Uveal melanoma (UM) is a rare but frequently metastasizing cancer. Genome-wide association studies have identified three common genome-wide significant germline risk loci. Here, we perform a genome-wide association study on 401 new cases and conduct a meta-analysis with three independent previously published cohorts for a total sample size of 2,426 cases. We confirm the three previously identified risk loci and identify four additional genome-wide significant loci. We find that eye pigmentation-decreasing variants are systematically associated with increased UM risk and that selection for lighter pigmentation in the past 5,000 years explains about 73% of the difference in UM incidence between Northern and Southern Europe. We find evidence of effect size heterogeneity at significant loci across cohorts, in particular, a weaker association between eye pigmentation and UM in a Finnish cohort. Finally, we confirm differential effect sizes between uveal melanoma cases with and without loss of chromosome 3, the major determinant of metastatic risk. Our study identifies novel germline risk factors for UM and highlights genetic and environmental heterogeneity in its etiology.

• Keywords
• eye pigmentation, genome-wide association study, uveal melanoma,
• MeSH
• Genome-Wide Association Study * MeSH
• Genetic Heterogeneity * MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Loci * MeSH
• Polymorphism, Single Nucleotide MeSH
• Humans MeSH
• Melanoma * genetics   epidemiology   pathology   MeSH
• Uveal Neoplasms * genetics   epidemiology   pathology   MeSH
• Risk Factors MeSH
• Uveal Melanoma MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

BACKGROUND: Processes shaping the formation of the present-day population structure in highly urbanized Northern Europe are still poorly understood. Gaps remain in our understanding of when and how currently observable regional differences emerged and what impact city growth, migration, and disease pandemics during and after the Middle Ages had on these processes. RESULTS: We perform low-coverage sequencing of the genomes of 338 individuals spanning the eighth to the eighteenth centuries in the city of Sint-Truiden in Flanders, in the northern part of Belgium. The early/high medieval Sint-Truiden population was more heterogeneous, having received migrants from Scotland or Ireland, and displayed less genetic relatedness than observed today between individuals in present-day Flanders. We find differences in gene variants associated with high vitamin D blood levels between individuals with Gaulish or Germanic ancestry. Although we find evidence of a Yersinia pestis infection in 5 of the 58 late medieval burials, we were unable to detect a major population-scale impact of the second plague pandemic on genetic diversity or on the elevated differentiation of immunity genes. CONCLUSIONS: This study reveals that the genetic homogenization process in a medieval city population in the Low Countries was protracted for centuries. Over time, the Sint-Truiden population became more similar to the current population of the surrounding Limburg province, likely as a result of reduced long-distance migration after the high medieval period, and the continuous process of local admixture of Germanic and Gaulish ancestries which formed the genetic cline observable today in the Low Countries.

• Keywords
• Flanders, Low countries, Medieval, Migration, Palaeo-genomics, Plague, Urbanization,
• MeSH
• History, Medieval MeSH
• Genetic Variation MeSH
• Genome, Human MeSH
• Genomics MeSH
• Humans MeSH
• Plague epidemiology   history   genetics   MeSH
• Genetics, Population MeSH
• Urbanization * history   MeSH
• Check Tag
• History, Medieval MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Geographicals
• Belgium MeSH

The Yamnaya archaeological complex appeared around 3300 BC across the steppes north of the Black and Caspian Seas, and by 3000 BC it reached its maximal extent, ranging from Hungary in the west to Kazakhstan in the east. To localize Yamnaya origins among the preceding Eneolithic people, we assembled ancient DNA from 435 individuals, demonstrating three genetic clines. A Caucasus-lower Volga (CLV) cline suffused with Caucasus hunter-gatherer1 ancestry extended between a Caucasus Neolithic southern end and a northern end at Berezhnovka along the lower Volga river. Bidirectional gene flow created intermediate populations, such as the north Caucasus Maikop people, and those at Remontnoye on the steppe. The Volga cline was formed as CLV people mixed with upriver populations of Eastern hunter-gatherer2 ancestry, creating hypervariable groups, including one at Khvalynsk. The Dnipro cline was formed when CLV people moved west, mixing with people with Ukraine Neolithic hunter-gatherer ancestry3 along the Dnipro and Don rivers to establish Serednii Stih groups, from whom Yamnaya ancestors formed around 4000 BC and grew rapidly after 3750-3350 BC. The CLV people contributed around four-fifths of the ancestry of the Yamnaya and, entering Anatolia, probably from the east, at least one-tenth of the ancestry of Bronze Age central Anatolians, who spoke Hittite4,5. We therefore propose that the final unity of the speakers of 'proto-Indo-Anatolian', the language ancestral to both Anatolian and Indo-European people, occurred in CLV people some time between 4400 BC and 4000 BC.

