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Summary - The animal and plant biodiversity of the Italian territory is known to be one of the richest in the Mediterranean basin and Europe as a whole, but does the genetic diversity of extant human populations show a comparable pattern? According to a number of studies, the genetic structure of Italian populations retains the signatures of complex peopling processes which took place from the Paleolithic to modern era. Although the observed patterns highlight a remarkable degree of genetic heterogeneity, they do not, however, take into account an important source of variation. In fact, Italy is home to numerous ethnolinguistic minorities which have yet to be studied systematically. Due to their difference in geographical origin and demographic history, such groups not only signal the cultural and social diversity of our country, but they are also potential contributors to its bio-anthropological heterogeneity. To fill this gap, research groups from four Italian Universities (Bologna, Cagliari, Pisa and Roma Sapienza) started a collaborative study in 2007, which was funded by the Italian Ministry of Education, University and Research and received partial support by the Istituto Italiano di Antropologia. In this paper, we present an account of the results obtained in the course of this initiative. Four case-studies relative to linguistic minorities from the Eastern Alps, Sardinia, Apennines and Southern Italy are first described and discussed, focusing on their micro-evolutionary and anthropological implications. Thereafter, we present the results of a systematic analysis of the relations between linguistic, geographic and genetic isolation. Integrating the data obtained in the course of the long-term study with literature and unpublished results on Italian populations, we show that a combination of linguistic and geographic factors is probably responsible for the presence of the most robust signatures of genetic isolation. Finally, we evaluate the magnitude of the diversity of Italian populations in the European context. The human genetic diversity of our country was found to be greater than observed throughout the continent at short (0-200 km) and intermediate (700-800km) distances, and accounted for most of the highest values of genetic distances observed at all geographic ranges. Interestingly, an important contribution to this pattern comes from the “linguistic islands” (e.g. German speaking groups of Sappada and Luserna from the Eastern Italian Alps), further proof of the importance of considering social and cultural factors when studying human genetic variation.

Genetic signatures from the Paleolithic inhabitants of Eurasia can be traced from the early divergent mitochondrial DNA lineages still present in contemporary human populations. Previous studies already suggested a pre-Neolithic diffusion of mitochondrial haplogroup HV*(xH, V) lineages, a relatively rare class of mtDNA types that includes parallel branches mainly distributed across Europe and West Asia with a certain degree of structure. Up till now, variation within haplogroup HV was addressed mainly by analyzing sequence data from the mtDNA control region, except for specific sub-branches, such as HV4 or the widely distributed haplogroups H and V. In this study, we present a revised HV topology based on full mtDNA genome data, and we include a comprehensive dataset consisting of 316 complete mtDNA sequences including 60 new samples from the Italian peninsula, a previously underrepresented geographic area. We highlight points of instability in the particular topology of this haplogroup, reconstructed with BEAST-generated trees and networks. We also confirm a major lineage expansion that probably followed the Late Glacial Maximum and preceded Neolithic population movements. We finally observe that Italy harbors a reservoir of mtDNA diversity, with deep-rooting HV lineages often related to sequences present in the Caucasus and the Middle East. The resulting hypothesis of a glacial refugium in Southern Italy has implications for the understanding of late Paleolithic population movements and is discussed within the archaeological cultural shifts occurred over the entire continent.

Cultural and environmental factors interact in determining the genetic structure of human populations. Bio-demographic investigations of ethnic minorities are able to disentangle the influences that these two components have on the evolution of the genetic structure of a population. The ethnic minority of the Arbëreshe of the province of Cosenza (Calabria, southern Italy) is analyzed in this paper and its bio-demographic structure in the early 1800s is compared with that of neighboring Italian populations. The data derive from surnames recorded in the birth registers of the 19 Arbdreshe municipalities of the province of Cosenza and in 5 non-Arbëreshe municipalities of the same province. Isonymy and repeated pairs of surnames are used to analyze the bio-demographic structure of these populations, while analysis of isonymic relationships is used to investigate the variability between populations. Higher values of marital isonymy and subdivision into subpopulations characterize the Arbëreshe populations with respect to their non-Arbëreshe neighbors. However, the high range of variability of these parameters suggests a strong influence of geographic location on the marriage pattern of each community. At the same time, cultural differences linked to group identity had a strong impact in limiting marriage exchanges between the different ethnic groups living in the province of Cosenza in the early 1800s. In fact, the analysis of isonymic relationships demonstrates that geographic location shaped kinship patterns among the Arbereshe communities, but it also shows that the non-Arbëreshe neighbors formed a clearly separate reproductive cluster.

OBJECTIVES: Behçet's disease is a multifactorial vasculitis that shows its highest prevalence in geographical areas historically involved in the Silk Road, suggesting that it might have originated somewhere along these ancient trade routes. This study aims to provide a first clue towards genetic evidence for this hypothesis by testing it via an anthropological evolutionary genetics approach. METHODS: Behçet's disease variation at ancestry informative mitochondrial DNA control region and haplogroup diagnostic sites was characterised in 185 disease subjects of Italian descent and set into the Eurasian mitochondrial landscape by comparison with nearly 9,000 sequences representative of diversity observable in Italy and along the main Silk Road routes. RESULTS: Dissection of the actual genetic ancestry of disease individuals by means of population structure, spatial autocorrelation and haplogroup analyses revealed their closer relationships with some Middle Eastern and Central Asian groups settled along the Silk Road than with healthy Italians. CONCLUSIONS: These findings support the hypothesis that the Behçet's disease genetic risk has migrated to western Eurasia in parallel with ancestry components typical of Silk Road-related groups. This provided new insights that are useful to improve the understanding of disease origins and diffusion, as well as to inform future association studies aimed at properly accounting for the actual genetic ancestry of the examined Behçet's disease samples in order to minimise the detection of spurious associations and to improve the identification of genetic variants with actual clinical relevance.

The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes.

Giant cell tumor (GCT) of the bone is a locally aggressive and rarely metastasizing neoplasm. It is composed of neoplastic mononuclear stromal cells with a monotonous appearance admixed with macrophages and osteoclast-like giant cells. In a small subset of cases, GCT is malignant. Terminology previously related to this entity, and which is no longer supported by the World Health Organization, includes osteoclastoma and benign fibrous histiocytoma (BFH). Giant cells occur in numerous other pathologic conditions of the bone, which accounts for the misrepresentation of these non-GCT tumors in the early literature. Non-ossifying fibroma (NOF), aneurysmal bone cyst, and chondroblastoma have been erroneously labeled GCT for this reason. A single description of an ancient GCT was reported by Brothwell and Sandison and subsequently mentioned by Aufderheide and Rodrìguez-Martìn who were astonished that more of these tumors had not been identified in archaeological cases. To the best of our knowledge, no other cases of ancient GCT have been cited in the paleopathology literature. The study of this type of neoplasm in antiquity can be used as a means to better understand its characteristics and behavior and to expand the depth of time of the etiology of these lesions. We report a case of GCT of the left femur observed following the total body CT imaging of a partially mummified adult female, dating to eighteenth century.

