Ancient genomes reveal origin and rapid trans-Eurasian migration of 7th century Avar elites.

The Avars settled the Carpathian Basin in 567/68 CE, establishing an empire lasting over 200 years. Who they were and where they came from is highly debated. Contemporaries have disagreed about whether they were, as they claimed, the direct successors of the Mongolian Steppe Rouran empire that was destroyed by the Turks in ∼550 CE. Here, we analyze new genome-wide data from 66 pre-Avar and Avar-period Carpathian Basin individuals, including the 8 richest Avar-period burials and further elite sites from Avar's empire core region. Our results provide support for a rapid long-distance trans-Eurasian migration of Avar-period elites. These individuals carried Northeast Asian ancestry matching the profile of preceding Mongolian Steppe populations, particularly a genome available from the Rouran period. Some of the later elite individuals carried an additional non-local ancestry component broadly matching the steppe, which could point to a later migration or reflect greater genetic diversity within the initial migrant population.

Network of large pedigrees reveals social practices of Avar communities.

From AD 567-568, at the onset of the Avar period, populations from the Eurasian Steppe settled in the Carpathian Basin for approximately 250 years1. Extensive sampling for archaeogenomics (424 individuals) and isotopes, combined with archaeological, anthropological and historical contextualization of four Avar-period cemeteries, allowed for a detailed description of the genomic structure of these communities and their kinship and social practices. We present a set of large pedigrees, reconstructed using ancient DNA, spanning nine generations and comprising around 300 individuals. We uncover a strict patrilineal kinship system, in which patrilocality and female exogamy were the norm and multiple reproductive partnering and levirate unions were common. The absence of consanguinity indicates that this society maintained a detailed memory of ancestry over generations. These kinship practices correspond with previous evidence from historical sources and anthropological research on Eurasian Steppe societies2. Network analyses of identity-by-descent DNA connections suggest that social cohesion between communities was maintained via female exogamy. Finally, despite the absence of major ancestry shifts, the level of resolution of our analyses allowed us to detect genetic discontinuity caused by the replacement of a community at one of the sites. This was paralleled with changes in the archaeological record and was probably a result of local political realignment.

The origins and spread of domestic horses from the Western Eurasian steppes.

Domestication of horses fundamentally transformed long-range mobility and warfare1. However, modern domesticated breeds do not descend from the earliest domestic horse lineage associated with archaeological evidence of bridling, milking and corralling2-4 at Botai, Central Asia around 3500 BC3. Other longstanding candidate regions for horse domestication, such as Iberia5 and Anatolia6, have also recently been challenged. Thus, the genetic, geographic and temporal origins of modern domestic horses have remained unknown. Here we pinpoint the Western Eurasian steppes, especially the lower Volga-Don region, as the homeland of modern domestic horses. Furthermore, we map the population changes accompanying domestication from 273 ancient horse genomes. This reveals that modern domestic horses ultimately replaced almost all other local populations as they expanded rapidly across Eurasia from about 2000 BC, synchronously with equestrian material culture, including Sintashta spoke-wheeled chariots. We find that equestrianism involved strong selection for critical locomotor and behavioural adaptations at the GSDMC and ZFPM1 genes. Our results reject the commonly held association7 between horseback riding and the massive expansion of Yamnaya steppe pastoralists into Europe around 3000 BC8,9 driving the spread of Indo-European languages10. This contrasts with the scenario in Asia where Indo-Iranian languages, chariots and horses spread together, following the early second millennium BC Sintashta culture11,12.

Interdisciplinary Analyses of Bronze Age Communities from Western Hungary Reveal Complex Population Histories.

In this study, we report 21 ancient shotgun genomes from present-day Western Hungary, from previously understudied Late Copper Age Baden, and Bronze Age Somogyvár-Vinkovci, Kisapostag, and Encrusted Pottery archeological cultures (3,530-1,620 cal Bce). Our results indicate the presence of high steppe ancestry in the Somogyvár-Vinkovci culture. They were then replaced by the Kisapostag group, who exhibit an outstandingly high (up to ∼47%) Mesolithic hunter-gatherer ancestry, despite this component being thought to be highly diluted by the time of the Early Bronze Age. The Kisapostag population contributed the genetic basis for the succeeding community of the Encrusted Pottery culture. We also found an elevated hunter-gatherer component in a local Baden culture-associated individual, but no connections were proven to the Bronze Age individuals. The hunter-gatherer ancestry in Kisapostag is likely derived from two main sources, one from a Funnelbeaker or Globular Amphora culture-related population and one from a previously unrecognized source in Eastern Europe. We show that this ancestry not only appeared in various groups in Bronze Age Central Europe but also made contributions to Baltic populations. The social structure of Kisapostag and Encrusted Pottery cultures is patrilocal, similarly to most contemporaneous groups. Furthermore, we developed new methods and method standards for computational analyses of ancient DNA, implemented to our newly developed and freely available bioinformatic package. By analyzing clinical traits, we found carriers of aneuploidy and inheritable genetic diseases. Finally, based on genetic and anthropological data, we present here the first female facial reconstruction from the Bronze Age Carpathian Basin.

