Recent improvements in ancient DNA analysis approaches have enabled researchers from the Max Planck Institute for Evolutionary Anthropology to uncover more clues about Ludwig van Beethoven’s progressive hearing loss and other health conditions. In their study, published in Current Biology, the researchers used whole-genome sequencing on locks of the composer’s hair to investigate the underlying genetic and infectious causes of his many maladies.
Analysing ancestry
After his death in 1802, Beethoven requested that his ill health be described and made public. Since then, numerous studies have proposed he was afflicted with a range of heritable conditions. Now, improvements in ancient DNA analysis methods have enabled the Max Planck team to produce high-coverage genomes from small quantities of historical hair.
The first task was to analyse eight locks of historical hair attributed to Beethoven. The team discovered that only five of these were “almost certainly authentic” – they all came from the same European male. They used these specific samples to sequence Beethoven’s genome to 24-fold genomic coverage.
“Our primary goal was to shed light on Beethoven’s health problems, which famously include progressive hearing loss, beginning in his mid- to late-20s and eventually leading to him being functionally deaf by 1818,” said Johannes Krause from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.
However, during their analysis they made an intriguing discovery – Beethoven’s Y chromosome was different to his modern-day relatives who share a common ancestor in his paternal line. This finding suggests there was an extramarital “event” at some point in the family’s history.
“This finding suggests an extrapair paternity event in his paternal line between the conception of Hendrik van Beethoven in Kampenhout, Belgium in c.1572 and the conception of Ludwig van Beethoven seven generations later in 1770, in Bonn, Germany,” said Tristan Begg, now at the University of Cambridge, U.K.
What’s up Doc?
Family histories aside, the team set about looking for potential causes of the composer’s many maladies. They used WGS to look for genetic causes of and risk for somatic disease. Though they couldn’t find a direct genetic explanation for his progressive hearing loss or gastrointestinal problems, they did analyse Beethoven’s polygenic risk score for live cirrhosis and found that he was genetically predisposed to liver disease. In fact, he was found to be homozygous for the variant consistently implicated as the most strongly associated locus for liver cirrhosis in GWASs.
Further metagenomics analysis also suggested that he had a hepatitis B infection in the months leading up to his death. These findings, combined with his well-documented high alcohol consumption provide a plausible explanation for his cause of death.
Phylogenetic tree of HBV with branches in substitutions per site estimated using RAxML. Clades corresponding to the main genotypes were collapsed and annotated with their typical geographic location, except for subgenotype D2, in which the HBV genome recovered from Beethoven was placed. Bootstrap supports are reported on the nodes.
Looking ahead
The team noted that “this initial series of five hair samples, spanning approximately the last 7 years of Beethoven’s life, is hoped to be expanded through the authentication testing of additional independent locks of hair, and enables future testing for infections, informative biomarkers, and exposures to environmental causes of or contributors to disease.” Previous studies suggesting Beethoven had lead poisoning turned out to be based on a sample from a European female, suggesting the need for authenticated samples in any further studies into Beethoven’s life.
Besides authentication testing, the team would like to see future studies exploring the biological relationship between the composer and his modern descendants. They conclude that “increases in the size of consumer genetics databases, as well as the testing of additional hypothesized relatives both living and deceased, will lend further clarity to our understanding of Beethoven’s genetic genealogy.”
