The Digital Atlas of Ancient Rare Diseases (DAARD) and its relevance for current research.

BACKGROUND: The history of rare diseases is largely unknown. Research on this topic has focused on individual cases of prominent (historical) individuals and artistic (e.g., iconographic) representations. Medical collections include large numbers of specimens that exhibit signs of rare diseases, but most of them date to relatively recent periods. However, cases of rare diseases detected in mummies and skeletal remains derived from archaeological excavations have also been recorded. Nevertheless, this direct evidence from historical and archaeological contexts is mainly absent from academic discourse and generally not consulted in medical research on rare diseases. RESULTS: This desideratum is addressed by the Digital Atlas of Ancient Rare Diseases (DAARD: https://daard.dainst.org ), which is an open access/open data database and web-based mapping tool that collects evidence of different rare diseases found in skeletons and mummies globally and throughout all historic and prehistoric time periods. This easily searchable database allows queries by diagnosis, the preservation level of human remains, research methodology, place of curation and publications. In this manuscript, the design and functionality of the DAARD are illustrated using examples of achondroplasia and other types of stunted growth. CONCLUSIONS: As an open, collaborative repository for collecting, mapping and querying well-structured medical data on individuals from ancient times, the DAARD opens new avenues of research. Over time, the number of rare diseases will increase through the addition of new cases from varied backgrounds such as museum collections and archaeological excavations. Depending on the research question, phenotypic or genetic information can be retrieved, as well as information on the general occurrence of a rare disease in selected space-time intervals. Furthermore, for individuals diagnosed with a rare disease, this approach can help them to build identity and reveal an aspect of their condition they might not have been aware of. Thus, the DAARD contributes to the understanding of rare diseases from a long-term perspective and adds to the latest medical research.

Testing the Digital Atlas of Ancient Rare Diseases (DAARD) using a new case of Legg-Calvé-Perthes disease from Early Byzantine (500-700 CE) Olympia, Greece.

OBJECTIVE: The first case of Legg-Calvé-Perthes disease (LCPD) in Greece is presented. LCPD, a rare disease, is discussed using the Digital Atlas of Ancient Rare Diseases (DAARD), which tests the benefits of the database for diagnosing and contextualizing the new case with 42 archaeological cases of LCPD recorded in the DAARD. MATERIALS: A 30-40-year-old, probable male individual was found at the archaeological site of Olympia, Greece, dating to 500-700 CE. METHODS: Biological sex, age-at-death and pathological changes were investigated using macroscopic and osteometric methods. The DAARD provided the typical characteristics of LCPD. RESULTS: Pathological changes in both hip joints without any other related changes in the skeleton corresponded to the skeletal features of LCPD. The DAARD produced 42 cases of LCPD, most of which from Europe, with a preference for male sex and unilateral involvement of the hip joint. CONCLUSIONS: The DAARD aids in diagnosing rare diseases and interpreting new cases in the context of already known studies. SIGNIFICANCE: This study shows that the DAARD has the potential to help researchers move beyond the level of single case studies and create a broader picture of the history of rare diseases. LIMITATIONS: This paper focuses on the benefits of the DAARD in relation to LCPD but not all rare diseases have been included in the database. SUGGESTIONS FOR FURTHER RESEARCH: More rare diseases from archaeological contexts should be added to the DAARD to create a base for the interpretation of their history and expand our understanding of rare diseases in the past.

Assessing autosomal aneuploidy in ancient genomes.

Using genetic methods, aneuploidies can be detected in ancient human remains, which is so far the only way to reliably prove their existence in the past. As highlighted in recent studies by Rohrlach et al. and by Anastasiadou et al., this initial step enables a deeper exploration of the history of rare diseases, encompassing the social and historical contexts of the afflicted individuals.

Activity induced worsening of a tuberculous process in the vertebral column of a Late Bronze Age female from Liushui, Xinjiang (China)?

The partial skeleton of a 22-24-year old female from Liushui, Southern Silk Road, Xinjiang (China) was analyzed using morphological and biochemical methods. The most striking finding in this individual of a Late Bronze Age mounted nomadic population was the complete ossification of the caudal vertebral column including parts of the ligaments of this region due to chronic tuberculosis (Pott's disease). The morphological diagnosis is definitely confirmed by the results of the proteomic analysis. The bacterial protein Ag85 and, for the first time in archaeological skeletal remains, also ESAT-6 was detected, which are typical for Mycobacterium tuberculosis. Extremely intense physical stress aggravated the pathological kyphosis primarily caused by the tuberculous process and promoted dislocation of the caudal thoracic versus the lumbar vertebrae. The fate of this young female suffering from tuberculosis and the consequences of this extreme physical stress characterize the harsh living conditions of typical prehistoric population of mounted nomadic pastoralists.

