Genome of Peştera Muierii skull shows high diversity and low mutational load in pre-glacial Europe.

Few complete human genomes from the European Early Upper Palaeolithic (EUP) have been sequenced. Using novel sampling and DNA extraction approaches, we sequenced the genome of a woman from "Peştera Muierii," Romania who lived ∼34,000 years ago to 13.5× coverage.

Contribution of ancient human remains analysis to the understanding of the variability in HLA-B gene variants in relation to the diagnosis of spondyloarthropathies.

Genetic investigations on ancient human remains affected by rheumatological pathologies are a research field of particular interest for identifying the pathogenesis of diseases, especially those having an autoimmune background such as spondyloarthopaties (SpA). Reliable studies concerning this topic require collaboration between multiple disciplines, usually starting from paleopathologic observations up to molecular genetic screening. Here, we focused our investigation in a medieval necropolis in the Basque Country (13th-15th century, N = 163), which presents a high frequency of joint pathologies through two approaches: on the one hand, the analysis of joint manifestations for the differential diagnosis of the SpA and, on the other hand, the determination of the alleles of the HLA-B gene.

A recording form for differential diagnosis of arthropathies.

The present study is focused on a group of arthropathies that may have very similar bone manifestations (rheumatoid arthritis, ankylosing spondylitis, reactive arthritis, psoriatic arthritis, osteoarthritis and diffuse idiopathic skeletal hyperostosis), which makes it more difficult to diagnose them in human remains from archaeological contexts. A stepwise recording form was designed in order to improve the identification and differential diagnosis of these pathological conditions in bone remains, particularly in joint manifestations of the spine, pelvis, hands, feet and other limb joints. This recording form was applied in the analysis of two medieval individuals from the Basque Country (Spain) who presented very severe arthropathic manifestations.

Direct U-series analysis of the Lezetxiki humerus reveals a Middle Pleistocene age for human remains in the Basque Country (northern Iberia).

In 1964, a human humerus was found in a sedimentary deposit in Lezetxiki Cave (Basque Country, northern Iberia). The first studies on the stratigraphy, associated mammal faunal remains and lithic implements placed the deposits containing the humerus into the Riss glacial stage. Direct chronometric evidence has so far been missing, and the previous chronostratigraphic framework and faunal dating gave inconsistent results.

Demographic differences between funerary caves and megalithic graves of northern Spanish Late Neolithic/Early Chalcolithic.

Objectives: The study focuses on the estimation of demographic parameters of Late Neolithic/Early Chalcolithic (mid 4th-early 3rd millenniums cal. BC) burial sites from the La Rioja region (Ebro valley, northern Spain) to identify demographic characteristics.

Materials And Methods: The human remains come from three caves (Las Yurdinas II, Peña Larga, and La Peña de Marañón) and three megalithic graves (Alto de la Huesera, San Martín, and Peña Guerra II).

Comparison of the Transcriptional Profiles of Melanocytes from Dark and Light Skinned Individuals under Basal Conditions and Following Ultraviolet-B Irradiation.

We analysed the whole-genome transcriptional profile of 6 cell lines of dark melanocytes (DM) and 6 of light melanocytes (LM) at basal conditions and after ultraviolet-B (UVB) radiation at different time points to investigate the mechanisms by which melanocytes protect human skin from the damaging effects of UVB. Further, we assessed the effect of different keratinocyte-conditioned media (KCM+ and KCM-) on melanocytes. Our results suggest that an interaction between ribosomal proteins and the P53 signaling pathway may occur in response to UVB in both DM and LM.

Ancient DNA from South-East Europe Reveals Different Events during Early and Middle Neolithic Influencing the European Genetic Heritage.

The importance of the process of Neolithization for the genetic make-up of European populations has been hotly debated, with shifting hypotheses from a demic diffusion (DD) to a cultural diffusion (CD) model. In this regard, ancient DNA data from the Balkan Peninsula, which is an important source of information to assess the process of Neolithization in Europe, is however missing. In the present study we show genetic information on ancient populations of the South-East of Europe.