Tracing genetic connections of ancient Hungarians to the 6th-14th century populations of the Volga-Ural region.

Most of the early Hungarian tribes originated from the Volga-Kama and South-Ural regions, where they were composed of a mixed population based on historical, philological and archaeological data. We present here the uniparental genetic makeup of the mediaeval era of these regions that served as a melting pot for ethnic groups with different linguistic and historical backgrounds. Representing diverse cultural contexts, the new genetic data originate from ancient proto-Ob-Ugric people from Western Siberia (6th-13th century), the pre-Conquest period and subsisting Hungarians from the Volga-Ural region (6th-14th century) and their neighbours. By examining the eastern archaeology traits of Hungarian prehistory, we also study their genetic composition and origin in an interdisciplinary framework. We analyzed 110 deep-sequenced mitogenomes and 42 Y-chromosome haplotypes from 18 archaeological sites in Russia. The results support the studied groups' genetic relationships regardless of geographical distances, suggesting large-scale mobility. We detected long-lasting genetic connections between the sites representing the Kushnarenkovo and Chiyalik cultures and the Carpathian Basin Hungarians and confirmed the Uralic transmission of several East Eurasian uniparental lineages in their gene pool. Based on phylogenetics, we demonstrate and model the connections and splits of the studied Volga-Ural and conqueror groups. Early Hungarians and their alliances conquered the Carpathian Basin around 890 AD. Re-analysis of the Hungarian conquerors' maternal gene pool reveals numerous surviving maternal relationships in both sexes; therefore, we conclude that men and women came to the Carpathian Basin together, and although they were subsequently genetically fused into the local population, certain eastern lineages survived for centuries.

A comprehensive review of HVS-I mitochondrial DNA variation of 19 Iranian populations.

Iran is located along the Central Asian corridor, a natural artery that has served as a cross-continental route since the first anatomically modern human populations migrated out of Africa. We compiled and reanalyzed the HVS-I (hypervariable segment-I) of 3840 mitochondrial DNA (mtDNA) sequences from 19 Iranian populations and from 26 groups from adjacent countries to give a comprehensive review of the maternal genetic variation and investigate the impact of historical events and cultural factors on the maternal genetic structure of modern Iranians. We conclude that Iranians have a high level of genetic diversity. Thirty-six haplogroups were observed in Iran's populations, and most of them belong to widespread West-Eurasian haplogroups, such as H, HV, J, N, T, and U. In contrast, the predominant haplogroups observed in most of the adjacent countries studied here are H, M, D, R, U, and C haplogroups. Using principal component analysis, clustering, and genetic distance-based calculations, we estimated moderate genetic relationships between Iranian and other Eurasian groups. Further, analyses of molecular variance and comparing geographic and genetic structures indicate that mtDNA HVS-I sequence diversity does not exhibit any sharp geographic structure in the country. Barring a few from some culturally distinct and naturally separated minorities, most Iranian populations have a homogenous maternal genetic structure.

The genomic history of southeastern Europe.

Farming was first introduced to Europe in the mid-seventh millennium bc, and was associated with migrants from Anatolia who settled in the southeast before spreading throughout Europe. Here, to understand the dynamics of this process, we analysed genome-wide ancient DNA data from 225 individuals who lived in southeastern Europe and surrounding regions between 12000 and 500 bc. We document a west-east cline of ancestry in indigenous hunter-gatherers and, in eastern Europe, the early stages in the formation of Bronze Age steppe ancestry. We show that the first farmers of northern and western Europe dispersed through southeastern Europe with limited hunter-gatherer admixture, but that some early groups in the southeast mixed extensively with hunter-gatherers without the sex-biased admixture that prevailed later in the north and west. We also show that southeastern Europe continued to be a nexus between east and west after the arrival of farmers, with intermittent genetic contact with steppe populations occurring up to 2,000 years earlier than the migrations from the steppe that ultimately replaced much of the population of northern Europe.

The Beaker phenomenon and the genomic transformation of northwest Europe.