Threads of memory: Reviving the ornament of a dead child at the Neolithic village of Ba`ja (Jordan).

In 2018, a well-constructed cist-type grave was discovered at Ba`ja, a Neolithic village (7,400-6,800 BCE) in Southern Jordan. Underneath multiple grave layers, an 8-year-old child was buried in a fetal position. Over 2,500 beads were found on the chest and neck, along with a double perforated stone pendant and a delicately engraved mother-of-pearl ring discovered among the concentration of beads. The first was found behind the neck, and the second on the chest. The meticulous documentation of the bead distribution indicated that the assemblage was a composite ornament that had gradually collapsed, partly due to the burying position. Our aim was to challenge time degradation and to reimagine the initial composition in order to best explore the significance of this symbolic category of material culture, not as mere group of beads, but as an ornamental creation with further aesthetic, artisanal and socioeconomic implications. The reconstruction results exceeded our expectations as it revealed an imposing multi-row necklace of complex structure and attractive design. Through multiple lines of evidence, we suggest that the necklace was created at Ba`ja, although significant parts of beads were made from exotic shells and stones, including fossil amber, an unprecedented material never attested before for this period. The retrieval of such an ornament from life and its attribution to a young dead child highlights the significant social status of this individual. Beyond the symbolic functions related to identity, the necklace is believed to have played a key role in performing the inhumation rituals, understood as a public event gathering families, relatives, and people from other villages. In this sense, the necklace is not seen as belonging completely to the realm of death but rather to the world of the living, materializing a collective memory and shared moments of emotions and social cohesion.

First osteological evidence of severed hands in Ancient Egypt.

For the first time, the severed right hands of 12 individuals have been analysed osteologically. The hands were deposited in three pits within a courtyard in front of the throne room of a 15th Dynasty (c.1640-1530 BC) Hyksos palace at Avaris/Tell el-Dab'a in north-eastern Egypt. Although this kind of practice is known from tomb or temple inscriptions and reliefs from the New Kingdom onwards, this is the first time that physical evidence has been used to learn more about the procedure and the individuals whose hands were taken. Here, we show that the right hands belonged to at least 12 adults, 11 males, and possibly one female. It is unclear if the hands were taken from dead or living individuals. After removing any attached parts of the forearm, the hands were placed in the ground with wide-splayed fingers, mainly on their palmar sides. The osteological analysis not only supports the archaeological interpretation of this evidence but also adds more detail regarding trophy-taking practices in Ancient Egypt.

Isotopic and DNA analyses reveal multiscale PPNB mobility and migration across Southeastern Anatolia and the Southern Levant.

Growing reliance on animal and plant domestication in the Near East and beyond during the Pre-Pottery Neolithic B (PPNB) (the ninth to eighth millennium BC) has often been associated with a "revolutionary" social transformation from mobility toward more sedentary lifestyles. We are able to yield nuanced insights into the process of the Neolithization in the Near East based on a bioarchaeological approach integrating isotopic and archaeogenetic analyses on the bone remains recovered from Nevali Çori, a site occupied from the early PPNB in Turkey where some of the earliest evidence of animal and plant domestication emerged, and from Ba'ja, a typical late PPNB site in Jordan. In addition, we present the archaeological sequence of Nevali Çori together with newly generated radiocarbon dates. Our results are based on strontium (87Sr/86Sr), carbon, and oxygen (δ18O and δ13Ccarb) isotopic analyses conducted on 28 human and 29 animal individuals from the site of Nevali Çori. 87Sr/86Sr results indicate mobility and connection with the contemporaneous surrounding sites during the earlier PPNB prior to an apparent decline in this mobility at a time of growing reliance on domesticates. Genome-wide data from six human individuals from Nevali Çori and Ba'ja demonstrate a diverse gene pool at Nevali Çori that supports connectedness within the Fertile Crescent during the earlier phases of Neolithization and evidence of consanguineous union in the PPNB Ba'ja and the Iron Age Nevali Çori.

Massive periostosis in a child from Neolithic Gebel es-Silsileh, Egypt.

