The emerging complexity of Open Science: assessing Intelligent Data Openness in Genomic Anthropology and Human Genomics.

In recent decades, the scientific community has become aware of the importance of science being effectively open in order to speed up scientific and technological progress. In this context, the achievement of a robust, effective and responsible form of data sharing is now widely acknowledged as a fundamental part of the research process. The production and resolution of human genomic data has steadily increased in recent years, mainly due to technological advances and decreasing costs of DNA genotyping and sequencing. There is, however, a downside to this process due to the huge increase in the complexity of the data and related metadata. This means it is advisable to go beyond traditional forms of sharing analysis, which have focused on data availability only. Here we present a pilot study that aims to complement a survey on the availability of data related to peer-reviewed publications with an analysis of their findability, accessibility, useability and assessability (according to the "intelligent data openness" scheme). Sharing rates in genomic anthropology (73.0%) were found to be higher than human genomics (32.4%), but lower than closely related research fields (from 96.8% to 79.2% for paleogenetics and evolutionary genetics, respectively). We discuss the privacy and methodological issues that could be linked to this finding. Comparisons of sharing rates across a wide range of disciplines has suggested that the idea of human genomics as a forerunner for the open data movement should be questioned. Finally, both in genomic anthropology and human genomics, findability and useability were found to be compliant with the expectations of an intelligent data openness, whereas only a minor part of studies met the need to make the data completely assessable.

Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug induced arrhythmia and sudden unexplained deaths

Abstract Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analyzing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity. (AU)

Iron Age Italic population genetics: the Piceni from Novilara (8th-7th century BC).

BACKGROUND: Archaeological data provide evidence that Italy, during the Iron Age, witnessed the appearance of the first communities with well defined cultural identities. To date, only a few studies report genetic data about these populations and, in particular, the Piceni have never been analysed. AIMS: To provide new data about mitochondrial DNA (mtDNA) variability of an Iron Age Italic population, to understand the contribution of the Piceni in shaping the modern Italian gene pool and to ascertain the kinship between some individuals buried in the same grave within the Novilara necropolis. SUBJECTS AND METHODS: In a first set of 10 individuals from Novilara, we performed deep sequencing of the HVS-I region of the mtDNA, combined with the genotyping of 22 SNPs in the coding region and the analysis of several autosomal markers. RESULTS: The results show a low nucleotide diversity for the inhabitants of Novilara and highlight a genetic affinity of this ancient population with the current inhabitants of central Italy. No family relationship was observed between the individuals analysed here. CONCLUSIONS: This study provides a preliminary characterisation of the mtDNA variability of the Piceni of Novilara, as well as a kinship assessment of two peculiar burials.

Stuck in fragments: Population genetics of the Endangered collared brown lemur Eulemur collaris in the Malagasy littoral forest.

OBJECTIVES: The Endangered collared brown lemur (Eulemur collaris) is the largest primate living in the littoral forest of southeastern Madagascar, a top priority habitat for biodiversity conservation on the island. Because this lemur is a key seed-disperser, an evaluation of the structure and connectivity of the populations surviving in the forest fragments is urgently needed to guide conservation plans. MATERIALS AND METHODS: Genetic variability at autosomal microsatellites and mitochondrial DNA was investigated in a total of 49 collared brown lemurs sampled by non-invasive methods in three littoral forest fragments and in the nearby lowland humid forest. RESULTS: The overall genetic diversity of E. collaris in the southeastern coastal region of Madagascar was lower than in other populations, as well as in other lemur species. The population appears highly structured, with less variable and more inbred groups inhabiting the littoral forest fragments compared to the inland area. Major barriers to gene flow were identified isolating littoral forest fragments from each other and from the inland lowland humid forest. DISCUSSION: Medium to long-term drift and scarce gene flow is the scenario that best explains the current genetic distribution. Habitat discontinuities such as rivers and grassland between forest fragments played a major role in structuring the population. A common history of size contraction is pointed out by several genetic estimators, indicating a possible ecological crisis triggered around 1,300 years ago. The adoption of strategies aimed at facilitating gene flow and population growth appears crucial to delay further loss of genetic diversity.

Charting the Y-chromosome ancestry of present-day Argentinean Mennonites.

