Daniel Fernandes preparing to take a sample
Photo Credit: ©Adrian Daly
Scientific Frontline: Extended "At a Glance" Summary
The Core Concept: Researchers have successfully performed the earliest known genetic diagnosis in humans, identifying a rare inherited growth disorder called acromesomelic dysplasia in a 12,000-year-old skeleton found in Italy.
Key Distinction/Mechanism: While traditional archaeology often relies on skeletal measurements to infer health conditions, this study utilized ancient DNA (aDNA) sequencing to pinpoint specific mutations. By extracting DNA from the petrous part of the temporal bone, scientists identified a homozygous mutation in the NPR2 gene responsible for the severe short stature in the daughter, and a heterozygous mutation in the mother, which caused a milder form of the condition.
Origin/History: The skeletal remains were originally excavated in 1963 at the Grotta del Romito in southern Italy and date back to the Upper Paleolithic period (over 12,000 years ago).
Major Frameworks/Components:
- Ancient DNA (aDNA) Analysis: Extraction and sequencing of genetic material from prehistoric bone samples.
- Targeted Gene Screening: Focusing specifically on genes known to influence skeletal growth, such as NPR2.
- Comparative Clinical Genetics: Cross-referencing ancient genetic variants with modern medical databases to confirm diagnoses.
Branch of Science: Paleogenomics, Clinical Genetics, Evolutionary Anthropology, and Physical Anthropology.
Future Application: This methodology paves the way for reconstructing the medical history of ancient populations, diagnosing other rare diseases in the archaeological record, and understanding the evolutionary timeline of specific genetic mutations.
Why It Matters: This discovery proves that rare genetic diseases are not exclusively modern phenomena but have persisted throughout human history. Furthermore, the survival of the severely disabled individual into adulthood provides profound evidence of social care and community support in prehistoric hunter-gatherer societies.
Researchers led by the University of Vienna and Liège University Hospital Centre have identified genetic variants associated with a rare inherited growth disorder in two prehistoric individuals who lived more than 12,000 years ago. Using ancient DNA analysis and modern clinical genetics, they diagnosed the condition in a mother and daughter buried together in southern Italy. Published in the New England Journal of Medicine, the study shows that paleogenomics can now reconstruct ancient population history and diagnose rare genetic diseases in prehistoric individuals.
The discovery builds on a reanalysis of a well-known Upper Paleolithic burial discovered in 1963 at Grotta del Romito in southern Italy, which has long puzzled researchers. Unusual skeletal features and the circumstances of the burial raised longstanding questions about the relationship between the individuals and the medical reasons for their short stature.
A remarkable double burial raises questions
The two were interred together in an embrace. "Romito 2", an adolescent with pronounced limb shortening, previously assumed to be male, lay in the arms of "Romito 1", thought to be an adult female. No signs of trauma were observed. Romito 2 had an estimated height of about 110 cm, consistent with a rare skeletal growth disorder known as acromesomelic dysplasia, though this could not be confirmed solely from bones. Romito 1 was also shorter – about 145 cm –than average for the period. For decades, researchers debated their gender, relationship, and the possibility of a common cause of their short stature.
The team analyzed ancient DNA extracted from the petrous part of the temporal bone of both individuals, a region known for preserving genetic material well. Genetic analysis established a first-degree relationship. The researchers then screened genes associated with skeletal growth and compared the identified variants with modern clinical data. This interdisciplinary approach, combining paleogenomics, clinical genetics, and physical anthropology, involved an international team from the University of Vienna and collaborators in Italy, Portugal, and Belgium.
Earliest genetic diagnosis in humans
The analysis showed that both individuals were female and first-degree relatives, most likely a mother and daughter. In Romito 2, researchers identified a homozygous variant in the NPR2 gene, which is essential for bone growth. This confirmed a diagnosis of acromesomelic dysplasia, Maroteaux type — a very rare inherited disorder characterized by severe short stature and marked shortening of the limbs. Genetic data from Romito 1 indicates that she carried one altered copy of the same gene, a condition associated with milder short stature.
Rare diseases in human history
Ron Pinhasi, University of Vienna, who co-led the study says: "By applying ancient DNA analysis, we can now identify specific mutations in prehistoric individuals. This helps establish how far back rare genetic conditions existed and may also uncover previously unknown variants." Daniel Fernandes of the University of Coimbra, first author of the study, adds: "Identifying both individuals as female and closely related turns this burial into a familial genetic case. The older woman's milder short stature likely reflects a heterozygous mutation, showing how the same gene affected members of a prehistoric family differently." Clinically, the results highlight the deep history of rare diseases. Adrian Daly of Liège University Hospital Centre, a co-leader of the study, notes: "Rare genetic diseases are not a modern phenomenon but have been present throughout human history. Understanding their history may help recognizing such conditions today."
Evidence of social care
Despite severe physical limitations, Romito 2 survived into adolescence or adulthood, suggesting sustained care within her community. Alfredo Coppa of Sapienza University of Rome, who also co-led the study, says: "We believe her survival would have required sustained supp
Published in journal: New England Journal of Medicine
Title: A 12,000-Year-Old Case of NPR2-Related Acromesomelic Dysplasia
Authors: Daniel M. Fernandes, Alejandro Llanos-Lizcano, Florian Brück, Kadir T. Özdoğan, Olivia Cheronet, Michaela Lucci, Albert Beckers, Patrick Pétrossians, Alfredo Coppa, Ron Pinhasi, and Adrian F. Daly
Source/Credit: Universität Wien
Reference Number: anth012926_01
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