Discovery of copy number variants by multiplex amplifiable probe hybridization (MAPH) in candidate pigmentation genes.

Background: Copy Number Variants (CNVs) contribute to a large fraction of genetic diversity and some of them have been reported to offer an evolutionary advantage.

Aim: To identify CNVs in pigmentary loci that could contribute to human skin pigmentation diversity.

Subjects And Methods: This study assessed the existence of CNVs in every exon of candidate genes: TYR, TYRP1, DCT, MC1R and SLC24A5, using the Multiplex Amplifiable Probe Hybridization technique (MAPH).

The interplay between natural selection and susceptibility to melanoma on allele 374F of SLC45A2 gene in a South European population.

We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin.

Nondestructive methods for recovery of biological material from human teeth for DNA extraction.

The extraction of DNA from human skeletal remains applied to forensic, and evolutionary studies do not exclude risks, which are to be evaluated when working with unique specimens that could be damaged or even destroyed. In the present study were evaluated several nondestructive methods for recovering DNA instead of the most currently used pulverization method. Three different procedures to access inside the dental pieces (occlusal perforation, cervical perforation, and cervical cut) have been compared with the aim of recovering as many cell remains as possible to carry out a DNA extraction.

The Carpathian range represents a weak genetic barrier in South-East Europe.

Background: In the present study we have assessed whether the Carpathian Mountains represent a genetic barrier in East Europe. Therefore, we have analyzed the mtDNA of 128 native individuals of Romania: 62 of them from the North of Romania, and 66 from South Romania.

Results: We have analyzed their mtDNA variability in the context of other European and Near Eastern populations through multivariate analyses.

Simultaneous purifying selection on the ancestral MC1R allele and positive selection on the melanoma-risk allele V60L in south Europeans.

In humans, the geographical apportionment of the coding diversity of the pigmentary locus melanocortin-1 receptor (MC1R) is, unusually, higher in Eurasians than in Africans. This atypical observation has been interpreted as the result of purifying selection due to functional constraint on MC1R in high UV-B radiation environments. By analyzing 3,142 human MC1R alleles from different regions of Spain in the context of additional haplotypic information from the 1000 Genomes (1000G) Project data, we show that purifying selection is also strong in southern Europe, but not so in northern Europe.

The loss of functional caspase-12 in Europe is a pre-neolithic event.

Background: Caspase-12 (CASP12) modulates the susceptibility to sepsis. In humans, the "C" allele at CASP12 rs497116 has been associated with an increased risk of sepsis. Instead, the derived "T" allele encodes for an inactive caspase-12.

Ancient DNA from hunter-gatherer and farmer groups from Northern Spain supports a random dispersion model for the Neolithic expansion into Europe.

Background/principal Findings: The phenomenon of Neolithisation refers to the transition of prehistoric populations from a hunter-gatherer to an agro-pastoralist lifestyle. Traditionally, the spread of an agro-pastoralist economy into Europe has been framed within a dichotomy based either on an acculturation phenomenon or on a demic diffusion. However, the nature and speed of this transition is a matter of continuing scientific debate in archaeology, anthropology, and human population genetics.

Low prevalence of lactase persistence in Neolithic South-West Europe.

The ability of humans to digest the milk component lactose after weaning requires persistent production of the lactose-converting enzyme lactase. Genetic variation in the promoter of the lactase gene (LCT) is known to be associated with lactase production and is therefore a genetic determinant for either lactase deficiency or lactase persistence during adulthood. Large differences in this genetic trait exist between populations in Africa and the Middle-East on the one hand, and European populations on the other; this is thought to be due to evolutionary pressures exerted by consumption of dairy products in Neolithic populations in Europe.

The evolutionary history of TLR4 polymorphisms in Europe.

