Genobiography: The Beethoven Genome Project as a case study integrating genomics into historical biography

Ludwig van Beethoven (1770-1827) is among the most influential and popular composers in Western Art Music. Health problems significantly impacted his career as a composer and pianist, including progressive hearing loss, recurring bowel problems and liver disease. In 1802, Beethoven requested that following his death, the causes of his illness be described and made public. Medical biographers have since proposed numerous hypotheses to account for Beethoven’s history of poor health, including several with heritable or infectious aetiologies that are potentially amenable to diagnostic testing or risk stratification via genomic analyses. A series of recent advances in laboratory and bioinformatics methods were integrated into existing methods to produce a highly sensitive protocol for historical hair samples, enabling the sequencing of high-coverage genomes from small quantities of historical hair. Eight independently sourced locks of hair plausibly attributed to Beethoven underwent genomic analyses. Five of these were found to originate from a single European male with an ancestry profile and DNA damage patterns consistent with that expected for Beethoven. In light of their reconstructed provenance histories, two of which were perfect, these matching samples were deemed to be almost certainly authentic. Beethoven’s genome was sequenced to 24-fold genomic coverage using extract from 275cm of hair. Although no genetic predisposition for hearing or gastrointestinal disorders could be identified, several significant heritable and infectious risk factors for liver disease were discovered. Beethoven was homozygous for the most robustly implicated variant associated with the full range of progressive liver disease in *PNPLA3*, and compound heterozygous for two hereditary hemochromatosis variants in *HFE*. In addition, metagenomic analyses and targeted capture revealed that Beethoven was infected with hepatitis B virus during at least the months leading to his final illness. The definite identification of heritable and infectious risk factors for liver disease refines the range of plausible aetiologies for Beethoven’s final illness. Unexpectedly, an analysis of Y-chromosomes sequenced from five living members of the Van Beethoven patrilineage revealed the occurrence of an extra-pair paternity event in Ludwig van Beethoven’s patrilineal ancestry. In addition, no long shared identical-by-descent segments were detected among three descendents of Beethoven’s nephew, Karl van Beethoven, suggesting the possibility of a second EPP event. Finally, authentication analyses revealed that a lock of hair, previous analyses of which have led to conclusions that plumbism caused or compounded Beethoven’s health problems, is inauthentic.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Begg, Tristan

Advisors dc:contributor.advisor

• Kivisild, Toomas
• Attenborough, Robert

• ancient DNA
• Beethoven’s genome
• extra-pair paternity
• forensic genetics
• Genetic genealogy
• genobiography
• hair DNA
• hepatitis B virus
• liver disease
• Ludwig van Beethoven
• medical genetics
• population genetics

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a798c45e-0fd7-4970-a98f-334a640025ba/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.107274

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/366293