Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century.

We report genome-wide data from 33 Ashkenazi Jews (AJ), dated to the 14th century, obtained following a salvage excavation at the medieval Jewish cemetery of Erfurt, Germany. The Erfurt individuals are genetically similar to modern AJ, but they show more variability in Eastern European-related ancestry than modern AJ. A third of the Erfurt individuals carried a mitochondrial lineage common in modern AJ and eight carried pathogenic variants known to affect AJ today. These observations, together with high levels of runs of homozygosity, suggest that the Erfurt community had already experienced the major reduction in size that affected modern AJ. The Erfurt bottleneck was more severe, implying substructure in medieval AJ. Overall, our results suggest that the AJ founder event and the acquisition of the main sources of ancestry pre-dated the 14th century and highlight late medieval genetic heterogeneity no longer present in modern AJ.

A Dynamic 6,000-Year Genetic History of Eurasia's Eastern Steppe.

The Eastern Eurasian Steppe was home to historic empires of nomadic pastoralists, including the Xiongnu and the Mongols. However, little is known about the region's population history. Here, we reveal its dynamic genetic history by analyzing new genome-wide data for 214 ancient individuals spanning 6,000 years. We identify a pastoralist expansion into Mongolia ca. 3000 BCE, and by the Late Bronze Age, Mongolian populations were biogeographically structured into three distinct groups, all practicing dairy pastoralism regardless of ancestry. The Xiongnu emerged from the mixing of these populations and those from surrounding regions. By comparison, the Mongols exhibit much higher eastern Eurasian ancestry, resembling present-day Mongolic-speaking populations. Our results illuminate the complex interplay between genetic, sociopolitical, and cultural changes on the Eastern Steppe.

Uganda Genome Resource Enables Insights into Population History and Genomic Discovery in Africa.

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

Reconstructing the Deep Population History of Central and South America.

We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least ∼9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by ∼4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions.

Ethics of DNA research on human remains: five globally applicable guidelines.

We are a group of archaeologists, anthropologists, curators and geneticists representing diverse global communities and 31 countries. All of us met in a virtual workshop dedicated to ethics in ancient DNA research held in November 2020. There was widespread agreement that globally applicable ethical guidelines are needed, but that recent recommendations grounded in discussion about research on human remains from North America are not always generalizable worldwide. Here we propose the following globally applicable guidelines, taking into consideration diverse contexts. These hold that: (1) researchers must ensure that all regulations were followed in the places where they work and from which the human remains derived; (2) researchers must prepare a detailed plan prior to beginning any study; (3) researchers must minimize damage to human remains; (4) researchers must ensure that data are made available following publication to allow critical re-examination of scientific findings; and (5) researchers must engage with other stakeholders from the beginning of a study and ensure respect and sensitivity to stakeholder perspectives. We commit to adhering to these guidelines and expect they will promote a high ethical standard in DNA research on human remains going forward.

Estimating human mobility in Holocene Western Eurasia with large-scale ancient genomic data.

The recent increase in openly available ancient human DNA samples allows for large-scale meta-analysis applications. Trans-generational past human mobility is one of the key aspects that ancient genomics can contribute to since changes in genetic ancestry-unlike cultural changes seen in the archaeological record-necessarily reflect movements of people. Here, we present an algorithm for spatiotemporal mapping of genetic profiles, which allow for direct estimates of past human mobility from large ancient genomic datasets. The key idea of the method is to derive a spatial probability surface of genetic similarity for each individual in its respective past. This is achieved by first creating an interpolated ancestry field through space and time based on multivariate statistics and Gaussian process regression and then using this field to map the ancient individuals into space according to their genetic profile. We apply this algorithm to a dataset of 3138 aDNA samples with genome-wide data from Western Eurasia in the last 10,000 y. Finally, we condense this sample-wise record with a simple summary statistic into a diachronic measure of mobility for subregions in Western, Central, and Southern Europe. For regions and periods with sufficient data coverage, our similarity surfaces and mobility estimates show general concordance with previous results and provide a meta-perspective of genetic changes and human mobility.

Palaeo-Eskimo genetic ancestry and the peopling of Chukotka and North America.