Background The cline of human genetic diversity observable across Europe is recapitulated at a micro-geographic scale by variation within the Italian population. Besides resulting from extensive gene flow, this might be ascribable also to local adaptations to diverse ecological contexts evolved by people who anciently spread along the Italian Peninsula. Dissecting the evolutionary history of the ancestors of present-day Italians may thus improve the understanding of demographic and biological processes that contributed to shape the gene pool of European populations. However, previous SNP array-based studies failed to investigate the full spectrum of Italian variation, generally neglecting low-frequency genetic variants and examining a limited set of small effect size alleles, which may represent important determinants of population structure and complex adaptive traits. To overcome these issues, we analyzed 38 high-coverage whole-genome sequences representative of population clusters at the opposite ends of the cline of Italian variation, along with a large panel of modern and ancient Euro-Mediterranean genomes. Results We provided evidence for the early divergence of Italian groups dating back to the Late Glacial and for Neolithic and distinct Bronze Age migrations having further differentiated their gene pools. We inferred adaptive evolution at insulin-related loci in people from Italian regions with a temperate climate, while possible adaptations to pathogens and ultraviolet radiation were observed in Mediterranean Italians. Some of these adaptive events may also have secondarily modulated population disease or longevity predisposition. Conclusions We disentangled the contribution of multiple migratory and adaptive events in shaping the heterogeneous Italian genomic background, which exemplify population dynamics and gene-environment interactions that played significant roles also in the formation of the Continental and Southern European genomic landscapes.

Together with Cayapas, the Tsachilas constitute the oldest population in the country of Ecuador and, according to some historians, they are the last descendants of the ancient Yumbos. Several anthropological issues underlie the interest towards this peculiar population: the uncertainty of their origin, their belonging to the Barbacoan linguistic family, which is still at the center of an intense linguistic debate, and the relations of their Yumbo ancestors with the Inca invaders who occupied their ancient territory. Our contribution to the knowledge of their complex past was the reconstruction of their genetic maternal and paternal inheritance through the sequencing of 70 entire mitochondrial genomes and the characterization of the non-recombinant region of the Y chromosome in 26 males. For both markers, we built comprehensive datasets of various populations from the surrounding geographical area, northwestern South America, NW, with a known linguistic affiliation, and we could then compare our sample against the overall variability to infer relationships with other Barbacoan people and with other NW natives. We found contrasting patterns of genetic diversity for the two markers, but generally, our results indicated a possible common origin between the Tsachilas, the Chachi, and other Ecuadorian and Colombian Barbacoans and are suggestive of an interesting ancient linkage to the Inca invaders in Yumbo country.

In the population genomics era, the study of Y-chromosome variability is still of the greatest interest for several fields ranging from molecular anthropology to forensics and genetic genealogy. In particular, mutation rates of Y-chromosomal Short Tandem Repeats markers (Y-STRs) are key parameters for different interdisciplinary applications. Among them, testing the patrilineal relatedness between individuals and calculating their Time of Most Recent Common Ancestors (TMRCAs) are of the utmost importance. To provide new valuable estimates and to address these issues, we typed 47 Y-STRs (comprising Yfiler, PowerPlex23 and YfilerPlus loci, the recently defined Rapidly Mutating [RM] panel and 11 additional markers often used in genetic genealogical applications) in 135 individuals belonging to 66 deep-rooting paternal genealogies from Northern Italy. Our results confirmed that the genealogy approach is an effective way to obtain reliable Y-STR mutation rate estimates even with a limited number of samples. Moreover, they showed that the impact of multi-step mutations and backmutations is negligible within the temporal scale usually adopted by forensic and genetic genealogy analyses. We then detected a significant association between the number of mutations within genealogies and observed TMRCAs. Therefore, we compared observed and expected TMRCAs by implementing a Bayesian procedure originally designed by Walsh (2001) and showed that the method yields a good performance (up to 96.72%), especially when using the Infinite Alleles Model (IAM). ispartof: SCIENTIFIC REPORTS vol:9 issue:1 ispartof: location:England status: published

One of the best documented Indo-European civilizations that inhabited Bulgaria is the Thracians, who lasted for more than five millennia and whose origin and relationships with other past and present-day populations are debated among researchers. Here we report 25 new complete mitochondrial genomes of ancient individuals coming from three necropolises located in different regions of Bulgaria – Shekerdja mogila, Gabrova mogila and Bereketska mogila – dated to II-III millennium BC. The identified mtDNA haplogroup composition reflects the mitochondrial variability of Western Eurasia. In particular, within the ancient Eurasian genetic landscape, Thracians locate in an intermediate position between Early Neolithic farmers and Late Neolithic-Bronze Age steppe pastoralists, supporting the scenario that the Balkan region has been a link between Eastern Europe and the Mediterranean since the prehistoric time. Spatial Principal Component Analysis (sPCA) performed on Thracian and modern mtDNA sequences, confirms the pattern highlighted on ancient populations, overall indicating that the maternal gene pool of Thracians reflects their central geographical position at the gateway of Europe.

Eritrea is a multi-ethnic country of over 3 million of people consisting of different ethnic groups, having each its own language and cultural tradition. Due to the lack of population genetic data for markers of forensic interest, in this study, we analyzed the genetic polymorphisms of 23 Y-chromosome STR loci and of 12 X-chromosome STR loci in a sample of 255 unrelated individuals from 8 Eritrean ethnic groups, with the aim to generate a reference haplotype database for anthropological and forensic applications. X- and Y-chromosomes markers may indeed offer information especially in personal identification and kinship testing, when relying on the availability of large local population data to derive sufficiently accurate frequency estimates. The population genetic analyses in the Eritrean sample for both the two set of Y- and X-STR markers showed high power of discrimination both at country-based and population levels. Comparison population results highlight the importance of considering the ethnic composition within the analyzed country and the necessity of increasing available data especially when referring to heterogeneous populations such as the African ones. Electronic supplementary material The online version of this article (10.1007/s00414-020-02446-2) contains supplementary material, which is available to authorized users.

With the recent advances in next-generation sequencing (NGS), mitochondrial whole-genome sequencing has begun to be applied to the field of the forensic biology as an alternative to the traditional Sanger-type sequencing (STS). However, experimental workflows, commercial solutions, and output data analysis must be strictly validated before being implemented into the forensic laboratory. In this study, we performed an internal validation for an NGS-based typing of the entire mitochondrial genome using the Precision ID mtDNA Whole Genome Panel (Thermo Fisher Scientific) on the Ion S5 sequencer (Thermo Fisher Scientific). Concordance, repeatability, reproducibility, sensitivity, and heteroplasmy detection analyses were assessed using the 2800 M and 9947A standard control DNA as well as typical casework specimens, and results were compared with conventional Sanger sequencing and another NGS sequencer in a different laboratory. We discuss the strengths and limitations of this approach, highlighting some issues regarding noise thresholds and heteroplasmy detection, and suggesting solutions to mitigate these effects and improve overall data interpretation. Results confirmed that the Precision ID Whole mtDNA Genome Panel is highly reproducible and sensitive, yielding useful full mitochondrial DNA sequences also from challenging DNA specimens, thus providing further support for its use in forensic practice. Supplementary Information The online version contains supplementary material available at 10.1007/s00414-021-02686-w.

Extreme longevity is the paradigm of healthy aging as individuals who reached the extreme decades of human life avoided or largely postponed all major age-related diseases. In this study, we sequenced at high coverage (90X) the whole genome of 81 semi-supercentenarians and supercentenarians [105+/110+] (mean age: 106.6 ± 1.6) and of 36 healthy unrelated geographically matched controls (mean age 68.0 ± 5.9) recruited in Italy. The results showed that 105+/110+ are characterized by a peculiar genetic background associated with efficient DNA repair mechanisms, as evidenced by both germline data (common and rare variants) and somatic mutations patterns (lower mutation load if compared to younger healthy controls). Results were replicated in a second independent cohort of 333 Italian centenarians and 358 geographically matched controls. The genetics of 105+/110+ identified DNA repair and clonal haematopoiesis as crucial players for healthy aging and for the protection from cardiovascular events.