From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.

Erratum: The Beaker phenomenon and the genomic transformation of northwest Europe.

This corrects the article DOI: 10.1038/nature25738.

Parallel palaeogenomic transects reveal complex genetic history of early European farmers.

Ancient DNA studies have established that Neolithic European populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Here we investigate the population dynamics of Neolithization across Europe using a high-resolution genome-wide ancient DNA dataset with a total of 180 samples, of which 130 are newly reported here, from the Neolithic and Chalcolithic periods of Hungary (6000-2900 bc, n = 100), Germany (5500-3000 bc, n = 42) and Spain (5500-2200 bc, n = 38). We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways in which gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modelling approaches to elucidate multiple dimensions of historical population interactions.

West Nile virus infections in Hungary: Epidemiological update and phylogenetic analysis of the Hungarian virus strains between 2015 and 2022.

Following the introduction of the West Nile virus (WNV) into Hungary in 2004, it has shortly become one of the most important human arbovirus infections, with a gradually increasing number of cases. The study aimed to summarize the current epidemiological situation in Hungary and sequence the WNV PCR-positive clinical specimens and virus isolates by next-generation whole genome sequencing (NGS) to obtain a detailed phylogenetic analysis of the circulating virus strains. Whole blood and urine samples from confirmed WNV-infected patients and WNV isolates were investigated by reverse transcription PCR assays. Genome sequencing was carried out by Sanger-method, followed by NGS on the Illumina MiSeq platform. Altogether 499 human infections were diagnosed between 2004 and 2022. A particularly remarkable increase in human WNV infections was observed in 2018, while the number of reported cases significantly decreased during the COVID-19 pandemic. Between 2015 and 2022, 15 WNV isolates, and 10 PCR-positive clinical specimens were investigated by NGS. Phylogenetic analysis revealed that the major European WNV lineage 2 clades, namely the Eastern European (or Russian) and the Central European (or Hungarian) clades, are presented in Hungary. Strains of the Balkan and other European clusters within the Central European clade are co-circulating in the country, following a characteristic geographical distribution. In Hungary, the presence and co-circulation of multiple lineage 2 WNV strains could be identified in the last few years. Therefore, in light of the 2018 WNV outbreak, sequence-based typing of the currently circulating strains could highly support outbreak investigations.

Comparison of Follicular Helper T-Cell Markers with the Expression of the Follicular Homing Marker CXCR5 in Peripheral T-Cell Lymphomas-A Reappraisal of Follicular Helper T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) expressing multiple follicular T helper (TFH) cell-related antigens are now classified as TFH lymphomas (TFHL), including angioimmunoblastic, follicular, and not otherwise specified (NOS) types. CXCR5 is the TFH cell-defining chemokine receptor that, together with its ligand CXCL13, plays a critical role in the development of follicles and the positioning of TFH and B cells within follicles. A comprehensive immunomorphologic study was performed to investigate the expression pattern of CXCR5 in a large cohort of nodal PTCLs, particularly those with a TFH cell phenotype, and to compare its expression with six other TFH cell-related antigens. We found that CXCR5 is widely expressed in neoplastic TFH cells, except in TFHL-NOS, and represents a specific marker of this lymphoma entity. Our results suggest that CXCR5 directs the distribution of neoplastic T cells in the affected lymph nodes and may influence the formation of the pathognomic pathological FDC network.

The effect of pH adjusted electrolytes on capillary isoelectric focusing assessed by high-resolution dynamic computer simulation.

The effect of the composition of electrolytes on capillary IEF is assessed for systems with carrier ampholytes covering two pH units and with catholytes of decreased pH, anolytes of increased pH, and both electrode solutions with adjusted pH values. For electrolytes composed of formic acid as anolyte and ammonium hydroxide as catholyte, simulation is demonstrated to provide the expected IEF system in which analytes with pI values within the formed pH gradient are focused and become immobile. Addition of formic acid to the catholyte results in the formation of an isotachophoretic zone structure that migrates toward the cathode. With ammonium hydroxide added to the anolyte migration occurs toward the anode. In the two cases, all carrier components and amphoteric analytes migrate isotachophoretically as cations or anions, respectively. The data reveal that millimolar amounts of a counter ion are sufficient to convert an IEF pattern into an ITP system. With increasing amounts of the added counter ion, the overall length of the migrating zone structure shrinks, the range of the pH gradient changes, and the migration rate increases. The studied examples indicate that systems of this type reported in the literature should be classified as ITP and not IEF. When both electrolytes are titrated, a non-uniform background electrolyte composed of formic acid and ammonium hydroxide is established in which analytes migrate according to local pH and conductivity without forming IEF or ITP zone structures. Simulation data are in qualitative agreement with previously published experimental data.