Old Order Mennonite communities initially arose in Northern Europe (centered in the Netherlands) and derived from the Anabaptist movement of the 16th century. Mennonites migrated to the New World in the early 18th century, first to North America, and more recently to Mesoamerica and South America. We analyzed Y-chromosome short tandem repeats (STRs) and single nucleotide polymorphisms in males from a community of Mennonites, 'La Nueva Esperanza', which arrived to Argentina in 1985 from colonies in Bolivia and Mexico. Molecular diversity indices coupled with demographic simulations show that Mennonites have a reduced variability when compared with local Argentinean populations and 69 European population samples. Mennonite Y-STR haplotypes were mainly observed in Central Europe. In agreement, multidimensional scaling analyses based on RST genetic distances indicate that Mennonite Y-chromosomes are closely related to Central/Northern Europeans (the Netherlands, Switzerland and Denmark). In addition, statistical inferences made on the most likely geographic origin of Y-chromosome haplotypes point more specifically to the Netherlands as the populations that best represent the majority of the Mennonite Y-chromosomes. Overall, Y-chromosome variation of Mennonites shows the signatures of moderate reduction of variability when compared with source populations, which is in good agreement with their lifestyle in small endogamous demes. These genetic singularities could also help to understand disease conditions that are more prevalent among Mennonites.

Analysis of Y-chromosome STRs in Chile confirms an extensive introgression of European male lineages in urban populations.

We analyzed the Y chromosome haplotypes (Yfiler) of 978 non-related Chilean males grouped in five sampling regions (Iquique, Santiago de Chile, Concepción, Temuco and Punta Arenas) covering main geo-political regions. Overall, 803 different haplotypes and 688 singletons were observed. Molecular diversity was moderately lower than in other neighboring countries (e.g. Argentina); and AMOVA analysis on Y-STR haplotypes showed that among variation within Chile accounted for only 0.25% of the total variation. Punta Arenas, in the southern cone, showed the lowest haplotype diversity, and discrimination capacity, and also the highest matching probability of the five Chilean samples, probably reflecting its more marked geographic isolation compared to the other regions. Multidimensional scaling (MDS) analysis based on RST genetic distances suggested a close proximity of Chilean Y-chromosome profiles to European ones. Consistently, haplogroups inferred from Y-STR profiles revealed that the Native American component constituted only 8% of all the haplotypes, and this component ranged from 5% in the Centre of the country to 9-10% in the South and 13% in the North, which is in good agreement with the distribution of Native American communities in these regions. AMOVA computed on inferred haplogroups confirmed the very low among variation observed in Chilean populations. The present project provides the first Chilean dataset to the international Y-chromosome STR Haplotype Reference Database (YHRD) and it is also the first reference database for Y-chromosome forensic casework of the country.

The Greeks in the West: genetic signatures of the Hellenic colonisation in southern Italy and Sicily.

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.

Shared language, diverging genetic histories: high-resolution analysis of Y-chromosome variability in Calabrian and Sicilian Arbereshe.

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.

The Role of Recent Admixture in Forming the Contemporary West Eurasian Genomic Landscape.

Over the past few years, studies of DNA isolated from human fossils and archaeological remains have generated considerable novel insight into the history of our species. Several landmark papers have described the genomes of ancient humans across West Eurasia, demonstrating the presence of large-scale, dynamic population movements over the last 10,000 years, such that ancestry across present-day populations is likely to be a mixture of several ancient groups [1-7]. While these efforts are bringing the details of West Eurasian prehistory into increasing focus, studies aimed at understanding the processes behind the generation of the current West Eurasian genetic landscape have been limited by the number of populations sampled or have been either too regional or global in their outlook [8-11]. Here, using recently described haplotype-based techniques [11], we present the results of a systematic survey of recent admixture history across Western Eurasia and show that admixture is a universal property across almost all groups. Admixture in all regions except North Western Europe involved the influx of genetic material from outside of West Eurasia, which we date to specific time periods. Within Northern, Western, and Central Europe, admixture tended to occur between local groups during the period 300 to 1200 CE. Comparisons of the genetic profiles of West Eurasians before and after admixture show that population movements within the last 1,500 years are likely to have maintained differentiation among groups. Our analysis provides a timeline of the gene flow events that have generated the contemporary genetic landscape of West Eurasia.

Static and moving frontiers: the genetic landscape of Southern African Bantu-speaking populations.