Much of the American Arctic was first settled 5,000 years ago, by groups of people known as Palaeo-Eskimos. They were subsequently joined and largely displaced around 1,000 years ago by ancestors of the present-day Inuit and Yup'ik1-3. The genetic relationship between Palaeo-Eskimos and Native American, Inuit, Yup'ik and Aleut populations remains uncertain4-6. Here we present genomic data for 48 ancient individuals from Chukotka, East Siberia, the Aleutian Islands, Alaska, and the Canadian Arctic. We co-analyse these data with data from present-day Alaskan Iñupiat and West Siberian populations and published genomes. Using methods based on rare-allele and haplotype sharing, as well as established techniques4,7-9, we show that Palaeo-Eskimo-related ancestry is ubiquitous among people who speak Na-Dene and Eskimo-Aleut languages. We develop a comprehensive model for the Holocene peopling events of Chukotka and North America, and show that Na-Dene-speaking peoples, people of the Aleutian Islands, and Yup'ik and Inuit across the Arctic region all share ancestry from a single Palaeo-Eskimo-related Siberian source.

PNPLA3 fatty liver allele was fixed in Neanderthals and segregates neutrally in humans.

OBJECTIVE: Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date. DESIGN: Here we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for PNPLA3 p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed. RESULTS: We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3 risk allele, whereas allele frequencies in modern human populations range from very low in Africa to >50% in Mesoamerica. Over the last 15 000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10 000 years. CONCLUSION: Archaic human individuals exclusively carried a fixed PNPLA3 allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of PNPLA3 p.I148M.

Tracking human population structure through time from whole genome sequences.

The genetic diversity of humans, like many species, has been shaped by a complex pattern of population separations followed by isolation and subsequent admixture. This pattern, reaching at least as far back as the appearance of our species in the paleontological record, has left its traces in our genomes. Reconstructing a population's history from these traces is a challenging problem. Here we present a novel approach based on the Multiple Sequentially Markovian Coalescent (MSMC) to analyze the separation history between populations. Our approach, called MSMC-IM, uses an improved implementation of the MSMC (MSMC2) to estimate coalescence rates within and across pairs of populations, and then fits a continuous Isolation-Migration model to these rates to obtain a time-dependent estimate of gene flow. We show, using simulations, that our method can identify complex demographic scenarios involving post-split admixture or archaic introgression. We apply MSMC-IM to whole genome sequences from 15 worldwide populations, tracking the process of human genetic diversification. We detect traces of extremely deep ancestry between some African populations, with around 1% of ancestry dating to divergences older than a million years ago.

A genomic history of Aboriginal Australia.

The population history of Aboriginal Australians remains largely uncharacterized. Here we generate high-coverage genomes for 83 Aboriginal Australians (speakers of Pama-Nyungan languages) and 25 Papuans from the New Guinea Highlands. We find that Papuan and Aboriginal Australian ancestors diversified 25-40 thousand years ago (kya), suggesting pre-Holocene population structure in the ancient continent of Sahul (Australia, New Guinea and Tasmania). However, all of the studied Aboriginal Australians descend from a single founding population that differentiated ~10-32 kya. We infer a population expansion in northeast Australia during the Holocene epoch (past 10,000 years) associated with limited gene flow from this region to the rest of Australia, consistent with the spread of the Pama-Nyungan languages. We estimate that Aboriginal Australians and Papuans diverged from Eurasians 51-72 kya, following a single out-of-Africa dispersal, and subsequently admixed with archaic populations. Finally, we report evidence of selection in Aboriginal Australians potentially associated with living in the desert.

The genetic history of Ice Age Europe.

Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. Here we analyse genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3-6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory.

The UK10K project identifies rare variants in health and disease.

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.

Tracing the route of modern humans out of Africa by using 225 human genome sequences from Ethiopians and Egyptians.

The predominantly African origin of all modern human populations is well established, but the route taken out of Africa is still unclear. Two alternative routes, via Egypt and Sinai or across the Bab el Mandeb strait into Arabia, have traditionally been proposed as feasible gateways in light of geographic, paleoclimatic, archaeological, and genetic evidence. Distinguishing among these alternatives has been difficult. We generated 225 whole-genome sequences (225 at 8× depth, of which 8 were increased to 30×; Illumina HiSeq 2000) from six modern Northeast African populations (100 Egyptians and five Ethiopian populations each represented by 25 individuals). West Eurasian components were masked out, and the remaining African haplotypes were compared with a panel of sub-Saharan African and non-African genomes. We showed that masked Northeast African haplotypes overall were more similar to non-African haplotypes and more frequently present outside Africa than were any sets of haplotypes derived from a West African population. Furthermore, the masked Egyptian haplotypes showed these properties more markedly than the masked Ethiopian haplotypes, pointing to Egypt as the more likely gateway in the exodus to the rest of the world. Using five Ethiopian and three Egyptian high-coverage masked genomes and the multiple sequentially Markovian coalescent (MSMC) approach, we estimated the genetic split times of Egyptians and Ethiopians from non-African populations at 55,000 and 65,000 years ago, respectively, whereas that of West Africans was estimated to be 75,000 years ago. Both the haplotype and MSMC analyses thus suggest a predominant northern route out of Africa via Egypt.