In 2015 a surprising find of human bone fragments from a child was made in a collection of the Egyptian Museum and Papyrus Collection, Berlin. These bone fragments from Southern Egypt date to 3400-3300 BC and represent the distal parts of both femora and the proximal parts of both tibiae (bones around the knee joint). The bones have a specific appearance, probably indicating a systemic disease. Due to the incomplete state of the skeletal remains, the distribution of the lesions throughout the entire skeleton could not be observed, thus preventing a better diagnosis of the underlying pathological process. The poor collagen preservation of the bone precluded aDNA testing for pathogens. The bone fragments were instead subjected to radiographic and microscopic analysis which revealed a recurrent periosteal process accompanied by a distinct osteoclastic component. A possible diagnosis might be an underlying unknown pathological process, leading to the development of a secondary Hypertrophic Osteoarthropathy (HOA).

A critical review of the anthropological and paleopathological literature on osteopetrosis as an ancient rare disease (ARD).

OBJECTIVE: A reappraisal of the available evidence of osteopetrosis in the archaeological record as first step in promoting new approaches to rare diseases in paleopathology. MATERIALS AND METHODS: Three different approaches are combined: a survey of the last 50 years of bioarchaeological publications; an online search addressing six of the more widely used search engines; macroscopic and radiographic analyses of the human remains from the Neolithic site of Palata 2 (Italy). RESULTS: The combined results of the literature survey and the online search identified six cases of osteopetrosis. The majority of search hits place this disease into differential diagnoses. The investigation of the remains from Palata 2, one of the six cases in literature, indicates a non-specific sclerosis of the cranial vault. CONCLUSIONS: Of the six cases of osteopetrosis, only two, one of the autosomal-recessive type (ARO) and one of the autosomal-dominant type (ADO), are supported by direct osteoarchaeological evidence. Therefore, inaccurate differential diagnoses generate an inflated number of cases in the paleopathological record. SIGNIFICANCE: This reappraisal calls for a more informed and evidence-based approach to osteopetrosis and, more generally, to rare diseases in paleopathology. LIMITATIONS: Lack of specific publications on osteopetrosis; more case studies may be present in "gray literature". SUGGESTIONS FOR FURTHER RESEARCH: Cases of osteopetrosis from archaeological and historical collections as well as medical literature are needed to increase knowledge about this rare disease. More precise differential diagnoses are required, particularly when dealing with rare diseases.

Ancient DNA analysis of rare genetic bone disorders.

OBJECTIVE: Review of the current advancements in the field of paleogenetics that provide new opportunities in studying the evolution of rare genetic bone diseases. MATERIAL AND METHODS: Based on cases from the literature, the genetics of rare bone diseases will be introduced and the main methodological issues will be addressed, focusing on the opportunities presented by the application of aDNA analyses in the field of paleopathology. RESULTS: Medical literature provides large datasets on the genes responsible for rare bone disorders. These genes, subdivided in functional categories, display important future targets when analyzing rare genetic bone disorders in ancient human remains. CONCLUSIONS: Knowledge on both phenotype and genotype is required to study rare diseases in ancient human remains. SIGNIFICANCE: The proposed interdisciplinary research will provide new insight into the occurrence and spread of genetic risk factors in the past and will help in the diagnostics of these rare and often neglected diseases. LIMITATIONS: The current limitations in ancient DNA research and targeting the disease-causing specific mutations (e.g., somatic or germline). SUGGESTIONS FOR FURTHER RESEARCH: Methodological advancements and candidate gene lists provide the optimal basis for future interdisciplinary studies of rare genetic bone disorders in ancient human remains.

How rare is rare? A literature survey of the last 45 years of paleopathological research on ancient rare diseases.

OBJECTIVE: This paper aims to provide a quantitative estimation of the representation of diseases defined as rare today in the bioarchaeological literature and to outline the reasons for this. MATERIALS: A 45-year bibliometric study of publications in seven bioarchaeological journals, along with two journals and editorial groups of broader scientific focus. METHODS: Analyses of distribution patterns of the search hits and diachronic trends for achondroplasia, autosomal-dominant osteopetrosis, osteogenesis imperfecta, and osteopoikilosis, compared to those for tuberculosis as control measure of coverage. RESULTS: Studies of ancient rare diseases (ARD) are mostly published as case reports in specialized journals and their number did not benefit from the introduction of biomolecular studies. The higher frequency of cases of achondroplasia suggests that not all rare diseases are equally under-represented. CONCLUSIONS: Rare diseases are still largely under-represented in bioarchaeological literature. Their marginality likely results from a combination of taphonomic, methodological and public visibility factors. SIGNIFICANCE: This article is the first attempt to provide a quantitative assessment of the under-representation of ARD and to outline the factors behind it. LIMITATIONS: Rare diseases are an etiologically heterogeneous group. The number of surveyed journals and articles, as well as targeted diseases might be limiting factors. SUGGESTIONS FOR FURTHER RESEARCH: Increasing collection and dissemination of data on ARD; opening a wide-ranging debate on their definition; implementation of biomolecular studies.