The study of food choice, one of the most complex human traits, requires an integrated approach that takes into account environmental, socio-cultural and biological diversity. We recruited 183 volunteers from four geo-linguistic groups and highly diversified in terms of both genetic background and food habits from whom we collected genotypes and phenotypes tightly linked to taste perception. We confirmed previous genetic associations, in particular with stevioside perception, and noted significant differences in food consumption: in particular, broccoli, mustard and beer consumption scores were significantly higher (Adjusted P = 0.02, Adjusted P

The complexity of the admixture dynamics that shaped American populations is unveiled by Ongaro et al., where genetic data for more than 12,000 individuals from the continents are investigated. This study evaluates the dramatic impact of events after the colonial era, revealing a spatial and temporal heterogeneity and mirroring historical records. © 2019 Elsevier Ltd The human genetic diversity of the Americas has been affected by several events of gene flow that have continued since the colonial era and the Atlantic slave trade. Moreover, multiple waves of migration followed by local admixture occurred in the last two centuries, the impact of which has been largely unexplored. Here, we compiled a genome-wide dataset of ∼12,000 individuals from twelve American countries and ∼6,000 individuals from worldwide populations and applied haplotype-based methods to investigate how historical movements from outside the New World affected (1) the genetic structure, (2) the admixture profile, (3) the demographic history, and (4) sex-biased gene-flow dynamics of the Americas. We revealed a high degree of complexity underlying the genetic contribution of European and African populations in North and South America, from both geographic and temporal perspectives, identifying previously unreported sources related to Italy, the Middle East, and to specific regions of Africa. © 2019 Elsevier Ltd Preprint version of the article: "The genomic impact of European colonization of the Americas", posted June 28, 2019 on bioRxiv. Article is now published in Current Biology doi: [dx.doi.org/10.1016/j.cub.2019.09.076]. Published version on this repository: [http://vinar.vin.bg.ac.rs/handle/123456789/8654].

Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E (APOE) polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer’s disease (AD) and cardiovascular disease (CVD). In this case, the available literature on APOE and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of APOE haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of APOE alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of APOE variation evolved.

In the U.S., more than 80% of African-American smokers use mentholated cigarettes, compared to less than 30% of Caucasian smokers. The reasons for these differences are not well understood. To determine if genetic variation contributes to mentholated cigarette smoking, we performed an exome-wide association analysis in a multiethnic population-based sample from Dallas, TX (N = 561). Findings were replicated in an independent cohort of African Americans from Washington, DC (N = 741). We identified a haplotype of MRGPRX4 (composed of rs7102322[G], encoding N245S, and rs61733596[G], T43T), that was associated with a 5-to-8 fold increase in the odds of menthol cigarette smoking. The variants are present solely in persons of African ancestry. Functional studies indicated that the variant G protein-coupled receptor encoded by MRGPRX4 displays reduced agonism in both arrestin-based and G protein-based assays, and alteration of agonism by menthol. These data indicate that genetic variation in MRGPRX4 contributes to inter-individual and inter-ethnic differences in the preference for mentholated cigarettes, and that the existence of genetic factors predisposing vulnerable populations to mentholated cigarette smoking can inform tobacco control and public health policies., Author summary An exome-wide association study revealed a significant association between menthol cigarette use and coding variants in MRGPRX4, which encodes a G-protein coupled receptor expressed in sensory neurons. The variant haplotype is found only in populations of African ancestry, and encodes a receptor that displays reduced agonism by Nateglinide. Our findings indicate genetic variation contributes to the high rate of menthol cigarette use in African Americans.

Specific myeloid-related and inositide-specific gene mutations can be linked to myelodysplastic syndromes (MDS) pathogenesis and therapy. Here, 44 higher-risk MDS patients were treated with azacitidine and lenalidomide and mutations analyses were performed at baseline and during the therapy. Results were then correlated to clinical outcome, overall survival (OS), leukemia-free-survival (LFS) and response to therapy. Collectively, 34/44 patients were considered evaluable for response, with an overall response rate of 76.25% (26/34 cases): 17 patients showed a durable response, 9 patients early lost response and 8 patients never responded. The most frequently mutated genes were ASXL1, TET2, RUNX1, and SRSF2. All patients early losing response, as well as cases never responding, acquired the same 3 point mutations during therapy, affecting respectively PIK3CD (D133E), AKT3 (D280G), and PLCG2 (Q548R) genes, that regulate cell proliferation and differentiation. Moreover, Kaplan–Meier analyses revealed that this mutated cluster was significantly associated with a shorter OS, LFS, and duration of response. All in all, a common mutated cluster affecting 3 inositide-specific genes is significantly associated with loss of response to azacitidine and lenalidomide therapy in higher risk MDS. Further studies are warranted to confirm these data and to further analyze the functional role of this 3-gene cluster.

Human populations living at high altitude evolved a number of biological adjustments to cope with a challenging environment characterised especially by reduced oxygen availability and limited nutritional resources. This condition may also affect their gut microbiota composition. Here, we explored the impact of exposure to such selective pressures on human gut microbiota by considering different ethnic groups living at variable degrees of altitude: the high-altitude Sherpa and low-altitude Tamang populations from Nepal, the high-altitude Aymara population from Bolivia, as well as a low-altitude cohort of European ancestry, used as control. We thus observed microbial profiles common to the Sherpa and Aymara, but absent in the low-altitude cohorts, which may contribute to the achievement of adaptation to high-altitude lifestyle and nutritional conditions. The collected evidences suggest that microbial signatures associated to these rural populations may enhance metabolic functions able to supply essential compounds useful for the host to cope with high altitude-related physiological changes and energy demand. Therefore, these results add another valuable piece of the puzzle to the understanding of the beneficial effects of symbiosis between microbes and their human host even from an evolutionary perspective.

Because Africa’s climate hampers DNA preservation, knowledge of its genetic variability is mainly restricted to modern samples, even though population genetics dynamics and back-migrations from Eurasia may have modified haplotype frequencies, masking ancient genetic scenarios. Thanks to improved methodologies, ancient genetic data for the African continent are now increasingly available, starting to fill in the gap. Here we present newly obtained mitochondrial genomes from two ~7000-year-old individuals from Takarkori rockshelter, Libya, representing the earliest and first genetic data for the Sahara region. These individuals carry a novel mutation motif linked to the haplogroup N root. Our result demonstrates the presence of an ancestral lineage of the N haplogroup in the Holocene “Green Sahara”, associated to a Middle Pastoral (Neolithic) context.

