Senckenberg Centre for Human Evolution and Palaeoenvironment

The automated reconstruction of genome sequences in ancient genome analysis is a multifaceted process. Here we introduce EAGER, a time-efficient pipeline, which greatly simplifies the analysis of large-scale genomic data sets. EAGER provides features to preprocess, map, authenticate, and assess the quality of ancient DNA samples. Additionally, EAGER comprises tools to genotype samples to discover, filter, and analyze variants. EAGER encompasses both state-of-the-art tools for each step as well as new complementary tools tailored for ancient DNA data within a single integrated solution in an easily accessible format.

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.

Studies of the peopling of the Americas have focused on the timing and number of initial migrations. Less attention has been paid to the subsequent spread of people within the Americas. We sequenced 15 ancient human genomes spanning from Alaska to Patagonia; six are ≥10,000 years old (up to ~18× coverage). All are most closely related to Native Americans, including those from an Ancient Beringian individual and two morphologically distinct "Paleoamericans." We found evidence of rapid dispersal and early diversification that included previously unknown groups as people moved south. This resulted in multiple independent, geographically uneven migrations, including one that provides clues of a Late Pleistocene Australasian genetic signal, as well as a later Mesoamerican-related expansion. These led to complex and dynamic population histories from North to South America.

Neocortex, the neuronal structure at the base of the remarkable cognitive skills of mammals, is a layered sheet of neuronal tissue composed of juxtaposed and interconnected columns. A cortical column is considered the basic module of cortical processing present in all cortical areas. It is believed to contain a characteristic microcircuit composed of a few thousand neurons. The high degree of cortical segmentation into vertical columns and horizontal layers is a boon for scientific investigation because it eases the systematic dissection and functional analysis of intrinsic as well as extrinsic connections of the column. In this review we will argue that in order to understand neocortical function one needs to combine a microscopic view, elucidating the workings of the local columnar microcircuits, with a macroscopic view, which keeps track of the linkage of distant cortical modules in different behavioral contexts. We will exemplify this strategy using the model system of vibrissal touch in mice and rats. On the macroscopic level vibrissal touch is an important sense for the subterranean rodents and has been honed by evolution to serve an array of distinct behaviors. Importantly, the vibrissae are moved actively to touch - requiring intricate sensorimotor interactions. Vibrissal touch, therefore, offers ample opportunities to relate different behavioral contexts to specific interactions of distant columns. On the microscopic level, the cortical modules in primary somatosensory cortex process touch inputs at highest magnification and discreteness - each whisker is represented by its own so-called barrel column. The cellular composition, intrinsic connectivity and functional aspects of the barrel column have been studied in great detail. Building on the versatility of genetic tools available in rodents, new, highly selective and flexible cellular and molecular tools to monitor and manipulate neuronal activity have been devised. Researchers have started to combine these with advanced and highly precise behavioral methods, on par with the precision known from monkey preparations. Therefore, the vibrissal touch model system is exquisitely positioned to combine the microscopic with the macroscopic view and promises to be instrumental in our understanding of neocortical function.

Ancient DNA research has been revolutionized following development of next-generation sequencing platforms. Although a number of such platforms have been applied to ancient DNA samples, the Illumina series are the dominant choice today, mainly because of high production capacities and short read production. Recently a potentially attractive alternative platform for palaeogenomic data generation has been developed, the BGISEQ-500, whose sequence output are comparable with the Illumina series. In this study, we modified the standard BGISEQ-500 library preparation specifically for use on degraded DNA, then directly compared the sequencing performance and data quality of the BGISEQ-500 to the Illumina HiSeq2500 platform on DNA extracted from 8 historic and ancient dog and wolf samples. The data generated were largely comparable between sequencing platforms, with no statistically significant difference observed for parameters including level (P = 0.371) and average sequence length (P = 0718) of endogenous nuclear DNA, sequence GC content (P = 0.311), double-stranded DNA damage rate (v. 0.309), and sequence clonality (P = 0.093). Small significant differences were found in single-strand DNA damage rate (δS; slightly lower for the BGISEQ-500, P = 0.011) and the background rate of difference from the reference genome (θ; slightly higher for BGISEQ-500, P = 0.012). This may result from the differences in amplification cycles used to polymerase chain reaction-amplify the libraries. A significant difference was also observed in the mitochondrial DNA percentages recovered (P = 0.018), although we believe this is likely a stochastic effect relating to the extremely low levels of mitochondria that were sequenced from 3 of the samples with overall very low levels of endogenous DNA. Although we acknowledge that our analyses were limited to animal material, our observations suggest that the BGISEQ-500 holds the potential to represent a valid and potentially valuable alternative platform for palaeogenomic data generation that is worthy of future exploration by those interested in the sequencing and analysis of degraded DNA.

