Key Revelations Uncovered from Ancient Human DNA

January 13, 2024

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By the University of Copenhagen

Four studies published in Nature explore the genetic links and geographic origins of human diseases through ancient times. The studies present a comprehensive view of early human diversity and migration and propose one possible origin for the increased genetic risk for multiple sclerosis (MS).

By studying the world's largest data set to date, consisting of 5,000 ancient human genomes from Europe and Western Asia (Eurasia), new insights have been gained about the ancient human gene pools of western Eurasia in unparalleled detail.

An international team of researchers, spearheaded by experts from the University of Copenhagen with contributions from roughly 175 individuals from universities and museums worldwide, has published the results in four articles in one issue of Nature. These contributors represent a variety of scientific fields, such as archaeology, evolutionary biology, medicine, ancient DNA research, infectious disease research, and epidemiology.

The scientific breakthroughs described in these Nature articles rely on the analysis of a subset of the 5,000 genomes and include:

The enormous data set of 5,000 ancient human genomes was reconstructed through the analysis of bones and teeth, made possible through collaborations with museums and universities across Europe and western Asia. The sequencing work was made possible through the use of Illumina technology.

The ages of the specimens span from the Mesolithic and Neolithic through the Bronze Age, Iron Age, Viking period, and into the Middle Ages. The earliest genome in the data set belonged to someone who lived nearly 34,000 years ago.

'The original objective of the ancient human genomes project was to reconstruct 1,000 ancient human genomes from Eurasia as a tool for researching brain disorders,' say three professors from the University of Copenhagen who conceived of the DNA data set back in 2018 and initially described the project concept: Eske Willerslev, Thomas Werge, and Rasmus Nielsen, experts respectively in the analysis of ancient DNA, genetic factors linked to mental disorders, and statistical and computational analyses of ancient DNA.

The goal was to assemble a unique old genomic data set to probe the genetic evolutionary history of brain disorders to expand our medical and biological understanding of these disorders. Comparisons would come not only from the ancient DNA profiles but from data across multiple scientific disciplines.

The trio of professors initially identified neurological and mental conditions such as Parkinson's disease, Alzheimer's disease, MS, ADHD, and schizophrenia as subjects for this study.

In 2018, the professors sought funding from the Lundbeck Foundation, a prominent Danish research foundation, to compile the DNA data set. They received a five-year research grant of approximately DKK 60 million (approximately EUR 8 million) for the project, which would be coordinated at the University of Copenhagen via a newly constructed hub, the Lundbeck Foundation GeoGenetics Center.

'The reason for granting such a significant research grant to this project in 2018 was the potential it held for ground-breaking understanding of how the genetic architecture underlying brain disorders evolved over time. And brain disorders are our specific area of interest,' states Jan Egebjerg, Director of Research at the Lundbeck Foundation.

The Lundbeck Foundation also backs the iPYSCH consortium, one of the globe's largest studies examining genetic and environmental factors leading to mental disorders like autism, ADHD, schizophrenia, bipolar disorder, and depression. The aim here is also to refine genetic risk profiles for these disorders as much as possible.

The results reported in Nature, were substantiated by comparing the ancient genomic data set with de-identified genetic data from the large Danish iPYSCH consortium and DNA profiles from 400,000 present-day individuals registered in UK Biobank.

The premise for the project was experimental, recounts Professor Werge. 'We wanted to collect ancient human specimens to see what we could get out of them, like trying to understand some of the environmental background to how diseases and disorders evolved. As I see it, the fact that the project took on such vast, complex proportions that Nature wanted it described in four articles is quite unique.'

Professor Willerslev comments that compiling the DNA data set posed major logistical challenges. 'We needed access to archaeological specimens of human teeth and bones that we knew were scattered around in museums and other institutions in the Eurasian region, and that called for many collaboration agreements. But once they were in place, things really took off—the data set was booming, and it now exceeds 5,000 ancient human genomes. The size of the data set has tremendously enhanced both the usability and precision of the results.'

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

'No one had previously analyzed so many ancient genomes. Now we had to find out how to handle such vast data volumes. The problem was that the raw data is very difficult to work with because you end up with many short DNA sequences with many errors, and then those sequences have to be correctly mapped to the right position in the human genome. Plus, there is the issue of contamination from all the microorganisms present on the ancient teeth and bones.

'Imagine having a jigsaw puzzle consisting of millions of pieces mixed up with four other incomplete puzzle sets, and then running all that in the dishwasher for an hour. Piecing it all together afterwards is no easy task. One of the keys to our success in the end was that we teamed up with Dr. Olivier Delanau from the University of Lausanne who developed algorithms to overcome that very problem,' says Professor Nielsen.

Rumors that a large ancient human genome data set was being compiled were soon circulating in scientific circles. And since 2022 interest has been running very high, say Professors Werge, Willerslev and Nielsen. 'We are constantly taking inquiries from researchers all over the globe—especially those investigating diseases—who typically request access to explore the ancient DNA data set.'

The four Nature articles demonstrate that the large data set of 5,000 genomes serves as a precision tool capable of providing new insights into diseases when combined with analyses of present-day human DNA data and inputs from several other research fields.

That in itself is immensely amazing, according to Professor Willerslev. 'There's 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-genome data set become published, more data will gradually be made freely available to all researchers. Ultimately, the complete data set will be open access for everyone.'

Journal information: Nature

Provided by University of Copenhagen