The earliest hominin occupation of Europe is one of the most debated topics in palaeoanthropology. However, the purportedly oldest of the Early Pleistocene sites in Eurasia lack precise age control and contain stone tools rather than human fossil remains. Here we report the discovery of a human mandible associated with an assemblage of Mode 1 lithic tools and faunal remains bearing traces of hominin processing, in stratigraphic level TE9 at the site of the Sima del Elefante, Atapuerca, Spain. Level TE9 has been dated to the Early Pleistocene (approximately 1.2-1.1 Myr), based on a combination of palaeomagnetism, cosmogenic nuclides and biostratigraphy. The Sima del Elefante site thus emerges as the oldest, most accurately dated record of human occupation in Europe, to our knowledge. The study of the human mandible suggests that the first settlement of Western Europe could be related to an early demographic expansion out of Africa. The new evidence, with previous findings in other Atapuerca sites (level TD6 from Gran Dolina), also suggests that a speciation event occurred in this extreme area of the Eurasian continent during the Early Pleistocene, initiating the hominin lineage represented by the TE9 and TD6 hominins.

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype–phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café‐au‐lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan‐like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1‐patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi‐exon deletion, providing genetic evidence that p.Arg1809Cys is a loss‐of‐function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype–phenotype correlation will affect counseling and management of a significant number of patients.

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The hypothesis that Neanderthals exploited birds for the use of their feathers or claws as personal ornaments in symbolic behaviour is revolutionary as it assigns unprecedented cognitive abilities to these hominins. This inference, however, is based on modest faunal samples and thus may not represent a regular or systematic behaviour. Here we address this issue by looking for evidence of such behaviour across a large temporal and geographical framework. Our analyses try to answer four main questions: 1) does a Neanderthal to raptor-corvid connection exist at a large scale, thus avoiding associations that might be regarded as local in space or time?; 2) did Middle (associated with Neanderthals) and Upper Palaeolithic (associated with modern humans) sites contain a greater range of these species than Late Pleistocene paleontological sites?; 3) is there a taphonomic association between Neanderthals and corvids-raptors at Middle Palaeolithic sites on Gibraltar, specifically Gorham's, Vanguard and Ibex Caves? and; 4) was the extraction of wing feathers a local phenomenon exclusive to the Neanderthals at these sites or was it a geographically wider phenomenon?. We compiled a database of 1699 Pleistocene Palearctic sites based on fossil bird sites. We also compiled a taphonomical database from the Middle Palaeolithic assemblages of Gibraltar. We establish a clear, previously unknown and widespread, association between Neanderthals, raptors and corvids. We show that the association involved the direct intervention of Neanderthals on the bones of these birds, which we interpret as evidence of extraction of large flight feathers. The large number of bones, the variety of species processed and the different temporal periods when the behaviour is observed, indicate that this was a systematic, geographically and temporally broad, activity that the Neanderthals undertook. Our results, providing clear evidence that Neanderthal cognitive capacities were comparable to those of Modern Humans, constitute a major advance in the study of human evolution.

The production of purposely made painted or engraved designs on cave walls-a means of recording and transmitting symbolic codes in a durable manner-is recognized as a major cognitive step in human evolution. Considered exclusive to modern humans, this behavior has been used to argue in favor of significant cognitive differences between our direct ancestors and contemporary archaic hominins, including the Neanderthals. Here we present the first known example of an abstract pattern engraved by Neanderthals, from Gorham's Cave in Gibraltar. It consists of a deeply impressed cross-hatching carved into the bedrock of the cave that has remained covered by an undisturbed archaeological level containing Mousterian artifacts made by Neanderthals and is older than 39 cal kyr BP. Geochemical analysis of the epigenetic coating over the engravings and experimental replication show that the engraving was made before accumulation of the archaeological layers, and that most of the lines composing the design were made by repeatedly and carefully passing a pointed lithic tool into the grooves, excluding the possibility of an unintentional or utilitarian origin (e.g., food or fur processing). This discovery demonstrates the capacity of the Neanderthals for abstract thought and expression through the use of geometric forms.Middle Paleolithic | symbolism | art | Iberia | cognition