Bronze age Northern Eurasian genetics in the context of development of metallurgy and Siberian ancestry.

The Eurasian Bronze Age (BA) has been described as a period of substantial human migrations, the emergence of pastoralism, horse domestication, and development of metallurgy. This study focuses on two north Eurasian sites sharing Siberian genetic ancestry. One of the sites, Rostovka, is associated with the Seima-Turbino (ST) phenomenon (~2200-1900 BCE) that is characterized by elaborate metallurgical objects found throughout Northern Eurasia. The genetic profiles of Rostovka individuals vary widely along the forest-tundra Siberian genetic cline represented by many modern Uralic-speaking populations, and the genetic heterogeneity observed is consistent with the current understanding of the ST being a transcultural phenomenon. Individuals from the second site, Bolshoy Oleni Ostrov in Kola, in comparison form a tighter cluster on the Siberian ancestry cline. We further explore this Siberian ancestry profile and assess the role of the ST phenomenon and other contemporaneous BA cultures in the spread of Uralic languages and Siberian ancestry.

Evidence for dynastic succession among early Celtic elites in Central Europe.

The early Iron Age (800 to 450 BCE) in France, Germany and Switzerland, known as the 'West-Hallstattkreis', stands out as featuring the earliest evidence for supra-regional organization north of the Alps. Often referred to as 'early Celtic', suggesting tentative connections to later cultural phenomena, its societal and population structure remain enigmatic. Here we present genomic and isotope data from 31 individuals from this context in southern Germany, dating between 616 and 200 BCE. We identify multiple biologically related groups spanning three elite burials as far as 100 km apart, supported by trans-regional individual mobility inferred from isotope data. These include a close biological relationship between two of the richest burial mounds of the Hallstatt culture. Bayesian modelling points to an avuncular relationship between the two individuals, which may suggest a practice of matrilineal dynastic succession in early Celtic elites. We show that their ancestry is shared on a broad geographic scale from Iberia throughout Central-Eastern Europe, undergoing a decline after the late Iron Age (450 BCE to ~50 CE).

Cases of trisomy 21 and trisomy 18 among historic and prehistoric individuals discovered from ancient DNA.

Aneuploidies, and in particular, trisomies represent the most common genetic aberrations observed in human genetics today. To explore the presence of trisomies in historic and prehistoric populations we screen nearly 10,000 ancient human individuals for the presence of three copies of any of the target autosomes. We find clear genetic evidence for six cases of trisomy 21 (Down syndrome) and one case of trisomy 18 (Edwards syndrome), and all cases are present in infant or perinatal burials. We perform comparative osteological examinations of the skeletal remains and find overlapping skeletal markers, many of which are consistent with these syndromes. Interestingly, three cases of trisomy 21, and the case of trisomy 18 were detected in two contemporaneous sites in early Iron Age Spain (800-400 BCE), potentially suggesting a higher frequency of burials of trisomy carriers in those societies. Notably, the care with which the burials were conducted, and the items found with these individuals indicate that ancient societies likely acknowledged these individuals with trisomy 18 and 21 as members of their communities, from the perspective of burial practice.

Quantifying selection acting on a complex trait using allele frequency time series data.