International audience; Genetic variation is an important determinant affecting either drug response or susceptibility to adverse drug reactions. Several studies have highlighted the importance of ethnicity in influencing drug response variability that should be considered during drug development. Our objective is to characterize the genetic variability of some pharmacogenes involved in the response to drugs used for the treatment of Metabolic Syndrome (MetS) in Tunisia and to compare our results to the worldwide populations. A set of 135 Tunisians was genotyped using the Affymetrix Chip 6.0 genotyping array. Variants located in 24 Very Important Pharmacogenes (VIP) involved in MetS drug response were extracted from the genotyping data. Analysis of variant distribution in Tunisian population compared to 20 worldwide populations publicly available was performed using R software packages. Common variants between Tunisians and the 20 investigated populations were extracted from genotyping data. Multidimensional screening showed that Tunisian population is clustered with North African and European populations. The greatest divergence was observed with the African and Asian population. In addition, we performed Inter-ethnic comparison based on the genotype frequencies of five VIP biomarkers. The genotype frequencies of the biomarkers rs3846662, rs1045642, rs7294 and rs12255372 located respectively in HMGCR, ABCB1, VKORC1 and TCF7L2 are similar between Tunisian, Tuscan (TSI) and European (CEU). The genotype frequency of the variant rs776746 located in CYP3A5 gene is similar between Tunisian and African populations and different from CEU and TSI. The present study shows that the genetic make up of the Tunisian population is relatively complex in regard to pharmacogenes and reflects previous historical events. It is important to consider this ethnic difference in drug prescription in order to optimize drug response to avoid serious adverse drug reactions. Taking into account similarities with other neighboring populations, our study has an impact not only on the Tunisian population but also on North African population which are underrepresented in pharmacogenomic studies.

During the Vietnam War, the United States military sprayed over 74 million litres of Agent Orange (AO) to destroy forest cover as a counterinsurgency tactic in Vietnam, Laos and Cambodia. The main ingredient was contaminated by 2,3,7,8-tetrachlorodibenzo-paradioxin (TCDD). DNA methylation (DNAm) differences are potential biomarker of environmental toxicants exposure. The aim of this study was to perform a preliminary investigation of the DNAm levels from peripheral blood of the present-day Vietnamese population, including individuals whose parents, according to historical data, were exposed to AO/TCDD during the war. 94 individuals from heavily sprayed areas (cases) and 94 individuals from non-sprayed areas (controls) were studied, and historical data on alleged exposure of parents collected. 94 cases were analysed considering those whose father/parents participated in the war (N = 29) and considering the place of residence of both parents (64 living in sprayed areas versus 30 in non-contaminated areas). DNAm levels in CYP1A1 and IGF2 genes were measured (MALDI-TOF technology). The analyses showed that: 1) one CpG site in the CYP1A1 and one in the IGF2 gene showed significant differences in DNAm levels between cases and controls; 2) the CYP1A1 region resulted to be hypomethylated (in 9 out of 16 sites/units; p-val

Objectives Assuming that the differences between the Andes and the Amazon rainforest at environmental and historical levels have influenced the distribution patterns of genes, languages, and cultures, the maternal and paternal genetic reconstruction of the Peruvian Amazon populations was used to test the relationships within and between these two extreme environments. Materials and Methods We analyzed four Peruvian Amazon communities (Ashaninka, Huambisa, Cashibo, and Shipibo) for both Y chromosome (17 STRs and 8 SNPs) and mtDNA data (control region sequences, two diagnostic sites of the coding region, and one INDEL), and we studied their variability against the rest of South America. Results We detected a high degree of genetic diversity in the Peruvian Amazon people, both for mtDNA than for Y chromosome, excepting for Cashibo people, who seem to have had no exchanges with their neighbors, in contrast with the others communities. The genetic structure follows the divide between the Andes and the Amazon, but we found a certain degree of gene flow between these two environments, as particularly emerged with the Y chromosome descent cluster's (DCs) analysis. Discussion The Peruvian Amazon is home to an array of populations with differential rates of genetic exchanges with their neighbors and with the Andean people, depending on their peculiar demographic histories. We highlighted some successful Y chromosome lineages expansions originated in Peru during the pre-Columbian history which involved both Andeans and Amazon Arawak people, showing that at least a part of the Amazon rainforest did not remain isolated from those exchanges.

The present day distribution of Y chromosomes bearing the haplogroup J1 M267(*)G variant has been associated with different episodes of human demographic history, the main one being the diffusion of Islam since the Early Middle Ages. To better understand the modes and timing of J1 dispersals, we reconstructed the genealogical relationships among 282 M267(*)G chromosomes from 29 populations typed at 20 YSTRs and 6 SNPs. Phylogenetic analyses depicted a new genetic background consistent with climate-driven demographic dynamics occurring during two key phases of human pre-history: (1) the spatial expansion of hunter gatherers in response to the end of the late Pleistocene cooling phases and (2) the displacement of groups of foragers/herders following the mid-Holocene rainfall retreats across the Sahara and Arabia. Furthermore, J1 STR motifs previously used to trace Arab or Jewish ancestries were shown unsuitable as diagnostic markers for ethnicity.

Greek colonisation of South Italy and Sicily (Magna Graecia) was a defining event in European cultural history, although the demographic processes and genetic impacts involved have not been systematically investigated. Here, we combine high-resolution surveys of the variability at the uni-parentally inherited Y chromosome and mitochondrial DNA in selected samples of putative source and recipient populations with forward-in-time simulations of alternative demographic models to detect signatures of that impact. Using a subset of haplotypes chosen to represent historical sources, we recover a clear signature of Greek ancestry in East Sicily compatible with the settlement from Euboea during the Archaic Period (eighth to fifth century BCE). We inferred moderate sex-bias in the numbers of individuals involved in the colonisation: a few thousand breeding men and a few hundred breeding women were the estimated number of migrants. Last, we demonstrate that studies aimed at quantifying Hellenic genetic flow by the proportion of specific lineages surviving in present-day populations may be misleading.European Journal of Human Genetics advance online publication, 15 July 2015; doi:10.1038/ejhg.2015.124.

Humans and their ancestors have traversed the Ethiopian landscape for millions of years, and present-day Ethiopians show great cultural, linguistic, and historical diversity, which makes them essential for understanding African variability and human origins. We genotyped 235 individuals from ten Ethiopian and two neighboring (South Sudanese and Somali) populations on an Illumina Omni 1M chip. Genotypes were compared with published data from several African and non-African populations. Principal-component and STRUCTURE-like analyses confirmed substantial genetic diversity both within and between populations, and revealed a match between genetic data and linguistic affiliation. Using comparisons with African and non-African reference samples in 40-SNP genomic windows, we identified "African" and "non-African" haplotypic components for each Ethiopian individual. The non-African component, which includes the SLC24A5 allele associated with light skin pigmentation in Europeans, may represent gene flow into Africa, which we estimate to have occurred ∼3 thousand years ago (kya). The non-African component was found to be more similar to populations inhabiting the Levant rather than the Arabian Peninsula, but the principal route for the expansion out of Africa ∼60 kya remains unresolved. Linkage-disequilibrium decay with genomic distance was less rapid in both the whole genome and the African component than in southern African samples, suggesting a less ancient history for Ethiopian populations.

Pharmacogenetic testing of drug metabolizing enzyme polymorphisms provides an important tool to improve prescribing decisions, avoiding therapeutic failure and adverse drug reactions. Cytochrome P450 2D6 isoform plays an important role in the metabolism of about 20%-25% of widely used clinical drugs. Interethnic differences in allele frequency distribution of the CYP2D6 gene are well established, but interethnic admixture, introducing variations in population ancestry and resulting in distinct levels of population structure, should be acknowledged in pharmacogenomic studies to avoid inappropriate extrapolation of CYP2D6 data. The aim of the present research was to characterize CYP2D6 polymorphism in a random sample of 122 natives and 175 immigrants from Africa, Asia, and South America living in the Emilia-Romagna region (Italy), considering the present scenario of immigration and back migration events, which is a source of admixture. The results are today consistent with the known interethnic genetic variation, but the observed significant divergence between natives and Africans or South-East Asians predicts that admixture will reshape the population structure and the native metabolic ratio curve requiring, for drug prescription and pharmacogenetics studies, an interdisciplinary approach applied in an appropriate biogeographical and anthropological frame.