Clinical Trial-Ready Patient Cohorts for Multiple System Atrophy: Coupling Biospecimen and iPSC Banking to Longitudinal Deep-Phenotyping.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease of unknown etiology characterized by widespread aggregation of the protein alpha-synuclein in neurons and glia. Its orphan status, biological relationship to Parkinson's disease (PD), and rapid progression have sparked interest in drug development. One significant obstacle to therapeutics is disease heterogeneity. Here, we share our process of developing a clinical trial-ready cohort of MSA patients (69 patients in 2 years) within an outpatient clinical setting, and recruiting 20 of these patients into a longitudinal "n-of-few" clinical trial paradigm. First, we deeply phenotype our patients with clinical scales (UMSARS, BARS, MoCA, NMSS, and UPSIT) and tests designed to establish early differential diagnosis (including volumetric MRI, FDG-PET, MIBG scan, polysomnography, genetic testing, autonomic function tests, skin biopsy) or disease activity (PBR06-TSPO). Second, we longitudinally collect biospecimens (blood, CSF, stool) and clinical, biometric, and imaging data to generate antecedent disease-progression scores. Third, in our Mass General Brigham SCiN study (stem cells in neurodegeneration), we generate induced pluripotent stem cell (iPSC) models from our patients, matched to biospecimens, including postmortem brain. We present 38 iPSC lines derived from MSA patients and relevant disease controls (spinocerebellar ataxia and PD, including alpha-synuclein triplication cases), 22 matched to whole-genome sequenced postmortem brain. iPSC models may facilitate matching patients to appropriate therapies, particularly in heterogeneous diseases for which patient-specific biology may elude animal models. We anticipate that deeply phenotyped and genotyped patient cohorts matched to cellular models will increase the likelihood of success in clinical trials for MSA.

Identifying risks for severity of neurological symptoms in Hungarian West Nile virus patients.

BACKGROUND: West Nile virus (WNV) infections have become increasingly prevalent in certain European countries, including Hungary. Although most human infections do not cause severe symptoms, in approximately 1% of cases WNV infections can lead to severe WNV neuroinvasive disease (WNND) and death. The goal of our study was to assess the neurological status changes of WNV -infected patients admitted to inpatient care and to identify potential risk factors as underlying reasons for severe neurological outcome. METHODS: We conducted a retrospective chart review of 66 WNV-infected patients from four Hungarian medical centers. Patients' neurological status at hospital admission and at two follow-up intervals (1st follow-up, within 60-90 days and 2nd follow-up, within 150-180 days, after hospital discharge) were assessed. All of the 66 patients in the initial sample had some type of neurological symptoms and 56 patients were diagnosed with WNND. The modified Rankin Scale (mRS) and the West Nile Virus Neurological Index (WNV-N Index), a scoring system designed for the purpose of this study, were used for neurological status assessment. Patients were dichotomized into two categories, "moderately severe" and "severe" based on their neurological status. Descriptive analysis for sample description, stratified analysis for calculation of odds ratio (OR) and logistic regression for continuous input variables, were performed. RESULTS: The average number of days between the onset of neurological symptoms and hospital admission (the neurological symptom interval) was 6.01 days. Complications during the hospital stay arose in almost a fifth of the patients (18.2%) and 5 patients died. Each day's increase in the neurological symptom interval significantly increased the risk for developing a severe neurological status following hospital admission (0.799-fold and 0.688-fold, based on the WNV-N Index and mRS, respectively). Patients' age, comorbidity, presence of complications and symptoms of malaise, and gait uncertainty were shown to be independent risk factors for severe neurological status. CONCLUSIONS: Timely hospital admission of patients with neurological symptoms as well as risk assessment by clinicians - possibly with an optimal assessment tool for estimating neurological status- could improve the neurological outcome of WNV-infected patients.

Massive migration from the steppe was a source for Indo-European languages in Europe.