When selection is acting on a large genetically diverse population, beneficial alleles increase in frequency. This fact can be used to map quantitative trait loci by sequencing the pooled DNA from the population at consecutive time points and observing allele frequency changes. Here, we present a population genetic method to analyze time series data of allele frequencies from such an experiment. Beginning with a range of proposed evolutionary scenarios, the method measures the consistency of each with the observed frequency changes. Evolutionary theory is utilized to formulate equations of motion for the allele frequencies, following which likelihoods for having observed the sequencing data under each scenario are derived. Comparison of these likelihoods gives an insight into the prevailing dynamics of the system under study. We illustrate the method by quantifying selective effects from an experiment, in which two phenotypically different yeast strains were first crossed and then propagated under heat stress (Parts L, Cubillos FA, Warringer J, et al. [14 co-authors]. 2011. Revealing the genetic structure of a trait by sequencing a population under selection. Genome Res). From these data, we discover that about 6% of polymorphic sites evolve nonneutrally under heat stress conditions, either because of their linkage to beneficial (driver) alleles or because they are drivers themselves. We further identify 44 genomic regions containing one or more candidate driver alleles, quantify their apparent selective advantage, obtain estimates of recombination rates within the regions, and show that the dynamics of the drivers display a strong signature of selection going beyond additive models. Our approach is applicable to study adaptation in a range of systems under different evolutionary pressures.

High-coverage genome of the Tyrolean Iceman reveals unusually high Anatolian farmer ancestry.

The Tyrolean Iceman is known as one of the oldest human glacier mummies, directly dated to 3350-3120 calibrated BCE. A previously published low-coverage genome provided novel insights into European prehistory, despite high present-day DNA contamination. Here, we generate a high-coverage genome with low contamination (15.3×) to gain further insights into the genetic history and phenotype of this individual. Contrary to previous studies, we found no detectable Steppe-related ancestry in the Iceman. Instead, he retained the highest Anatolian-farmer-related ancestry among contemporaneous European populations, indicating a rather isolated Alpine population with limited gene flow from hunter-gatherer-ancestry-related populations. Phenotypic analysis revealed that the Iceman likely had darker skin than present-day Europeans and carried risk alleles associated with male-pattern baldness, type 2 diabetes, and obesity-related metabolic syndrome. These results corroborate phenotypic observations of the preserved mummified body, such as high pigmentation of his skin and the absence of hair on his head.

Confronting historical legacies of biological anthropology in South Africa-Restitution, redress and community-centered science: The Sutherland Nine.

We describe a process of restitution of nine unethically acquired human skeletons to their families, together with attempts at redress. Between 1925-1927 C.E., the skeletonised remains of nine San or Khoekhoe people, eight of them known-in-life, were removed from their graves on the farm Kruisrivier, near Sutherland in the Northern Cape Province of South Africa. They were donated to the Anatomy Department at the University of Cape Town. This was done without the knowledge or permission of their families. The donor was a medical student who removed the remains from the labourers' cemetery on his family farm. Nearly 100 years later, the remains are being returned to their community, accompanied by a range of community-driven interdisciplinary historical, archaeological and analytical (osteobiographic, craniofacial, ancient DNA, stable isotope) studies to document, as far as possible, their lives and deaths. The restitution process began by contacting families living in the same area with the same surnames as the deceased. The restitution and redress process prioritises the descendant families' memories, wishes and desire to understand the situation, and learn more about their ancestors. The descendant families have described the process as helping them to reconnect with their ancestors. A richer appreciation of their ancestors' lives, gained in part from scientific analyses, culminating with reburial, is hoped to aid the descendant families and wider community in [re-]connecting with their heritage and culture, and contribute to restorative justice, reconciliation and healing while confronting a traumatic historical moment. While these nine individuals were exhumed as specimens, they will be reburied as people.

4000-year-old hair from the Middle Nile highlights unusual ancient DNA degradation pattern and a potential source of early eastern Africa pastoralists.

Petrous bones and teeth are the skeletal elements most often targeted by researchers for ancient DNA (aDNA) extraction, and the sources of the majority of previously published ancient African genomes. However, the high temperature environments that characterise much of Africa often lead to poor preservation of skeletal remains. Here, we successfully reconstruct and analyse genome-wide data from the naturally mummified hair of a 4000-year-old individual from Sudan in northeastern Africa, after failed attempts at DNA extraction from teeth, petrous, and cranium of this and other individuals from the Kadruka cemeteries. We find that hair DNA extracted with an established single-stranded library protocol is unusually enriched in ultra-short DNA molecules and exhibits substantial interior molecular damage. The aDNA was nonetheless amenable to genetic analyses, which revealed that the genome is genetically indistinguishable from that of early Neolithic eastern African pastoralists located 2500 kms away. Our findings are consistent with established models for the southward dispersal of Middle Nile Valley pastoral populations to the Rift Valley of eastern Africa, and provide a possible genetic source population for this dispersal. Our study highlights the value of mummified hair as an alternate source of aDNA from regions with poor bone preservation.