BACKGROUND: Liddle's syndrome (LS) is a monogenic form of hypertension simulating a mineralocorticoid excess, and is currently suspected in young hypokalemic hypertensives. The aims of the study were: (i) to evaluate the clinical phenotype of LS in a newly identified Italian family of Sicilian origin carrying a gain-of-function mutation of the β subunit of the epithelial sodium channel (ENaC) (P617L) previously reported by our group in an apparently unrelated Sicilian patient presenting the typical phenotype of LS including hypokalemia; (ii) to determine whether an unknown biological relationship exists between the newly identified family and the family of the proband previously reported. METHODS: Genetic analysis was performed in the present family, in the individual in which the βP617L mutation was first observed, and in his relatives. RESULTS: βP617L mutation was identified in the proband and in three maternal relatives. None of them showed hypokalemia. Mild to severe early onset hypertension and left ventricular hypertrophy were present in all of them. Analysis of mitochondrial DNA (mtDNA) and Y chromosome profiles in the present family and in the proband's family previously reported showed the absence of a relationship between them. The availability of only one carrier of the mutation in one of the two families meant that a genetic analysis able to assess a founder effect was not feasible. CONCLUSIONS: LS should be considered in all cases of early onset hypertension, independently of the plasma potassium concentration. The incidence of LS may be greater than is currently thought, because hypokalemia is not invariably present.

Little is known about alterations of cyclin dependent kinase inhibitors p15INK4B, p16INK4A and of MDM2 inhibitor p14ARF due to single nucleotide polymorphisms (SNPs) located within the CDKN2A/B genes and/or neighbouring loci. In order to investigate the potential involvement of such common DNA sequence variants in leukemia susceptibility, an association study was performed by genotyping 23 SNPs spanning the MTAP, CDKN2A/B and CDKN2BAS loci, as well as relative intergenic regions, in a case-control cohort made up of 149 leukemia patients, including Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples, and 183 healthy controls. rs564398, mapping to the CDKN2BAS locus that encodes for ANRIL antisense non-coding RNA, showed a statistically significant correlation with the ALL phenotype, with a risk pattern that was compatible with an overdominant model of disease susceptibility and a OR of 2 (95% CI, 1.20–3.33; p = 7.1 × 10−3). We hypothesized that this association reflects the capability of some ANRIL polymorphisms to contribute to its transcription changes responsible for alterations of CDKN2A/B expression profiles, thus leading to abnormal proliferative boosts and consequent increased ALL susceptibility.

Background/Aims: Present-day Iran has long represented a natural hub for the expansion of human genes and cultures. That being so, the overlapping of prehistoric and more recent demographic events interacting at different time scales with geographical and cultural barriers has yielded a tangled patchwork of anthropological types within this narrow area. This study aims to comprehensively evaluate this ethnic mosaic by depicting a fine-grained picture of the Iranian mitochondrial landscape. Methods: mtDNA variability at both HVS-I and coding regions was surveyed in 718 unrelated individuals belonging to 14 Iranian ethnic groups characterized by different languages, religions and patterns of subsistence. Results: A discordant pattern of high ethno-linguistic and low mtDNA heterogeneity was observed for the whole examined Iranian sample. Geographical factors and cultural/linguistic differences actually represented barriers to matrilineal gene flow only for the Baloch, Lur from Yasouj, Zoroastrian and Jewish groups, for which unusual reduced levels of mtDNA variability and high inter-population distances were found. Conclusion: Deep rooting genealogies and endogamy in a few of the examined ethnic groups might have preserved ancestral lineages that can be representative of Proto-Indo-Iranian or prehistoric mitochondrial profiles which survived relatively recent external contributions to the Iranian gene pool.

BACKGROUND: The choice of criteria for correct DNA sampling in isolated populations is often affected by ambiguities, despite its importance in medical and anthropological genetics. AIM: We propose a novel biodemographic approach to the study of isolates based on surname analysis and migration matrices, and we apply it to a candidate isolated population: the Val di Scalve (Italian Pre-Alps). METHODS: Kinship matrices and self-organizing maps (SOMs) were applied to information extracted from 2870 marriage records relative to the years 1866-1935. RESULTS: The Val di Scalve shows the typical genetic trademarks of an isolate at least up to the first half of the 20th century. Furthermore, the area was characterized by differential mobility patterns between males and females, consistent with the virilocal migration model. These data suggest reliable criteria for an efficient DNA sampling design by (a) detecting the units of analysis to be investigated (internal population subdivisions); (b) maximizing the number of paternal lineages in the sample for Y-chromosome studies (surnames); and (c) calculating the most convenient sample size. CONCLUSION: The surname-based sampling procedure can be exported and applied to larger and non-isolated populations.

The Malagasy have been shown to be a genetically admixed population combining parental lineages with African and South East Asian ancestry. In the present paper, we fit the Malagasy admixture history in a highly resolved phylogeographic framework by typing a large set of mitochondrial DNA and Y DNA markers in unrelated individuals from inland (Merina) and coastal (Antandroy, Antanosy, and Antaisaka) ethnic groups. This allowed performance of a multilevel analysis in which the diversity among main ethnic divisions, lineage ancestries, and modes of inheritance could be concurrently evaluated. Admixture was confirmed to result from the encounter of African and Southeast Asian people with minor recent male contributions from Europe. However, new scenarios are depicted about Malagasy admixture history. The distribution of ancestral components was ethnic and sex biased, with the Asian ancestry appearing more conserved in the female than in the male gene pool and in inland than in coastal groups. A statistic based on haplotype sharing (D(HS)), showing low sampling error and time linearity over the last 200 generations, was introduced here for the first time and helped to integrate our results with linguistic and archeological data. The focus about the origin of Malagasy lineages was enlarged in space and pushed back in time. Homelands could not be pinpointed but appeared to comprise two vast areas containing different populations from sub-Saharan Africa and South East Asia. The pattern of diffusion of uniparental lineages was compatible with at least two events: a primary admixture of proto-Malay people with Bantu speakers bearing a western-like pool of haplotypes, followed by a secondary flow of Southeastern Bantu speakers unpaired for gender (mainly male driven) and geography (mainly coastal).

Vitamin D and folate are activated and degraded by sunlight, respectively, and the physiological processes they control are likely to have been targets of selection as humans expanded from Africa into Eurasia. We investigated signals of positive selection in gene sets involved in the metabolism, regulation and action of these two vitamins in worldwide populations sequenced by Phase I of the 1000 Genomes Project. Comparing allele frequency-spectrum-based summary statistics between these gene sets and matched control genes, we observed a selection signal specific to East Asians for a gene set associated with vitamin D action in bones. The selection signal was mainly driven by three genes CXXC finger protein 1 (CXXC1), low density lipoprotein receptor-related protein 5 (LRP5) and runt-related transcription factor 2 (RUNX2). Examination of population differentiation and haplotypes allowed us to identify several candidate causal regulatory variants in each gene. Four of these candidate variants (one each in CXXC1 and RUNX2 and two in LRP5) had a >70% derived allele frequency in East Asians, but were present at lower (20–60%) frequency in Europeans as well, suggesting that the adaptation might have been part of a common response to climatic and dietary changes as humans expanded out of Africa, with implications for their role in vitamin D-dependent bone mineralization and osteoporosis insurgence. We also observed haplotype sharing between East Asians, Finns and an extinct archaic human (Denisovan) sample at the CXXC1 locus, which is best explained by incomplete lineage sorting., This work was supported by The Wellcome Trust (098051). EA was supported by the Erasmus Lifelong Learning Programme (LLP). LP was supported by the ERC Starting Investigator grant FP7 – 261213.