• MeSH
• White People genetics   history   MeSH
• History, Ancient MeSH
• European People MeSH
• Phylogeny MeSH
• Haplotypes MeSH
• Humans MeSH
• Human Migration * history   MeSH
• DNA, Mitochondrial analysis   MeSH
• Genetics, Population * MeSH
• Rivers MeSH
• DNA, Ancient analysis   MeSH
• Gene Flow MeSH
• Check Tag
• History, Ancient MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Names of Substances
• DNA, Mitochondrial MeSH
• DNA, Ancient MeSH

The Yamnaya archaeological complex appeared around 3300BCE across the steppes north of the Black and Caspian Seas, and by 3000BCE reached its maximal extent from Hungary in the west to Kazakhstan in the east. To localize the ancestral and geographical origins of the Yamnaya among the diverse Eneolithic people that preceded them, we studied ancient DNA data from 428 individuals of which 299 are reported for the first time, demonstrating three previously unknown Eneolithic genetic clines. First, a "Caucasus-Lower Volga" (CLV) Cline suffused with Caucasus hunter-gatherer (CHG) ancestry extended between a Caucasus Neolithic southern end in Neolithic Armenia, and a steppe northern end in Berezhnovka in the Lower Volga. Bidirectional gene flow across the CLV cline created admixed intermediate populations in both the north Caucasus, such as the Maikop people, and on the steppe, such as those at the site of Remontnoye north of the Manych depression. CLV people also helped form two major riverine clines by admixing with distinct groups of European hunter-gatherers. A "Volga Cline" was formed as Lower Volga people mixed with upriver populations that had more Eastern hunter-gatherer (EHG) ancestry, creating genetically hyper-variable populations as at Khvalynsk in the Middle Volga. A "Dnipro Cline" was formed as CLV people bearing both Caucasus Neolithic and Lower Volga ancestry moved west and acquired Ukraine Neolithic hunter-gatherer (UNHG) ancestry to establish the population of the Serednii Stih culture from which the direct ancestors of the Yamnaya themselves were formed around 4000BCE. This population grew rapidly after 3750-3350BCE, precipitating the expansion of people of the Yamnaya culture who totally displaced previous groups on the Volga and further east, while admixing with more sedentary groups in the west. CLV cline people with Lower Volga ancestry contributed four fifths of the ancestry of the Yamnaya, but also, entering Anatolia from the east, contributed at least a tenth of the ancestry of Bronze Age Central Anatolians, where the Hittite language, related to the Indo-European languages spread by the Yamnaya, was spoken. We thus propose that the final unity of the speakers of the "Proto-Indo-Anatolian" ancestral language of both Anatolian and Indo-European languages can be traced to CLV cline people sometime between 4400-4000 BCE.

• Publication type
• Journal Article MeSH
• Preprint MeSH

Snakes are known as highly fear-evoking animals, eliciting preferential attention and fast detection in humans. We examined the human fear response to snakes in the context of both current and evolutionary experiences, conducting our research in the cradle of humankind, the Horn of Africa. This region is characterized by the frequent occurrence of various snake species, including deadly venomous viperids (adders) and elapids (cobras and mambas). We conducted experiments in Somaliland and compared the results with data from Czech respondents to address the still unresolved questions: To which extent is human fear of snakes affected by evolutionary or current experience and local culture? Can people of both nationalities recognize venomous snakes as a category, or are they only afraid of certain species that are most dangerous in a given area? Are respondents of both nationalities equally afraid of deadly snakes from both families (Viperidae, Elapidae)? We employed a well-established picture-sorting approach, consisting of 48 snake species belonging to four distinct groups. Our results revealed significant agreement among Somali as well as Czech respondents. We found a highly significant effect of the stimulus on perceived fear in both populations. Vipers appeared to be the most salient stimuli in both populations, as they occupied the highest positions according to the reported level of subjectively perceived fear. The position of vipers strongly contrasts with the fear ranking of deadly venomous elapids, which were in lower positions. Fear scores of vipers were significantly higher in both populations, and their best predictor was the body width of the snake. The evolutionary, cultural, and cognitive aspects of this phenomenon are discussed.

• Keywords
• cross-cultural comparison, evolutionary psychology, fear, ophidiophobia, specific phobias,
• Publication type
• Journal Article MeSH

The demographic history of East-Central Europe after the Neolithic period remains poorly explored, despite this region being on the confluence of various ecological zones and cultural entities. Here, the descendants of societies associated with steppe pastoralists form Early Bronze Age were followed by Middle Bronze Age populations displaying unique characteristics. Particularly, the predominance of collective burials, the scale of which, was previously seen only in the Neolithic. The extent to which this re-emergence of older traditions is a result of genetic shift or social changes in the MBA is a subject of debate. Here by analysing 91 newly generated genomes from Bronze Age individuals from present Poland and Ukraine, we discovered that Middle Bronze Age populations were formed by an additional admixture event involving a population with relatively high proportions of genetic component associated with European hunter-gatherers and that their social structure was based on, primarily patrilocal, multigenerational kin-groups.