Ancient DNA is revealing new insights into the genetic relationship between Pleistocene hominins and modern humans. Nuclear DNA indicated Neanderthals as a sister group of Denisovans after diverging from modern humans. However, the closer affinity of the Neanderthal mitochondrial DNA (mtDNA) to modern humans than Denisovans has recently been suggested as the result of gene flow from an African source into Neanderthals before 100,000 years ago. Here we report the complete mtDNA of an archaic femur from the Hohlenstein-Stadel (HST) cave in southwestern Germany. HST carries the deepest divergent mtDNA lineage that splits from other Neanderthals ∼270,000 years ago, providing a lower boundary for the time of the putative mtDNA introgression event. We demonstrate that a complete Neanderthal mtDNA replacement is feasible over this time interval even with minimal hominin introgression. The highly divergent HST branch is indicative of greater mtDNA diversity during the Middle Pleistocene than in later periods.

Study of human adaptation to extreme environments is important for understanding our cultural and genetic capacity for survival. The Pucuncho Basin in the southern Peruvian Andes contains the highest-altitude Pleistocene archaeological sites yet identified in the world, about 900 meters above confidently dated contemporary sites. The Pucuncho workshop site [4355 meters above sea level (masl)] includes two fishtail projectile points, which date to about 12.8 to 11.5 thousand years ago (ka). Cuncaicha rock shelter (4480 masl) has a robust, well-preserved, and well-dated occupation sequence spanning the past 12.4 thousand years (ky), with 21 dates older than 11.5 ka. Our results demonstrate that despite cold temperatures and low-oxygen conditions, hunter-gatherers colonized extreme high-altitude Andean environments in the Terminal Pleistocene, within about 2 ky of the initial entry of humans to South America.

The nasal cavity is essential for humidifying and warming the air before it reaches the sensitive lungs. Because humans inhabit environments that can be seen as extreme from the perspective of respiratory function, nasal cavity shape is expected to show climatic adaptation. This study examines the relationship between modern human variation in the morphology of the nasal cavity and the climatic factors of temperature and vapor pressure, and tests the hypothesis that within increasingly demanding environments (colder and drier), nasal cavities will show features that enhance turbulence and air-wall contact to improve conditioning of the air. We use three-dimensional geometric morphometrics methods and multivariate statistics to model and analyze the shape of the bony nasal cavity of 10 modern human population samples from five climatic groups. We report significant correlations between nasal cavity shape and climatic variables of both temperature and humidity. Variation in nasal cavity shape is correlated with a cline from cold-dry climates to hot-humid climates, with a separate temperature and vapor pressure effect. The bony nasal cavity appears mostly associated with temperature, and the nasopharynx with humidity. The observed climate-related shape changes are functionally consistent with an increase in contact between air and mucosal tissue in cold-dry climates through greater turbulence during inspiration and a higher surface-to-volume ratio in the upper nasal cavity.

Abstract Modern humans have populated Europe for more than 45,000 years 1,2 . Our knowledge of the genetic relatedness and structure of ancient hunter-gatherers is however limited, owing to the scarceness and poor molecular preservation of human remains from that period 3 . Here we analyse 356 ancient hunter-gatherer genomes, including new genomic data for 116 individuals from 14 countries in western and central Eurasia, spanning between 35,000 and 5,000 years ago. We identify a genetic ancestry profile in individuals associated with Upper Palaeolithic Gravettian assemblages from western Europe that is distinct from contemporaneous groups related to this archaeological culture in central and southern Europe 4 , but resembles that of preceding individuals associated with the Aurignacian culture. This ancestry profile survived during the Last Glacial Maximum (25,000 to 19,000 years ago) in human populations from southwestern Europe associated with the Solutrean culture, and with the following Magdalenian culture that re-expanded northeastward after the Last Glacial Maximum. Conversely, we reveal a genetic turnover in southern Europe suggesting a local replacement of human groups around the time of the Last Glacial Maximum, accompanied by a north-to-south dispersal of populations associated with the Epigravettian culture. From at least 14,000 years ago, an ancestry related to this culture spread from the south across the rest of Europe, largely replacing the Magdalenian-associated gene pool. After a period of limited admixture that spanned the beginning of the Mesolithic, we find genetic interactions between western and eastern European hunter-gatherers, who were also characterized by marked differences in phenotypically relevant variants.