Social and cultural factors had a critical role in determining the genetic structure of Europe. Therefore, socially stratified populations may help to focus on specific episodes of European demographic history. In this study, we use uniparental markers to analyse the genetic structure of Partecipanza in San Giovanni in Persiceto (Northern Italy), a peculiar institution whose origins date back to the Middle Ages and whose members form the patrilineal descent of a group of founder families. From a maternal point of view (mtDNA), Partecipanza is genetically homogeneous with the rest of the population. However, we observed a significant differentiation for Y-chromosomes. In addition, by comparing 17 Y-STR profiles with deep-rooted paternal pedigrees, we estimated a Y-STR mutation rate equal to 3.90 * 10(-3) mutations per STR per generation and an average generation duration time of 33.38 years. When we used these values for tentative dating, we estimated 1300-600 years ago for the origins of the Partecipanza. These results, together with a peculiar Y-chromosomal composition and historical evidence, suggest that Germanic populations (Lombards in particular) settled in the area during the Migration Period (400-800 AD, approximately) and may have had an important role in the foundation of this community.

OBJECTIVE: Although genetic variants related to lactase persistence in European populations were supposed to have firstly undergone positive selection in farmers from the Balkans and Central Europe, demographic and evolutionary dynamics that subsequently shaped the distribution of this adaptive trait across the continent have still to be elucidated. To deepen the knowledge about potential routes of diffusion of lactase persistence to Western Europe we investigated variation at a large genomic region surrounding the LCT gene along the Italian peninsula, a geographical area that played a key role in population movements responsible for Neolithic diffusion across Europe. METHODS: By genotyping 40 highly selected SNPs in more than 400 Italian individuals we described gradients of nucleotide and haplotype variation potentially related to lactase persistence and compared them with those observed in several European and Mediterranean human groups. RESULTS: Multiple migratory events responsible for earlier introduction of the examined alleles in Italy than in Northern European regions could be invoked. Different demic processes occurred along the western and eastern sides of the peninsula were also inferred via linkage disequilibrium and population structure analyses. CONCLUSION: The appreciable genetic continuum observed between people from Northern or Central-Western Italy and Central European populations suggested a local arrival of lactase persistence-related variants mainly via overland routes. On the contrary, diversity of Central-Eastern and Southern Italian groups entailed also gene flow from South-Eastern Mediterranean regions, in accordance to the earlier entrance of the Neolithic in Southern Italy via maritime population movements along the Mediterranean coastlines

How and when the Americas were populated remains contentious. Using ancient and modern genome-wide data, we find that the ancestors of all present-day Native Americans, including Athabascans and Amerindians, entered the Americas as a single migration wave from Siberia no earlier than 23 thousand years ago (KYA), and after no more than 8,000-year isolation period in Beringia. Following their arrival to the Americas, ancestral Native Americans diversified into two basal genetic branches around 13 KYA, one that is now dispersed across North and South America and the other is restricted to North America. Subsequent gene flow resulted in some Native Americans sharing ancestry with present-day East Asians (including Siberians) and, more distantly, Australo-Melanesians. Putative ‘Paleoamerican’ relict populations, including the historical Mexican Pericúes and South American Fuego-Patagonians, are not directly related to modern Australo-Melanesians as suggested by the Paleoamerican Model.

The relationship between genetic and linguistic diversification in human populations has been often explored to interpret some specific issues in human history. The Albanian-speaking minorities of Sicily and Southern Italy (Arbereshe) constitute an important portion of the ethnolinguistic variability of Italy. Their linguistic isolation from neighboring Italian populations and their documented migration history, make such minorities particularly effective for investigating the interplay between cultural, geographic and historical factors. Nevertheless, the extent of Arbereshe genetic relationships with the Balkan homeland and the Italian recipient populations has been only partially investigated. In the present study we address the genetic history of Arbereshe people by combining highly resolved analyses of Y-chromosome lineages and extensive computer simulations. A large set of slow- and fast-evolving molecular markers was typed in different Arbereshe communities from Sicily and Southern Italy (Calabria), as well as in both the putative Balkan source and Italian sink populations. Our results revealed that the considered Arbereshe groups, despite speaking closely related languages and sharing common cultural features, actually experienced diverging genetic histories. The estimated proportions of genetic admixture confirm the tight relationship of Calabrian Arbereshe with modern Albanian populations, in accordance with linguistic hypotheses. On the other hand, population stratification and/or an increased permeability of linguistic and geographic barriers may be hypothesized for Sicilian groups, to account for their partial similarity with Greek populations and their higher levels of local admixture. These processes ultimately resulted in the differential acquisition or preservation of specific paternal lineages by the present-day Arbereshe communities.European Journal of Human Genetics advance online publication, 1 July 2015; doi:10.1038/ejhg.2015.138.

The levels of haplotype diversity within the lineages defined by two single-nucleotide polymorphisms (SNPs) (-13910 C/T and -22018 G/A) associated with human lactase persistence were assessed with four fast-evolving microsatellite loci in 794 chromosomes from Portugal, Italy, Fulbe from Cameroon, Sao Tome and Mozambique. Age estimates based on the intraallelic microsatellite variation indicate that the -13910*T allele, which is more tightly associated with lactase persistence, originated in Eurasia before the Neolithic and after the emergence of modern humans outside Africa. We detected significant departures from neutrality for the -13910*T variant in geographically and evolutionary distant populations from southern Europe (Portuguese and Italians) and Africa (Fulbe) by using a neutrality test based on the congruence between the frequency of the allele and the levels of intraallelic variability measured by the number of mutations in adjacent microsatellites. This result supports the role of selection in the evolution of lactase persistence, ruling out possible confounding effects from recombination suppression and population history. Reevaluation of the available evidence on variation of the -13910 and -22018 loci indicates that lactase persistence probably originated from different mutations in Europe and most of Africa, even if 13910*T is not the causal allele, suggesting that selective pressure could have promoted the convergent evolution of the trait. Our study shows that a limited number of microsatellite loci may provide sufficient resolution to reconstruct key aspects of the evolutionary history of lactase persistence, providing an alternative to approaches based on large numbers of SNPs.

CONTEXT: Epigenetics represents a still unexplored research field in the understanding of micro- and macro-evolutionary mechanisms, as epigenetic changes create phenotypic diversity within both individuals and populations. OBJECTIVE: The purpose of this review is to dissect the landscape of studies focused on DNA methylation, one of the most described epigenetic mechanisms, emphasizing the aspects that could be relevant in human adaptations. METHODS: Theories and results here considered were collected from the most recent papers published. RESULTS: The matter of DNA methylation inheritance is here described as well as the recent evolutionary theories regarding the role of DNA methylation-and epigenetics in a broader sense-in human evolution. The complex relation between (1) DNA methylation and genetic variability and (2) DNA methylation and the environmental stimuli crucial in shaping genetic and phenotypic variability through the human lineage-such as diet, climate and pathogens exposure-are described. Papers about population epigenetics are also illustrated due to their high relevance in this context. CONCLUSION: Genetic, epigenetic and phenotypic variations of the species, together with cultural ones, are considerably shaped by a vast range of environmental stimuli, thus representing the foundation of all human bio-cultural adaptations.

