NEW YORK – An international team has sequenced the genome of German composer Ludwig van Beethoven using DNA extracted from hair locks of the composer, identifying features that may have contributed to his early death, at age 56, in 1827.
Their findings included genetic susceptibility to liver disease and an infection with hepatitis B virus (HBV), factors that may have been exacerbated by alcohol consumption documented in the composer's own writing.
"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," co-senior author Johannes Krause, a researcher at the University of Tübingen, the Max Planck Institute of Evolutionary Anthropology, and the Max Planck Institute for the Science of Human History, said in a statement.
While his team was unable to find a cause of the composer's deafness or gastrointestinal problems, "we did discover a number of significant genetic risk factors for liver disease," Krause added. "We also found evidence of an infection with hepatitis B virus in [the last few] months before the composer's final illness. Those likely contributed to his death."
For a paper published in Current Biology on Wednesday, he and his colleagues started by authenticating five of eight hairs samples that had been attributed to Beethoven using low-coverage shotgun sequencing, coupled with sex chromosome, DNA damage, and ancestry analyses.
After that, they sequenced the composer's genome to 24-fold average coverage using one of the so-called "Stumpff Lock" hair samples from a private collector in the US.
While the investigators did not detect genetic factors that could have accounted for the progressive hearing loss that plagued Beethoven or for the noted gastrointestinal maladies he suffered, they did find evidence of germline genetic factors and an infection that possibly contributed to his death from liver disease in 1827.
In particular, the genome sequence pointed to an elevated polygenic risk score for liver cirrhosis, along with liver cirrhosis-associated variants in specific genes such as PNPLA3 and HFE.
Consistent with some historical medical reports, the team also detected HBV genetic material in Beethoven's hair samples, which they assessed by metagenomic sequencing and hybridization capture sequence experiments targeting HBV.
The investigators were also able to rule out conclusions made about Beethoven's health based on non-authenticated samples. When they examined a lock of hair reportedly cropped from the composer's head after his death by 15-year-old musician Ferdinand Hiller, for example, they found that it came from a woman with North African, Middle Eastern, and Jewish ancestry.
That, in turn, suggested that toxicological clues gleaned from the Hiller sample — including potential opiate use or mercury exposure — did not reflect events in Beethoven's life. On the other hand, the team turned to Beethoven's own writing to get a glimpse at his lifestyle habits, including alcohol consumption.
"We can surmise from Beethoven's 'conversation books,' which he used during the last decade of his life, that his alcohol consumption was very regular, although it is difficult to estimate the volumes being consumed," first author Tristan Begg, a researcher at the University of Cambridge, said in a statement.
"While most of his contemporaries claim his consumption was moderate by early 19th century Viennese standards, there is not complete agreement among these sources, and this still likely amounted to quantities of alcohol known today to be harmful to the liver," Begg added. "If his alcohol consumption was sufficiently heavy over a long enough period of time, the interaction with his genetic risk factors presents one possible explanation for his cirrhosis."
The team got more surprises when it tested samples from individuals in Belgium who were expected to share a paternal ancestor with Beethoven going back to the 1500s or 1600s.
Contrary to available genealogical data, the investigators found that Beethoven's family members did not carry the same Y chromosome as the composer, pointing to a so-called "extra-pair paternity event" in the composer's lineage.
"Through the combination of DNA data and archival documents, we were able to observe a discrepancy between Ludwig van Beethoven's legal and biological genealogy," co-author Maarten Larmuseau, a genetic genealogist affiliated with KU Leuven, the University of Antwerp, and non-profit organization Histories, said in a statement.