Groundbreaking Study Unravels Beethoven's Genetic Mysteries: A Glimpse into the Composer's Life, Ancestry and Health

In a landmark study, a team of dedicated researchers has pieced together the elusive genetic puzzle of Ludwig van Beethoven, one of the most influential and popular classical music composers of all time. Through their meticulous work, the scientists have uncovered fascinating insights into Beethoven's health, progressive hearing loss, and ancestry.

A Revolutionary Approach to Ancient DNA

Beethoven's life was plagued by various health problems, including debilitating hearing loss, gastrointestinal issues, and liver disease. In 1802, the composer requested that his ailments be described and made public after his death. Medical biographers have since proposed numerous hypotheses about the underlying causes of his illnesses, with many suggesting heritable conditions.

 The researchers in the study made significant strides in understanding Beethoven's health by incorporating recent advancements in ancient DNA methods. They did this by acquiring eight locks of hair attributed to Beethoven from public and private collections, each with independent provenance histories. These locks are referred to as the Müller, Bermann, Halm-Thayer, Moscheles, Stumpff, Cramolini-Brown, Hiller, and Kessler Locks. The provenance histories of two of these locks, the Stumpff and Halm-Thayer Locks, have intact chains of custody.

 The study aimed to confirm the authenticity of these locks by determining whether they belonged to a single male individual of predominantly Central European ancestry, with DNA degradation patterns consistent with the early 19th century. The research team performed shallow shotgun sequencing on the hair samples to assess DNA preservation and authenticity. They discovered that five of the samples – the Müller, Bermann, Halm-Thayer, Moscheles, and Stumpff Locks – shared identical mitochondrial genomes and had male XY karyotypes. Relatedness testing confirmed that these samples originated either from a single individual or monozygotic twins.

 These five samples also exhibited DNA damage patterns consistent with their early 19th-century provenance. The researchers concluded that these genetic findings, alongside their provenance histories, provide compelling evidence that these hair samples are authentic.

 The researchers also tested for identity-by-descent (IBD) segment sharing among three living descendants of Beethoven's nephew, Karl van Beethoven. While the IBD-sharing and mitochondrial relatedness detected among the participants were consistent with their documented genealogy, no IBD segments were detected between Beethoven and the three participants.

 Thus, the researchers were unable to conclusively prove or disprove relatedness between Beethoven and the descendants of Karl van Beethoven, and thus could not provide further verification of sample authenticity based on this criterion.

Beethoven's Unfortunate Troubles with Disease and Debunking Rumors

The study also investigated whether Beethoven had a monogenic condition, meaning a disease caused by a single gene. Although they didn't find evidence for some of the suspected monogenic diseases, they discovered that Beethoven carried two genetic variants associated with a condition called hereditary hemochromatosis (HH). This disorder causes the body to absorb too much iron, which can lead to liver damage if left untreated. It is unclear whether this condition played a role in Beethoven's liver cirrhosis, as there were too few individuals with similar genetic makeup to make a clear conclusion.

 Many of Beethoven's biographers have suggested that he may have suffered from irritable bowel syndrome (IBS) or an inflammatory bowel disease, such as Crohn's disease (CD) or ulcerative colitis (UC), due to his persistent gastrointestinal issues. Using genetic data, researchers calculated Beethoven's risk of developing these conditions. They found that he had a slightly increased risk of UC, while his risk of developing CD was relatively low. Surprisingly, the study suggested that Beethoven's genetic makeup actually provided some protection against IBS.

 The researchers also looked for genetic markers of other possible causes of gastrointestinal distress, such as celiac disease, lactose intolerance, and cystic fibrosis. Beethoven didn't have the genetic markers for celiac disease, and he was likely lactose tolerant. No disease-causing variants for cystic fibrosis were identified either.

 In addition to his liver and gastrointestinal issues, Beethoven famously suffered from hearing loss, which progressed to complete deafness later in his life. The study found that he had a genetic predisposition to age-related hearing loss. However, it's important to note that environmental factors, such as exposure to loud music or infections, may have also contributed to the severity of his hearing loss.

 Another interesting finding of the study was the detection of hepatitis B virus (HBV) DNA in Beethoven's hair. An infection with this virus has been suggested by some biographers as a possible cause of his liver disease. The researchers were able to reconstruct the HBV sequence from Beethoven's hair and found that it belonged to a specific subgenotype. However, it's still unclear whether the presence of the virus played a significant role in Beethoven's health issues.

 The researchers were also able to debunk previous claims about the composer's health. A lock of hair, known as the Hiller Lock, was once believed to be Beethoven's and was used to argue that his health problems were caused by lead poisoning. However, this study revealed that the hair actually belonged to a woman with close genetic affinity to North African, Middle Eastern, and Jewish populations. Consequently, previous conclusions about Beethoven's health based on this sample are now considered invalid.

Beethoven's Ancestry

The study has also uncovered surprising details about Beethoven's paternal ancestry. Researchers compared the Y chromosome from Beethoven's genome with those of five living men from the Van Beethoven family line, tracing back to their common ancestor, Aert van Beethoven (1535-1609). Surprisingly, the Y chromosomes of the living descendants didn't match Beethoven's or the ones from five authenticated hair samples.

 Based on the strong evidence from these hair samples, the researchers concluded that the most likely explanation is that an extra-pair paternity (EPP) event happened in Beethoven's direct paternal line between 1572 and his birth in 1770. To dig deeper into this EPP scenario and possibly determine Beethoven's true genetic patrilineage, the researchers searched the FamilyTreeDNA Y chromosome database, which has over 52,500 high-resolution user records.

 They found five closely related profiles within the I1a-Z139 lineage (a record in the FamilyTreeDNA database), but all of them had different surnames. This made it impossible to pinpoint Beethoven's direct genetic patrilineage and the surname of the individual involved in the EPP event.

 Furthermore, by conducting principal component analyses (PCAs), researchers were able to place Beethoven's genome among Europeans, showing a strong connection to modern Germans. This comes as no surprise, as Beethoven was born in Bonn, Germany, in 1770.

 To further understand Beethoven's genetic makeup, the researchers used a technique called ADMIXTURE, which analyzes the distribution of genetic ancestry across global populations. The results showed that Beethoven's ancestry was more than 99% European, further confirming his Germanic heritage. In an effort to pinpoint the geographic distribution of Beethoven's ancestors, the study examined the genealogical records of 665 individuals who share long segments of DNA with the composer. The findings revealed a strong clustering of matches along the Rhine River and within present-day North Rhine-Westphalia in Germany. This aligns with the known birthplaces of Beethoven's German ancestors.

Citations

1. Begg et al., Genomic analyses of hair from Ludwig van Beethoven, Current Biology (2023), https://doi.org/10.1016/ j.cub.2023.02.041