The last 30 years of research greatly contributed to shed light on the role of mitochondrial DNA (mtDNA) variability in aging, although contrasting results have been reported, mainly due to bias regarding the population size and stratification, and to the use of analysis methods (haplogroup classification) that resulted to be not sufficiently adequate to grasp the complexity of the phenomenon. A 5-years European study (the GEHA EU project) collected and analyzed data on mtDNA variability on an unprecedented number of long-living subjects (enriched for longevity genes) and a comparable number of controls (matched for gender and ethnicity) in Europe. This very large study allowed a reappraisal of the role of both the inherited and the somatic mtDNA variability in aging, as an association with longevity emerged only when mtDNA variants in OXPHOS complexes co-occurred. Moreover, the availability of data from both nuclear and mitochondrial genomes on a large number of subjects paves the way for an evaluation at a very large scale of the epistatic interactions at a higher level of complexity. This scenario is expected to be even more clarified in the next future with the use of next generation sequencing (NGS) techniques, which are becoming applicable to evaluate mtDNA variability and, then, new mathematical/bioinformatic analysis methods are urgently needed. Recent advances of association studies on age-related diseases and mtDNA variability will also be discussed in this review, taking into account the bias hidden by population stratification. Finally, very recent findings in terms of mtDNA heteroplasmy (i.e. the coexistence of wild type and mutated copies of mtDNA) and aging as well as mitochondrial epigenetic mechanisms will also be discussed.

Due to their strategic geographic location between three different continents, Sicily and Southern Italy have long represented a major Mediterranean crossroad where different peoples and cultures came together over time. However, its multi-layered history of migration pathways and cultural exchanges, has made the reconstruction of its genetic history and population structure extremely controversial and widely debated. To address this debate, we surveyed the genetic variability of 326 accurately selected individuals from 8 different provinces of Sicily and Southern Italy, through a comprehensive evaluation of both Y-chromosome and mtDNA genomes. The main goal was to investigate the structuring of maternal and paternal genetic pools within Sicily and Southern Italy, and to examine their degrees of interaction with other Mediterranean populations. Our findings show high levels of within-population variability, coupled with the lack of significant genetic sub-structures both within Sicily, as well as between Sicily and Southern Italy. When Sicilian and Southern Italian populations were contextualized within the Euro-Mediterranean genetic space, we observed different historical dynamics for maternal and paternal inheritances. Y-chromosome results highlight a significant genetic differentiation between the North-Western and South-Eastern part of the Mediterranean, the Italian Peninsula occupying an intermediate position therein. In particular, Sicily and Southern Italy reveal a shared paternal genetic background with the Balkan Peninsula and the time estimates of main Y-chromosome lineages signal paternal genetic traces of Neolithic and post-Neolithic migration events. On the contrary, despite showing some correspondence with its paternal counterpart, mtDNA reveals a substantially homogeneous genetic landscape, which may reflect older population events or different demographic dynamics between males and females. Overall, both uniparental genetic structures and TMRCA estimates confirm the role of Sicily and Southern Italy as an ancient Mediterranean melting pot for genes and cultures.

Most ancient specimens contain very low levels of endogenous DNA, precluding the shotgun sequencing of many interesting samples because of cost. Ancient DNA (aDNA) libraries often contain

East Africa (EA) has witnessed pivotal steps in the history of human evolution. Due to its high environmental and cultural variability, and to the long-term human presence there, the genetic structure of modern EA populations is one of the most complicated puzzles in human diversity worldwide. Similarly, the widespread Afro-Asiatic (AA) linguistic phylum reaches its highest levels of internal differentiation in EA. To disentangle this complex ethno-linguistic pattern, we studied mtDNA variability in 1,671 individuals (452 of which were newly typed) from 30 EA populations and compared our data with those from 40 populations (2970 individuals) from Central and Northern Africa and the Levant, affiliated to the AA phylum. The genetic structure of the studied populations—explored using spatial Principal Component Analysis and Model-based clustering—turned out to be composed of four clusters, each with different geographic distribution and/or linguistic affiliation, and signaling different population events in the history of the region. One cluster is widespread in Ethiopia, where it is associated with different AA-speaking populations, and shows shared ancestry with Semitic-speaking groups from Yemen and Egypt and AA-Chadic-speaking groups from Central Africa. Two clusters included populations from Southern Ethiopia, Kenya and Tanzania. Despite high and recent gene-flow (Bantu, Nilo-Saharan pastoralists), one of them is associated with a more ancient AA-Cushitic stratum. Most North-African and Levantine populations (AA-Berber, AA-Semitic) were grouped in a fourth and more differentiated cluster. We therefore conclude that EA genetic variability, although heavily influenced by migration processes, conserves traces of more ancient strata. Am J Phys Anthropol, 2013. © 2013 Wiley Periodicals, Inc.

Sub-population structure and intricate kinship dynamics might introduce biases in molecular anthropology studies and could invalidate the efforts to understand diseases in highly admixed populations. In order to clarify the previously observed distribution pattern and morbidity of Chagas disease in Gran Chaco, Argentina, we studied two populations (Wichı´ and Criollos) recruited following an innovative bio-cultural model considering their complex cultural interactions. By reconstructing the genetic background and the structure of these two culturally different populations, the pattern of admixture, the correspondence between genealogical and genetic relationships, this integrated perspective had the power to validate data and to link the gap usually relying on a singular discipline. Although Wichı´ and Criollos share the same area, these sympatric populations are differentiated from the genetic point of view as revealed by Non Recombinant Y Chromosome genotyping resulting in significantly high Fst values and in a lower genetic variability in the Wichı´ population. Surprisingly, the Amerindian and the European components emerged with comparable amounts (20%) among Criollos and Wichı´ respectively. The detailed analysis of mitochondrial DNA showed that the two populations have as much as 87% of private haplotypes. Moreover, from the maternal perspective, despite a common Amerindian origin, an Andean and an Amazonian component emerged in Criollos and in Wichı´ respectively. Our approach allowed us to highlight that quite frequently there is a discrepancy between self-reported and genetic kinship. Indeed, if self-reported identity and kinship are usually utilized in population genetics as a reliable proxy for genetic identity and parental relationship, in our model populations appear to be the result not only and not simply of the genetic background but also of complex cultural determinants. This integrated approach paves the way to a rigorous reconstruction of demographic and cultural history as well as of bioancestry and propensity to diseases of Wichı´ and Criollos.

Rapidly Mutating Y-STRs (RM Y-STRs) were recently introduced in forensics in order to increase the differentiation of Y-chromosomal profiles even in case of close relatives. We estimate RM Y-STRs mutation rates and their power to discriminate between related individuals by using samples extracted from a wide set of paternal pedigrees and by comparing RM Y-STRs results with those obtained from the Y-filer set. In addition, we tested the ability of RM Y-STRs to discriminate between unrelated individuals carrying the same Y-filer haplotype, using the haplogroup R-M269 (reportedly characterised by a strong resemblance in Y-STR profiles) as a case study. Our results, despite confirming the high mutability of RM Y-STRs, show significantly lower mutation rates than reference germline ones. Consequently, their power to discriminate between related individuals, despite being higher than the one of Y-filer, does not seem to improve significantly the performance of the latter. On the contrary, when considering R-M269 unrelated individuals, RM Y-STRs reveal significant discriminatory power and retain some phylogenetic signal, allowing the correct classification of individuals for some R-M269-derived sub-lineages. These results have important implications not only for forensics, but also for molecular anthropology, suggesting that RM Y-STRs are useful tools for exploring subtle genetic variability within Y-chromosomal haplogroups.