BACKGROUND: Leuciscinae is a subfamily belonging to the Cyprinidae fish family that is widely distributed in Circum-Mediterranean region. Many efforts have been carried out to deciphering the evolutionary history of this group. Thus, different biogeographical scenarios have tried to explain the colonization of Europe and Mediterranean area by cyprinids, such as the "north dispersal" or the "Lago Mare dispersal" models. Most recently, Pleistocene glaciations influenced the distribution of leuciscins, especially in North and Central Europe. Weighing up these biogeographical scenarios, this paper constitutes not only the first attempt at deciphering the mitochondrial and nuclear relationships of Mediterranean leuciscins but also a test of biogeographical hypotheses that could have determined the current distribution of Circum-Mediterranean leuciscins. RESULTS: A total of 4439 characters (mitochondrial + nuclear) from 321 individuals of 176 leuciscine species rendered a well-supported phylogeny, showing fourteen main lineages. Analyses of independent mitochondrial and nuclear markers supported the same main lineages, but basal relationships were not concordant. Moreover, some incongruence was found among independent mitochondrial and nuclear phylogenies. The monophyly of some poorly known genera such as Pseudophoxinus and Petroleuciscus was rejected. Representatives of both genera belong to different evolutionary lineages. Timing of cladogenetic events among the main leuciscine lineages was gained using mitochondrial and all genes data set. CONCLUSIONS: Adaptations to a predatory lifestyle or miniaturization have superimposed the morphology of some species. These species have been separated into different genera, which are not supported by a phylogenetic framework. Such is the case of the genera Pseudophoxinus and Petroleuciscus, which real taxonomy is not well known. The diversification of leuciscine lineages has been determined by intense vicariant events following the paleoclimatological and hydrogeological history of Mediterranean region. We propose different colonization models of Mediterranean region during the early Oligocene. Later vicariance events promoted Leuciscinae diversification during Oligocene and Miocene periods. Our data corroborate the presence of leuciscins in North Africa before the Messinian salinity crisis. Indeed, Messinian period appears as a stage of gradually Leuciscinae diversification. The rise of humidity at the beginning of the Pliocene promoted the colonization and posterior isolation of newly established freshwater populations. Finally, Pleistocene glaciations determined the current European distribution of some leuciscine species.

The role of Iran as a center of origin for domesticated cereals has long been debated. High stratigraphic resolution and rich archaeological remains at the aceramic Neolithic site of Chogha Golan (Ilam Province, present-day Iran) reveal a sequence ranging over 2200 years of cultivation of wild plants and the first appearance of domesticated-type species. The botanical record from Chogha Golan documents how the inhabitants of the site cultivated wild barley (Hordeum spontaneum) and other wild progenitor species of modern crops, such as wild lentil and pea. Wild wheat species (Triticum spp.) are initially present at less than 10% of total plant species but increase to more than 20% during the last 300 years of the sequence. Around 9800 calendar years before the present, domesticated-type emmer appears. The archaeobotanical remains from Chogha Golan represent the earliest record of long-term plant management in Iran.

Behavior relies on the distributed and coordinated activity of neural populations. Population activity can be measured using multi-neuron recordings and neuroimaging. Neural recordings reveal how the heterogeneity, sparseness, timing, and correlation of population activity shape information processing in local networks, whereas neuroimaging shows how long-range coupling and brain states impact on local activity and perception. To obtain an integrated perspective on neural information processing we need to combine knowledge from both levels of investigation. We review recent progress of how neural recordings, neuroimaging, and computational approaches begin to elucidate how interactions between local neural population activity and large-scale dynamics shape the structure and coding capacity of local information representations, make them state-dependent, and control distributed populations that collectively shape behavior.

