics studies are published, more data will gradually be made freely available to all researchers. Ultimately, the complete set of data will be freely accessible to all.”