• MeSH
• History, Ancient MeSH
• Genome, Human * genetics   MeSH
• Humans MeSH
• Human Migration * MeSH
• Social Change MeSH
• Check Tag
• History, Ancient MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH
• Poland MeSH

By sequencing 727 ancient individuals from the Southern Arc (Anatolia and its neighbors in Southeastern Europe and West Asia) over 10,000 years, we contextualize its Chalcolithic period and Bronze Age (about 5000 to 1000 BCE), when extensive gene flow entangled it with the Eurasian steppe. Two streams of migration transmitted Caucasus and Anatolian/Levantine ancestry northward, and the Yamnaya pastoralists, formed on the steppe, then spread southward into the Balkans and across the Caucasus into Armenia, where they left numerous patrilineal descendants. Anatolia was transformed by intra-West Asian gene flow, with negligible impact of the later Yamnaya migrations. This contrasts with all other regions where Indo-European languages were spoken, suggesting that the homeland of the Indo-Anatolian language family was in West Asia, with only secondary dispersals of non-Anatolian Indo-Europeans from the steppe.

• MeSH
• White People genetics   MeSH
• History, Ancient MeSH
• Genome, Human * MeSH
• Humans MeSH
• Human Migration * history   MeSH
• Gene Flow * MeSH
• Check Tag
• History, Ancient MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Geographicals
• Asia MeSH
• Balkan Peninsula MeSH
• Europe MeSH

In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years1. Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions2,3. Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation-proxies for these drivers-provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution.

• MeSH
• Archaeology * MeSH
• Biological Specimen Banks MeSH
• History, Ancient MeSH
• Animals, Wild MeSH
• Gene Frequency MeSH
• Genotype MeSH
• Famine statistics & numerical data   MeSH
• Ceramics history   MeSH
• Cohort Studies MeSH
• Lactase * genetics   MeSH
• Humans MeSH
• Dairying * history   MeSH
• Milk * metabolism   MeSH
• Disease * MeSH
• Genetics, Population * MeSH
• Selection, Genetic * MeSH
• Animals MeSH
• Check Tag
• History, Ancient MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Geographicals
• Europe epidemiology   ethnology   MeSH
• United Kingdom MeSH
• Names of Substances
• Lactase * MeSH

The precise genetic origins of the first Neolithic farming populations in Europe and Southwest Asia, as well as the processes and the timing of their differentiation, remain largely unknown. Demogenomic modeling of high-quality ancient genomes reveals that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Southwest Asian population with a strongly bottlenecked western hunter-gatherer population after the last glacial maximum. Moreover, the ancestors of the first farmers of Europe and Anatolia went through a period of extreme genetic drift during their westward range expansion, contributing highly to their genetic distinctiveness. This modeling elucidates the demographic processes at the root of the Neolithic transition and leads to a spatial interpretation of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene.

• Keywords
• Neolithic transition, ancient genomics, demogenomic modeling, demographic inference, demographic processes, human evolution, population admixture, upper Palaeolithic,
• MeSH
• History, Ancient MeSH
• Genetic Drift MeSH
• Genome * MeSH
• Genomics MeSH
• Humans MeSH
• Human Migration MeSH
• DNA, Mitochondrial genetics   MeSH
• Farmers * MeSH
• Agriculture MeSH
• Check Tag
• History, Ancient MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• DNA, Mitochondrial MeSH

Human culture, biology, and health were shaped dramatically by the onset of agriculture ∼12,000 y B.P. This shift is hypothesized to have resulted in increased individual fitness and population growth as evidenced by archaeological and population genomic data alongside a decline in physiological health as inferred from skeletal remains. Here, we consider osteological and ancient DNA data from the same prehistoric individuals to study human stature variation as a proxy for health across a transition to agriculture. Specifically, we compared “predicted” genetic contributions to height from paleogenomic data and “achieved” adult osteological height estimated from long bone measurements for 167 individuals across Europe spanning the Upper Paleolithic to Iron Age (∼38,000 to 2,400 B.P.). We found that individuals from the Neolithic were shorter than expected (given their individual polygenic height scores) by an average of −3.82 cm relative to individuals from the Upper Paleolithic and Mesolithic (P = 0.040) and −2.21 cm shorter relative to post-Neolithic individuals (P = 0.068), with osteological vs. expected stature steadily increasing across the Copper (+1.95 cm relative to the Neolithic), Bronze (+2.70 cm), and Iron (+3.27 cm) Ages. These results were attenuated when we additionally accounted for genome-wide genetic ancestry variation: for example, with Neolithic individuals −2.82 cm shorter than expected on average relative to pre-Neolithic individuals (P = 0.120). We also incorporated observations of paleopathological indicators of nonspecific stress that can persist from childhood to adulthood in skeletal remains into our model. Overall, our work highlights the potential of integrating disparate datasets to explore proxies of health in prehistory.

• Keywords
• agriculture transition, health, paleogenomics, stature variation,
• MeSH
• History, Ancient MeSH
• Child MeSH
• Adult MeSH
• Genetic Variation MeSH
• Genomics MeSH
• Skeleton * anatomy & histology   MeSH
• Humans MeSH
• Paleopathology MeSH
• DNA, Ancient MeSH
• Body Height * genetics   MeSH
• Health * history   MeSH
• Farmers * history   MeSH
• Agriculture * history   MeSH
• Check Tag
• History, Ancient MeSH
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH
• Geographicals
• Europe MeSH
• Names of Substances
• DNA, Ancient MeSH