By 4000 years ago, people had introduced maize to the southwestern United States; full agriculture was established quickly in the lowland deserts but delayed in the temperate highlands for 2000 years. We test if the earliest upland maize was adapted for early flowering, a characteristic of modern temperate maize. We sequenced fifteen 1900-year-old maize cobs from Turkey Pen Shelter in the temperate Southwest. Indirectly validated genomic models predicted that Turkey Pen maize was marginally adapted with respect to flowering, as well as short, tillering, and segregating for yellow kernel color. Temperate adaptation drove modern population differentiation and was selected in situ from ancient standing variation. Validated prediction of polygenic traits improves our understanding of ancient phenotypes and the dynamics of environmental adaptation.

Long perceived as a primitive and poorly differentiated brain structure, the primate insular cortex recently emerged as a highly evolved, organized and richly connected cortical hub interfacing bodily states with sensorimotor, environmental, and limbic activities. This insular interface likely substantiates emotional embodiment and has the potential to have a key role in the interoceptive shaping of cognitive processes, including perceptual awareness. In this review, we present a novel working model of the insular cortex, based on an accumulation of neuroanatomical and functional evidence obtained essentially in the macaque monkey. This model proposes that interoceptive afferents that represent the ongoing physiological status of all the organs of the body are first being received in the granular dorsal fundus of the insula or "primary interoceptive cortex," then processed through a series of dysgranular poly-modal "insular stripes," and finally integrated in anterior agranular areas that serve as an additional sensory platform for visceral functions and as an output stage for efferent autonomic regulation. One of the agranular areas hosts the specialized von Economo and Fork neurons, which could provide a decisive evolutionary advantage for the role of the anterior insula in the autonomic and emotional binding inherent to subjective awareness.

Ocular fixation is a dynamic process that is actively controlled by many of the same brain structures involved in the control of eye movements, including the superior colliculus, cerebellum and reticular formation. In this article, we review several aspects of this active control. First, the decision to move the eyes not only depends on target-related signals from the peripheral visual field, but also on signals from the currently fixated target at the fovea, and involves mechanisms that are shared between saccades and smooth pursuit. Second, eye position during fixation is actively controlled and depends on bilateral activity in the superior colliculi and medio-posterior cerebellum; disruption of activity in these circuits causes systematic deviations in eye position during both fixation and smooth pursuit eye movements. Third, the eyes are not completely still during fixation but make continuous miniature movements, including ocular drift and microsaccades, which are controlled by the same neuronal mechanisms that generate larger saccades. Finally, fixational eye movements have large effects on visual perception. Ocular drift transforms the visual input in ways that increase spatial acuity; microsaccades not only improve vision by relocating the fovea but also cause momentary changes in vision analogous to those caused by larger saccades.This article is part of the themed issue 'Movement suppression: brain mechanisms for stopping and stillness'.

Neurons in early sensory cortex show weak but systematic correlations with perceptual decisions when trained animals perform at psychophysical threshold. These correlations are observed across repeated presentations of identical stimuli and cannot be explained by variation in external factors. The relationship between the activity of individual sensory neurons and the animal's behavioral choice means that even neurons in early sensory cortex carry information about an upcoming decision. This relationship, termed choice probability, may reflect the effect of fluctuations in neuronal firing rate on the animal's decision, but it can also reflect modulation of sensory responses by cognitive factors, or network properties such as variability that is shared among populations of neurons. Here, we review recent work clarifying the relationship among fluctuations in the responses of individual neurons, correlated variability, and behavior in a variety of tasks and cortical areas. We also discuss the possibility that choice probability may in part reflect the influence of cognitive factors on sensory neurons and explore the situations in which choice probability can be used to make inferences about the role of particular sensory neurons in the decision-making process.