A consensus on Bantu-speaking populations being genetically similar has emerged in the last few years, but the demographic scenarios associated with their dispersal are still a matter of debate. The frontier model proposed by archeologists postulates different degrees of interaction among incoming agropastoralist and resident foraging groups in the presence of "static" and "moving" frontiers. By combining mitochondrial DNA and Y chromosome data collected from several southern African populations, we show that Bantu-speaking populations from regions characterized by a moving frontier developing after a long-term static frontier have larger hunter-gatherer contributions than groups from areas where a static frontier was not followed by further spatial expansion. Differences in the female and male components suggest that the process of assimilation of the long-term resident groups into agropastoralist societies was gender biased. Our results show that the diffusion of Bantu languages and culture in Southern Africa was a process more complex than previously described and suggest that the admixture dynamics between farmers and foragers played an important role in shaping the current patterns of genetic diversity.

Ancient human genomes suggest three ancestral populations for present-day Europeans.

We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations' deep relationships and show that early European farmers had ∼44% ancestry from a 'basal Eurasian' population that split before the diversification of other non-African lineages.

Collaborative EDNAP exercise on the IrisPlex system for DNA-based prediction of human eye colour.

The IrisPlex system is a DNA-based test system for the prediction of human eye colour from biological samples and consists of a single forensically validated multiplex genotyping assay together with a statistical prediction model that is based on genotypes and phenotypes from thousands of individuals. IrisPlex predicts blue and brown human eye colour with, on average, >94% precision accuracy using six of the currently most eye colour informative single nucleotide polymorphisms (HERC2 rs12913832, OCA2 rs1800407, SLC24A4 rs12896399, SLC45A2 (MATP) rs16891982, TYR rs1393350, and IRF4 rs12203592) according to a previous study, while the accuracy in predicting non-blue and non-brown eye colours is considerably lower. In an effort to vigorously assess the IrisPlex system at the international level, testing was performed by 21 laboratories in the context of a collaborative exercise divided into three tasks and organised by the European DNA Profiling (EDNAP) Group of the International Society of Forensic Genetics (ISFG). Task 1 involved the assessment of 10 blood and saliva samples provided on FTA cards by the organising laboratory together with eye colour phenotypes; 99.4% of the genotypes were correctly reported and 99% of the eye colour phenotypes were correctly predicted. Task 2 involved the assessment of 5 DNA samples extracted by the host laboratory from simulated casework samples, artificially degraded, and provided to the participants in varying DNA concentrations. For this task, 98.7% of the genotypes were correctly determined and 96.2% of eye colour phenotypes were correctly inferred. For Tasks 1 and 2 together, 99.2% (1875) of the 1890 genotypes were correctly generated and of the 15 (0.8%) incorrect genotype calls, only 2 (0.1%) resulted in incorrect eye colour phenotypes. The voluntary Task 3 involved participants choosing their own test subjects for IrisPlex genotyping and eye colour phenotype inference, while eye photographs were provided to the organising laboratory and judged; 96% of the eye colour phenotypes were inferred correctly across 100 samples and 19 laboratories. The high success rates in genotyping and eye colour phenotyping clearly demonstrate the reproducibility and the robustness of the IrisPlex assay as well as the accuracy of the IrisPlex model to predict blue and brown eye colour from DNA. Additionally, this study demonstrates the ease with which the IrisPlex system is implementable and applicable across forensic laboratories around the world with varying pre-existing experiences.

Linguistic, geographic and genetic isolation: a collaborative study of Italian populations.

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.

Correction: Uniparental Markers of Contemporary Italian Population Reveals Details on Its Pre-Roman Heritage.

[This corrects the article DOI: 10.1371/journal.pone.0050794.].

Demographic histories, isolation and social factors as determinants of the genetic structure of Alpine linguistic groups.

Great European mountain ranges have acted as barriers to gene flow for resident populations since prehistory and have offered a place for the settlement of small, and sometimes culturally diverse, communities. Therefore, the human groups that have settled in these areas are worth exploring as an important potential source of diversity in the genetic structure of European populations. In this study, we present new high resolution data concerning Y chromosomal variation in three distinct Alpine ethno-linguistic groups, Italian, Ladin and German. Combining unpublished and literature data on Y chromosome and mitochondrial variation, we were able to detect different genetic patterns. In fact, within and among population diversity values observed vary across linguistic groups, with German and Italian speakers at the two extremes, and seem to reflect their different demographic histories. Using simulations we inferred that the joint effect of continued genetic isolation and reduced founding group size may explain the apportionment of genetic diversity observed in all groups. Extending the analysis to other continental populations, we observed that the genetic differentiation of Ladins and German speakers from Europeans is comparable or even greater to that observed for well known outliers like Sardinian and Basques. Finally, we found that in south Tyroleans, the social practice of Geschlossener Hof, a hereditary norm which might have favored male dispersal, coincides with a significant intra-group diversity for mtDNA but not for Y chromosome, a genetic pattern which is opposite to those expected among patrilocal populations. Together with previous evidence regarding the possible effects of "local ethnicity" on the genetic structure of German speakers that have settled in the eastern Italian Alps, this finding suggests that taking socio-cultural factors into account together with geographical variables and linguistic diversity may help unveil some yet to be understood aspects of the genetic structure of European populations.