Towards a definition of Ancient Rare Diseases (ARD): Presenting a complex case of probable Legg-Calvé-Perthes Disease from the North Caucasian Bronze Age (2200-1650 cal BCE).

OBJECTIVE: This study discusses the challenges and possibilities of establishing a definition for Ancient Rare Diseases (ARD) in a probable case of Legg-Calvé-Perthes Disease (LCPD) from the Bronze Age cemetery Kudachurt 14, situated in the Northern Caucasus. MATERIALS: We investigated the skeletal remains of a male aged 35-45 years at death. For comparison we examined other males buried at Kudachurt 14 (n = 24) and reviewed 22 LCPD cases from the paleopathological literature. METHODS: We use macroscopic as well as osteometric examination methods and imaging techniques. RESULTS: The morphology of the left hip joint corresponds to skeletal characteristics for LCPD. Co-occurring osteochondrosis dissecans, femoral anteversion, and atrophy of the left femoral shaft suggest a complex disease course. CONCLUSIONS: Modern criteria of rare diseases applied on ancient skeletal remains are either non-transferable or require completion. We conclude that rarity is dynamic, etiological uncertainty has to be accepted, and the respective socioeconomic context is crucial. Degree of disability and level of sociomedical investment are not defining criteria for ARD. SIGNIFICANCE: Dating 2200-1650 cal BCE, this study currently presents the earliest case of probable LCPD. This is the first attempt to transform modern characteristics of rare diseases for establishing a paleopathological concept of ARD. LIMITATIONS: As this study is limited to LCPD, our conclusions are not directly applicable to other ARD in question. SUGGESTIONS FOR FURTHER RESEARCH: More focused paleopathological research on skeletal populations from different cultures and time periods is needed, enabling an evolutionary perspective on the comparability of ancient, modern and future rare diseases.

Fibro-osseous processes (FOPs) of the craniofacial skeleton: A neglected entity in paleopathology?

Discrete, small, roundish lesions of localized porous bone can be occasionally seen in the craniofacial skeleton. Such lesions are rarely mentioned and only occur as an incidental discovery being assigned to plenty of diagnoses. As an example, such multiple small lesions of the facial skeleton in a well-preserved skeleton of a 40-60 year old male of the Hunno-Sarmatian Period from Kazakhstan, are discussed. Some of the lesions were examined by digital microscopy, plain radiography, and plain and polarizing microscopy. Considering possible differential diagnoses of vascular, traumatic, inflammatory/reactive, metabolic, and neoplastic entities, as well as developmental conditions, its microscopic characteristics point to a fibro-osseous process. This paper intends to open a discussion on the diagnosis of such lesions, which have been relatively neglected in previous research.

Diet and subsistence in Bronze Age pastoral communities from the southern Russian steppes and the North Caucasus.

The flanks of the Caucasus Mountains and the steppe landscape to their north offered highly productive grasslands for Bronze Age herders and their flocks of sheep, goat, and cattle. While the archaeological evidence points to a largely pastoral lifestyle, knowledge regarding the general composition of human diets and their variation across landscapes and during the different phases of the Bronze Age is still restricted. Human and animal skeletal remains from the burial mounds that dominate the archaeological landscape and their stable isotope compositions are major sources of dietary information. Here, we present stable carbon and nitrogen isotope data of bone collagen of 105 human and 50 animal individuals from the 5th millennium BC to the Sarmatian period, with a strong focus on the Bronze Age and its cultural units including Maykop, Yamnaya, Novotitorovskaya, North Caucasian, Catacomb, post-Catacomb and late Bronze Age groups. The samples comprise all inhumations with sufficient bone preservation from five burial mound sites and a flat grave cemetery as well as subsamples from three further sites. They represent the Caucasus Mountains in the south, the piedmont zone and Kuban steppe with humid steppe and forest vegetation to its north, and more arid regions in the Caspian steppe. The stable isotope compositions of the bone collagen of humans and animals varied across the study area and reflect regional diversity in environmental conditions and diets. The data agree with meat, milk, and/or dairy products from domesticated herbivores, especially from sheep and goats having contributed substantially to human diets, as it is common for a largely pastoral economy. This observation is also in correspondence with the faunal remains observed in the graves and offerings of animals in the mound shells. In addition, foodstuffs with elevated carbon and nitrogen isotope values, such as meat of unweaned animals, fish, or plants, also contributed to human diets, especially among communities living in the more arid landscapes. The regional distinction of the animal and human data with few outliers points to mobility radii that were largely concentrated within the environmental zones in which the respective sites are located. In general, dietary variation among the cultural entities as well as regarding age, sex and archaeologically indicated social status is only weakly reflected. There is, however, some indication for a dietary shift during the Early Bronze Age Maykop period.