Gait and balance disturbances typically emerge in advanced Parkinson's disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson's Disease Rating Scale score (Scale II items 13-15, Scale III items 27-31) at '3-week follow-up'. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, nonmotor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the '3-week follow-up'. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no 'global' effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the

Egypt, located on the isthmus of Africa, is an ideal region to study historical population dynamics due to its geographic location and documented interactions with ancient civilizations in Africa, Asia and Europe. Particularly, in the first millennium BCE Egypt endured foreign domination leading to growing numbers of foreigners living within its borders possibly contributing genetically to the local population. Here we present 90 mitochondrial genomes as well as genome-wide data sets from three individuals obtained from Egyptian mummies. The samples recovered from Middle Egypt span around 1,300 years of ancient Egyptian history from the New Kingdom to the Roman Period. Our analyses reveal that ancient Egyptians shared more ancestry with Near Easterners than present-day Egyptians, who received additional sub-Saharan admixture in more recent times. This analysis establishes ancient Egyptian mummies as a genetic source to study ancient human history and offers the perspective of deciphering Egypt's past at a genome-wide level.

Purpose: We assessed the safety and efficacy of a technically advanced subretinal electronic implant, RETINA IMPLANT Alpha AMS, in end stage retinal degeneration in an interim analysis of two ongoing prospective clinical trials. Methods: The subretinal visual prosthesis RETINA IMPLANT Alpha AMS (Retina Implant AG, Reutlingen, Germany) was implanted in 15 blind patients with hereditary retinal degenerations at four study sites with a follow-up period of 12 months (www.clinicaltrials.gov NCT01024803 and NCT02720640). Functional outcome measures included 1) screen-based standardized 2- or 4-alternative forced-choice tests of light perception, light localization, grating detection (basic grating acuity (BaGA) test) and Landolt C-rings; 2) grey level discrimination; 3) performance during activities of daily living (ADL-table tasks). Results: Implant-mediated light perception was observed in 13/15 patients. During the observation period implant mediated localization of visual targets was possible in 13/15 patients. Correct grating detection was achieved for spatial frequencies of 0.1 cpd (cycles per degree) in 4/15; 0.33 cpd in 3/15; 0.66 cpd in 2/15; 1.0 cpd in 2/15 and 3.3 cpd in 1/15 patients. In two patients visual acuity assessed with Landolt C- rings was 20/546 and 20/1111. Of 6 possible grey levels on average 4.6 +/-0.8 (mean +/- SD, n=10) were discerned. Improvements (power ON vs. OFF) of ADL table tasks were measured in 13/15 patients. Overall, results were stable during the observation period. Serious adverse events were reported in 4 patients: 2 movements of the implant, readjusted in a second surgery; 4 conjunctival erosion/dehiscence, successfully treated; 1 pain event around the coil, successfully treated; 1 partial reduction of silicone oil tamponade leading to distorted vision (silicon oil successfully refilled). The majority of adverse events were transient and mostly of mild to moderate intensity. Conclusions: Psychophysical and subjective data show that RETINA IMPLANT Alpha AMS is reliable, well tolerated and can restore limited visual functions in blind patients with degenerations of the outer retina. Compared with the previous implant Alpha IMS, longevity of the new implant Alpha AMS has been considerably improved. Alpha AMS has meanwhile been certified as a commercially available medical device, reimbursed in Germany by the public health system.

Inherent in visual scene analysis is a bottleneck associated with the need to sequentially sample locations with foveating eye movements. The concept of a 'saliency map' topographically encoding stimulus conspicuity over the visual scene has proven to be an efficient predictor of eye movements. Our work reviews insights into the neurobiological implementation of visual salience computation. We start by summarizing the role that different visual brain areas play in salience computation, whether at the level of feature analysis for bottom-up salience or at the level of goal-directed priority maps for output behaviour. We then delve into how a subcortical structure, the superior colliculus (SC), participates in salience computation. The SC represents a visual saliency map via a centre-surround inhibition mechanism in the superficial layers, which feeds into priority selection mechanisms in the deeper layers, thereby affecting saccadic and microsaccadic eye movements. Lateral interactions in the local SC circuit are particularly important for controlling active populations of neurons. This, in turn, might help explain long-range effects, such as those of peripheral cues on tiny microsaccades. Finally, we show how a combination of in vitro neurophysiology and large-scale computational modelling is able to clarify how salience computation is implemented in the local circuit of the SC.This article is part of the themed issue 'Auditory and visual scene analysis'.