To investigate the genetic variability of IL-17A, IL17-RA, IL-23A and IL-23R genes on an in-depth phenotypically characterized northern Italian Psoriatic arthritis (PsA) case–control cohort, in search for associations specific to different PsA clinical sub-phenotypes. We examined 118 patients with PsA according to CASPAR criteria (mean age 57 ± 13, female 38.4 %, mean disease duration 13.9 ± 8.6 years, peripheral disease 83.8 %, axial manifestations 34.5 %, radiological erosive disease 49 %) compared with 248 controls of the same ethnic origin matched for age and sex. The presence of axial disease was defined by the clinical axial involvement and/or the presence of radiological alteration consistent with spondyloarthropathy according to New York criteria. The presence of peripheral disease (arthritis and/or enthesitis) was defined only on clinical basis. A total of 40 SNPs, mapping within the genes mentioned above, were genotyped in both groups and used to perform association analyses by subdividing the PsA sample into subgroups according to different clinical manifestations on the basis of axial and peripheral involvements. No differences between patients and controls were found in the distribution of the IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants. Comparing patients with axial disease versus those without, we found that axial manifestations were significantly associated with the presence of IL-23R rs12401432 GG homozygosity (26.8 % vs. 5.3 %, p corr = 0.019, OR 2.63 [95 % CI 1.13–6.16]). No differences in distribution of the allelic variants were found comparing patients with versus those without peripheral disease or patients with versus without radiological peripheral erosions. In PA patients of northern Italian origin, IL-17A, IL17-RA, IL-23A and IL-23R genes allelic variants are not associated with disease susceptibility. However, a strong association with the IL-23RA rs12401432 GG genotype is associated with axial involvement of the disease.

Contains fulltext : 108117.pdf (Publisher’s version ) (Closed access) Infectious diseases exert a constant evolutionary pressure on the innate immunity genes. TLR4, an important member of the TLR family, specifically recognizes conserved structures of various infectious pathogens. Two functional TLR4 polymorphisms, Asp299Gly and Thr399Ile, modulate innate host defense against infections, and their prevalence between various populations has been proposed to be influenced by local infectious pressures. If this assumption is true, strong local infectious pressures would lead to a homogeneous pattern of these ancient TLR4 polymorphisms in geographically-close populations, while a weak selection or genetic drift may result in a diverse pattern. We evaluated TLR4 polymorphisms in 15 ethnic groups in Iran, to assess whether infections exerted selective pressures on different haplotypes containing these variants. The Iranian subpopulations displayed a heterogeneous pattern of TLR4 polymorphisms, comprising various percentages of Asp299Gly and Thr399Ile, alone or in combination. The Iranian sample, as a whole, showed an intermediate mixed pattern when compared with commonly-found patterns in Africa, Europe, Eastern Asia and the Americas. These findings suggest a weak, or absent, selection pressure on TLR4 polymorphisms in the Middle-East that does not support the assumption of an important role of these polymorphisms in the host defense against local pathogens. 01 juni 2012

artículo (arbitrado). Universidad de Costa Rica, Centro de Investigación en Biología Celular y Molecular, 2012 Estimates of mutation rates for the noncoding hypervariable Region I (HVR-I) of mitochondrial DNA (mtDNA) vary widely, depending on whether they are inferred from phylogenies (assuming that molecular evolution is clock-like) or directly from pedigrees. All pedigree-based studies so far were conducted on populations of European origin. In this paper we analyzed 19 deep-rooting pedigrees in a population of mixed origin in Costa Rica. We calculated two estimates of the HVRI mutation rate, one considering all apparent mutations, and one disregarding changes at sites known to be mutational hot spots and eliminating genealogy branches which might be suspected to include errors, or unrecognized adoptions along the female lines. At the end of this procedure, we still observed a mutation rate equal to 1.24 × 10−6, per site per year, i.e., at least three-fold as high as estimates derived from phylogenies. Our results confirm that mutation rates observed in pedigrees are much higher than estimated assuming a neutral model of long-term HVRI evolution. We argue that, until the cause of these discrepancies will be fully understood, both lower estimates (i.e., those derived from phylogenetic comparisons) and higher, direct estimates such as those obtained in this study, should be considered when modeling evolutionary and demographic processes. Universidad de Costa Rica UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)

The human genome is constantly subjected to evolutionary forces which shape its architecture. Insertions of mitochondrial DNA sequences into nuclear genome (NumtS) have been described in several eukaryotic species, including Homo sapiens and other primates. The ongoing process of the generation of NumtS has made them valuable markers in primate phylogenetic studies, as well as potentially informative loci for reconstructing the genetic history of modern humans. Here, we report the identification of 53 human-specific NumtS by inspection of the UCSC genome browser, showing that they may be direct insertions of mitochondrial DNA into the human nuclear DNA after the human-chimpanzee split. In silico analyses allowed us to identify 14 NumtS which are polymorphic in terms of their presence/absence within the human genome in individuals of different ancestry. The allele frequencies of these polymorphic NumtS were calculated for 1000 Genomes Project sequence data from 13 populations worldwide, and principal components analysis and hierarchical clustering methods allowed the detection of strong signals of geographical structure related to the genetic diversity of these loci. All identified polymorphic human-specific NumtS together with a tandemly duplicated NumtS have also been validated by PCR amplification on a panel of 60 samples belonging to five native populations worldwide, confirming the expected NumtS variability. On the basis of these findings, we have succeeded in depicting the landscape of variation of a series of NumtS in several ethnic groups, making an advance in their identification as useful markers in the study on human population genetics.

The study of Y chromosome variation has helped reconstruct demographic events associated with the spread of languages, agriculture and pastoralism in sub-Saharan Africa, but little attention has been given to the early history of the continent. In order to overcome this lack of knowledge, we carried out a phylogeographic analysis of haplogroups A and B in a broad dataset of sub-Saharan populations. These two lineages are particularly suitable for this objective because they are the two most deeply rooted branches of the Y chromosome genealogy. Their distribution is almost exclusively restricted to sub-Saharan Africa where their frequency peaks at 65% in groups of foragers. The combined high resolution SNP analysis with STR variation of their sub-clades reveals strong geographic and population structure for both haplogroups., This has allowed us to identify specific lineages related to regional pre-agricultural dynamics in different areas of sub-Saharan Africa. In addition, we observed signatures of relatively recent contact, both among Pygmies, and between them and Khoisan speaker groups from southern Africa, thus contributing to the understanding of the complex evolutionary relationships among African hunter-gatherers. Finally, by revising the phylogeography of the very early human Y chromosome lineages, we have obtained support for the role of southern Africa as a sink, rather than a source, of the first migrations of modern humans from eastern and central parts of the continent. These results open new perspectives on the early history of Homo sapiens in Africa, with particular attention to areas of the continent where human fossil remains and archaeological data are scant.