Burying power: New insights into incipient leadership in the Late Pre-Pottery Neolithic from an outstanding burial at Ba'ja, southern Jordan.

In 2016, an extraordinary burial of a young adult individual was discovered at the Late Pre-Pottery Neolithic B (LPPNB, 7,500-6,900 BCE) settlement of Ba'ja in southern Jordan. This burial has exceptional grave goods and an elaborate grave construction. It suggests discussing anew reconstructions of early Neolithic social structures. In this article, we will summarize former theories on the emergence of leadership and hierarchies and present a multivariate model according to which anthropological and archaeological data of the burial will be analyzed. In conclusion, we surmise that early Neolithic hierarchization in southern Jordan was based on corporate pathways to power rather than self-interested aggrandizers. However, some aspects of the burial point to regional exchange networks of prestige goods, a trait considered characteristic of network based leadership. In line with anthropological and sociological research, we argue that pathways to power should be considered as relational processes that can be understood only when comparing traits of the outstanding person to her/his social environment.

Late Pleistocene human genome suggests a local origin for the first farmers of central Anatolia.

Anatolia was home to some of the earliest farming communities. It has been long debated whether a migration of farming groups introduced agriculture to central Anatolia. Here, we report the first genome-wide data from a 15,000-year-old Anatolian hunter-gatherer and from seven Anatolian and Levantine early farmers. We find high genetic continuity (~80-90%) between the hunter-gatherers and early farmers of Anatolia and detect two distinct incoming ancestries: an early Iranian/Caucasus related one and a later one linked to the ancient Levant. Finally, we observe a genetic link between southern Europe and the Near East predating 15,000 years ago. Our results suggest a limited role of human migration in the emergence of agriculture in central Anatolia.

Ancient human genome-wide data from a 3000-year interval in the Caucasus corresponds with eco-geographic regions.

Archaeogenetic studies have described the formation of Eurasian 'steppe ancestry' as a mixture of Eastern and Caucasus hunter-gatherers. However, it remains unclear when and where this ancestry arose and whether it was related to a horizon of cultural innovations in the 4th millennium BCE that subsequently facilitated the advance of pastoral societies in Eurasia. Here we generated genome-wide SNP data from 45 prehistoric individuals along a 3000-year temporal transect in the North Caucasus. We observe a genetic separation between the groups of the Caucasus and those of the adjacent steppe. The northern Caucasus groups are genetically similar to contemporaneous populations south of it, suggesting human movement across the mountain range during the Bronze Age. The steppe groups from Yamnaya and subsequent pastoralist cultures show evidence for previously undetected farmer-related ancestry from different contact zones, while Steppe Maykop individuals harbour additional Upper Palaeolithic Siberian and Native American related ancestry.

Language continuity despite population replacement in Remote Oceania.

Recent genomic analyses show that the earliest peoples reaching Remote Oceania-associated with Austronesian-speaking Lapita culture-were almost completely East Asian, without detectable Papuan ancestry. However, Papuan-related genetic ancestry is found across present-day Pacific populations, indicating that peoples from Near Oceania have played a significant, but largely unknown, ancestral role. Here, new genome-wide data from 19 ancient South Pacific individuals provide direct evidence of a so-far undescribed Papuan expansion into Remote Oceania starting ~2,500 yr BP, far earlier than previously estimated and supporting a model from historical linguistics. New genome-wide data from 27 contemporary ni-Vanuatu demonstrate a subsequent and almost complete replacement of Lapita-Austronesian by Near Oceanian ancestry. Despite this massive demographic change, incoming Papuan languages did not replace Austronesian languages. Population replacement with language continuity is extremely rare-if not unprecedented-in human history. Our analyses show that rather than one large-scale event, the process was incremental and complex, with repeated migrations and sex-biased admixture with peoples from the Bismarck Archipelago.

Benign fibro-osseous lesion of the mandible in a Middle Bronze Age skeleton from Southern Russia.

A discrete dysplastic lesion of the mandible found in a skeleton of a young adult male of the Middle Bronze Age in the Northern Caucasus/Russia is described. The periapical lesion of the right lower canine alveolus was examined by digital microscopy, plain radiology, and plain and polarizing microscopy. Its macroscopic, radiologic and microscopic characteristics are discussed in reference to different fibro-osseous lesions arising from the odontogenic apparatus and maxillofacial skeleton. Periapical osseous dysplasia was considered to be the most likely diagnosis.