Reevaluating a model of gender-biased gene flow among Sub-Saharan Hunter-gatherers and farmers.

In a previous study, we proposed a model for genetic admixture between African hunter-gatherers and food producers, in which we integrated demographic and genetic aspects together with ethnographic knowledge (Destro-Bisol et al. 2004b). In that study it was possible to test the model only using genetic information from widely dispersed and genetically heterogeneous populations. Here we reevaluate the congruence between the model and patterns of genetic variation using an anthropologically and geographically more homogeneous data set that includes Pygmies and farmers from Cameroon, Congo, and the Central African Republic. As implied by the model, the ratios of mtDNA to Y chromosome Nm estimates (effective population size, N, times the migration rate, m; 0.154 in Pygmies and 6.759 in farmers), support an asymmetric gene flow, with a higher Bantu-to-Pygmy gene flow for paternal than for maternal lineages, and vice versa for farmers. Analyses of intra- and interpopulation genetic variation further support the above observation, showing a prevailing effect of genetic drift on maternal lineages and gene flow on paternal lineages among Pygmies, and an opposite pattern among farmers. We also detected differences between patterns for classical and molecular measures of Y chromosome intrapopulation variation, which likely represent signatures of the introgression of Bantu lineages into the gene pool of Pygmy populations. On the whole, our results seem to reflect differences in the demographic history and the degree of patrilocality and polygyny between the two population groups, thus providing further support to our microevolutionary model in an anthropologically coherent framework.

Uniparental markers of contemporary Italian population reveals details on its pre-Roman heritage.

BACKGROUND: According to archaeological records and historical documentation, Italy has been a melting point for populations of different geographical and ethnic matrices. Although Italy has been a favorite subject for numerous population genetic studies, genetic patterns have never been analyzed comprehensively, including uniparental and autosomal markers throughout the country. METHODS/PRINCIPAL FINDINGS: A total of 583 individuals were sampled from across the Italian Peninsula, from ten distant (if homogeneous by language) ethnic communities--and from two linguistic isolates (Ladins, Grecani Salentini). All samples were first typed for the mitochondrial DNA (mtDNA) control region and selected coding region SNPs (mtSNPs). This data was pooled for analysis with 3,778 mtDNA control-region profiles collected from the literature. Secondly, a set of Y-chromosome SNPs and STRs were also analyzed in 479 individuals together with a panel of autosomal ancestry informative markers (AIMs) from 441 samples. The resulting genetic record reveals clines of genetic frequencies laid according to the latitude slant along continental Italy--probably generated by demographical events dating back to the Neolithic. The Ladins showed distinctive, if more recent structure. The Neolithic contribution was estimated for the Y-chromosome as 14.5% and for mtDNA as 10.5%. Y-chromosome data showed larger differentiation between North, Center and South than mtDNA. AIMs detected a minor sub-Saharan component; this is however higher than for other European non-Mediterranean populations. The same signal of sub-Saharan heritage was also evident in uniparental markers. CONCLUSIONS/SIGNIFICANCE: Italy shows patterns of molecular variation mirroring other European countries, although some heterogeneity exists based on different analysis and molecular markers. From North to South, Italy shows clinal patterns that were most likely modulated during Neolithic times.

Reconstructing ancient mitochondrial DNA links between Africa and Europe.

Mitochondrial DNA (mtDNA) lineages of macro-haplogroup L (excluding the derived L3 branches M and N) represent the majority of the typical sub-Saharan mtDNA variability. In Europe, these mtDNAs account for <1% of the total but, when analyzed at the level of control region, they show no signals of having evolved within the European continent, an observation that is compatible with a recent arrival from the African continent. To further evaluate this issue, we analyzed 69 mitochondrial genomes belonging to various L sublineages from a wide range of European populations. Phylogeographic analyses showed that ~65% of the European L lineages most likely arrived in rather recent historical times, including the Romanization period, the Arab conquest of the Iberian Peninsula and Sicily, and during the period of the Atlantic slave trade. However, the remaining 35% of L mtDNAs form European-specific subclades, revealing that there was gene flow from sub-Saharan Africa toward Europe as early as 11,000 yr ago.