We generated genome-wide data from 69 Europeans who lived between 8,000-3,000 years ago by enriching ancient DNA libraries for a target set of almost 400,000 polymorphisms. Enrichment of these positions decreases the sequencing required for genome-wide ancient DNA analysis by a median of around 250-fold, allowing us to study an order of magnitude more individuals than previous studies and to obtain new insights about the past. We show that the populations of Western and Far Eastern Europe followed opposite trajectories between 8,000-5,000 years ago. At the beginning of the Neolithic period in Europe, ∼8,000-7,000 years ago, closely related groups of early farmers appeared in Germany, Hungary and Spain, different from indigenous hunter-gatherers, whereas Russia was inhabited by a distinctive population of hunter-gatherers with high affinity to a ∼24,000-year-old Siberian. By ∼6,000-5,000 years ago, farmers throughout much of Europe had more hunter-gatherer ancestry than their predecessors, but in Russia, the Yamnaya steppe herders of this time were descended not only from the preceding eastern European hunter-gatherers, but also from a population of Near Eastern ancestry. Western and Eastern Europe came into contact ∼4,500 years ago, as the Late Neolithic Corded Ware people from Germany traced ∼75% of their ancestry to the Yamnaya, documenting a massive migration into the heartland of Europe from its eastern periphery. This steppe ancestry persisted in all sampled central Europeans until at least ∼3,000 years ago, and is ubiquitous in present-day Europeans. These results provide support for a steppe origin of at least some of the Indo-European languages of Europe.

Characterisation of the cerebrospinal fluid of horses with West Nile virus neuroinvasive disease.

West Nile virus (WNV) is a zoonotic arbovirus transmitted by mosquitoes between wild birds (natural hosts) and other vertebrates. Horses and humans are incidental, dead-end hosts, but can develop severe neurological disorders. Owing to the close contact of cerebrospinal fluid (CSF) with the extracellular fluid of the brain, the analysis of CSF composition can reflect central nervous system (CNS) impairments enabling the diagnosis and understanding of various neurodegenerative CNS disorders. Our objective was to compare the findings from the CSF samples of horses with neuroinvasive WNV infection with those of healthy controls. We compared findings from fifteen CSF samples of 13 horses with acute WNV encephalomyelitis with those of 20 healthy controls. Protein, particular enzymes and ions, glucose and lactate showed abnormal levels in a significant number of WNV cases. None of the six horses with elevated glucose concentrations survived. Rather neutrophilic than mononuclear pleocytosis was identified with WNV infection. Neutrophils probably play a role in the development of inflammatory response and brain damage. Although elevated glucose levels reliably predicted the outcome, they might be the consequence of increased plasma levels and reflect general stress rather than CNS pathophysiology. The CSF findings of WNV encephalomyelitis patients are non-specific and variable but facilitate the differential diagnosis.

Neuropsychiatric aspects of Parkinson's disease.

Throughout the natural history of Parkinson's Disease (PD), from the pre-diagnostic phase to end stage disease, neuropsychiatric manifestations represent a core feature of the disease. This review summarises current knowledge on the features of depression, anxiety, apathy, fatigue, impulse control disorders (ICDs) and psychosis in PD. These co-morbidities are common and still frequently under-recognised. Their impact on quality of life is considerable, with depression having been shown to be the main determinant of health-related quality of life in PD patients. As well as formal diagnostic criteria, multiple scales have been developed to allow for assessment of these symptoms in both the clinic and research settings. The evidence base for treatment is variable, with increasing evidence for pharmacological and non-pharmacological treatment options for depression, but less robust evidence for the treatment of other neuropsychiatric features. Imaging studies are increasingly providing insight into the neural basis of these symptoms, with the hope that this insight will translate into treatments that can benefit patients.

Imported Zika virus infections in Hungary between 2016 and 2018.

Zika virus is a mosquito-borne flavivirus with significant public health concern due to its association with neurological symptoms and intrauterine malformations. Although it is endemic in tropical and subtropical areas, sexual transmission raises the possibility of autochthonous spreading elsewhere. We describe the first laboratory diagnosed imported Zika-infections of Hungary, to highlight the challenges of microbiological identification of the pathogen, caused by serological cross-reactivity and short viremia. Serological examination was carried out using indirect immunofluorescent assay and enzyme-linked immunosorbent assay. Plaque-reduction neutralization test was used for verification purposes. A wide range of clinical specimens: serum, whole-blood, urine, saliva, and semen were analyzed by molecular methods, and sequencing was applied in case of PCR positive results to identify the virus strain. Zika-infected patients with previous vaccination against flaviviruses or possible flavivirus infection in the past showed high serological cross-reactivity, and even cross-neutralizing antibodies were observed. Zika virus RNA could be detected in urine specimen in case of two patients, and in EDTA-anticoagulated whole-blood sample of one patient. The detected strains belong to the Asian lineage of the virus. We presume that serological investigation of imported Zika virus could be altered by infections, vaccination of endemic flaviviruses in Hungary and vice versa.