etween 1994 and 1996, during the excavation of a 7-m 2 test pit, a sample of Ϸ100 hominin fossil remains was found in the so-called Aurora Stratum of the stratigraphic unit TD6 of the Gran Dolina site in Sierra de Atapuerca, Burgos, northern Spain (1). The hominin remains were associated with 268 lithic artifacts made of flint, quartzite, sandstone, limestone, and quartz. This sample is characterized by the presence of small artifacts, and includes flakes, denticulates, notches, and side-scrapers and can be characterized as Mode 1 technology (2). The excavation of the Aurora Stratum also yielded a rich small mammal assemblage (26 species, including the water vole Mimomys savini) as well as Ϸ1,000 large mammal fossil remains. The study of the arvicolids suggests that the TD6 level can be referred to the Biharian biochron (3). The macromammal assemblage is biochronologically consistent with the end of the Early Pleistocene or early Cromerian (4, 5). Paleomagnetic dating places TD6 in the Matuyama reversed Chron, hence, before 780 thousand years ago (6, 7). These paleomagnetic data combined with electron spin resonance and uranium series results give an age range of between 780 and 857 thousand years for TD6 (8). Pollen analysis suggests that the Aurora Stratum was deposited under wet, temperate conditions (9); thus, the Aurora Stratum possibly correlates to oxygen isotope stages 21 or 19.In 1997, the TD6 hominins were attributed to Homo antecessor, a new European Lower Pleistocene species (10). On the basis of cranial and dental features, it was suggested that this species could be the common ancestor of modern humans (Homo sapiens) and Neandertals (Homo neanderthalensis). The new taxon was defined in part by using facial and mandibular traits observed in immature individuals. Although the TD6 remains were compared with those of individuals of the same dental age (e.g., KNM-WT 15000), it was clear that the credibility of the species would improve if new specimens corresponding to adult individuals were found. In 2003, we obtained in the Aurora Stratum an excellently preserved mandible, whose description and comparative analysis is the subject of the present study. Mandible ATD6-96Preservation and Age at Death. The specimen catalogued as ATD6-96 was recovered in a planar section of Ͻ1 m 2 , near the area excavated during the 1994-1997 field seasons (1). ATD6-96 is a left half of a gracile mandible of an adult individual (Hominid 7) with the premolars and molars in place (Fig. 1). The specimen is broken at the level of the lateral incisor-canine septum, and the left genial apophysis is preserved. Some postmortem fractures are observed at the region between the corpus and ramus and near the neck of the condyle, but there is no noticeable distortion. Molar (M)3 is fully erupted and exhibits a minimal wear facet at the mesial marginal ridge. During restoration, the corpus and ramus were separated, and the roots of the M3 were observed directly. These roots are at stage Rc of tooth formation (11). Thus, according to mo...

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n=35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p adj =6.73x10-6). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.

Mutational analysis of the IDUA gene was performed in a cohort of 102 European patients with mucopolysaccharidosis type I. A total of 54 distinct mutant IDUA alleles were identified, 34 of which were novel including 12 missense mutations, 2 nonsense mutations, 12 splicing mutations, 5 micro-deletions, 1 micro-duplication 1 translational initiation site mutation, and 1 'no-stop' change (p.X654RextX62). Evidence for the pathological significance of all novel mutations identified was sought by means of a range of methodological approaches, including the assessment of evolutionary conservation, RT-PCR/in vitro splicing analysis, MutPred analysis and visual inspection of the 3D-model of the IDUA protein. Taken together, these data not only demonstrate the remarkable mutational heterogeneity characterizing type 1 mucopolysaccharidosis but also illustrate our increasing ability to make deductions pertaining to the genotype-phenotype relationship in disorders manifesting a high degree of allelic heterogeneity.