Infections exert important evolutionary pressures shaping the human genome, especially on genes involved in host defense. A crucial step for host defense is recognition of pathogens by pattern recognition receptors on innate immune cells, among which Toll-like receptor 4 (TLR4) is one of the best known. Genetic variation in TLR4 (Asp299Gly, Thr399Ile) has been recently described.

A customized pigmentation SNP array identifies a novel SNP associated with melanoma predisposition in the SLC45A2 gene.

As the incidence of Malignant Melanoma (MM) reflects an interaction between skin colour and UV exposure, variations in genes implicated in pigmentation and tanning response to UV may be associated with susceptibility to MM. In this study, 363 SNPs in 65 gene regions belonging to the pigmentation pathway have been successfully genotyped using a SNP array. Five hundred and ninety MM cases and 507 controls were analyzed in a discovery phase I.

The diversity profile of TP53 is influenced by positive selection on the immediately upstream locus WDR79.

Background/aim: TP53 is an efficient central node in a signal transduction network that responds to minimize cancer. However, over 50% of tumors show some mutation in TP53. Thus, one might argue that this single central node network lacks robustness.

Functional and genetic evidence that the Mal/TIRAP allele variant 180L has been selected by providing protection against septic shock.

Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation.

Complex signatures of selection for the melanogenic loci TYR, TYRP1 and DCT in humans.

Background: The observed correlation between ultraviolet light incidence and skin color, together with the geographical apportionment of skin reflectance among human populations, suggests an adaptive value for the pigmentation of the human skin. We have used Affymetrix U133a v2.0 gene expression microarrays to investigate the expression profiles of a total of 9 melanocyte cell lines (5 from lightly pigmented donors and 4 from darkly pigmented donors) plus their respective unirradiated controls.

Overdominance in the human genome and olfactory receptor activity.

We investigate the contribution of overdominance to the maintenance of polymorphism in the human genome during the recent evolution of our species. Using the HapMap genotypic information, we have detected that the Gene Ontology term "olfactory receptor activity" is a molecular function overrepresented in genes that have SNPs (Single Nucleotide Polymorphisms) showing higher than expected number of heterozygotes in the HapMap populations. Our results suggest that the diversity of a subset of human olfactory receptors (ORs) may have been maintained by balancing selection, in the form of overdominance.

TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans.

Infectious diseases exert a constant evolutionary pressure on the genetic makeup of our innate immune system. Polymorphisms in Toll-like receptor 4 (TLR4) have been related to susceptibility to Gram-negative infections and septic shock. Here we show that two polymorphisms of TLR4, Asp299Gly and Thr399Ile, have unique distributions in populations from Africa, Asia, and Europe.

Usefulness of microchip electrophoresis for the analysis of mitochondrial DNA in forensic and ancient DNA studies.

We evaluate the usefulness of a commercially available microchip CE (MCE) device in different genetic identification studies performed with mitochondrial DNA (mtDNA) targets, including the haplotype analysis of HVR1 and HVR2 and the study of interspecies diversity of cytochrome b (Cyt b) and 16S ribosomal RNA (16S rRNA) mitochondrial genes in forensic and ancient DNA samples. The MCE commercial system tested in this study proved to be a fast and sensitive detection method of length heteroplasmy in cytosine stretches produced by 16 189T>C transitions in HVR1 and by 309.1 and 309.

A scan for signatures of positive selection in candidate loci for skin pigmentation in humans.

Although the combination of pale skin and intense sun exposure results in an important health risk for the individual, it is less clear if at the population level this risk has possessed an evolutionary meaning. In this sense, a number of adaptive hypotheses have been put forward to explain the evolution of human skin pigmentation, such as photoprotection against sun-induced cancer, sexual selection, vitamin D synthesis or photoprotection of photolabile compounds, among others. It is expected that if skin pigmentation is adaptive, we might be able to see the signature of positive selection on some of the genes involved.