Polymorphic transposable elements provide new insights on high-altitude adaptation in the Tibetan Plateau.

Several studies demonstrated that populations living in the Tibetan plateau are genetically and physiologically adapted to high-altitude conditions, showing genomic signatures ascribable to the action of natural selection. However, so far most of them relied solely on inferences drawn from the analysis of coding variants and point mutations. To fill this gap, we focused on the possible role of polymorphic transposable elements in influencing the adaptation of Tibetan and Sherpa highlanders. To do so, we compared high-altitude and middle/low-lander individuals of East Asian ancestry by performing in silico analyses and differentiation tests on 118 modern and ancient samples. We detected several transposable elements associated with high altitude, which map genes involved in cardiovascular, hematological, chem-dependent and respiratory conditions, suggesting that metabolic and signaling pathways taking part in these functions are disproportionately impacted by the effect of environmental stressors in high-altitude individuals. To our knowledge, our study is the first hinting to a possible role of transposable elements in the adaptation of Tibetan and Sherpa highlanders.

First core microsatellite panel identification in Apennine brown bears (Ursus arctos marsicanus): a collaborative approach.

BACKGROUND: The low cost and rapidity of microsatellite analysis have led to the development of several markers for many species. Because in non-invasive genetics it is recommended to genotype individuals using few loci, generally a subset of markers is selected. The choice of different marker panels by different research groups studying the same population can cause problems and bias in data analysis. A priority issue in conservation genetics is the comparability of data produced by different labs with different methods. Here, we compared data from previous and ongoing studies to identify a panel of microsatellite loci efficient for the long-term monitoring of Apennine brown bears (Ursus arctos marsicanus), aiming at reducing genotyping uncertainty and allowing reliable individual identifications overtimes. RESULTS: We examined all microsatellite markers used up to now and identified 19 candidate loci. We evaluated the efficacy of 13 of the most commonly used loci analyzing 194 DNA samples belonging to 113 distinct bears selected from the Italian national biobank. We compared data from 4 different marker subsets on the basis of genotyping errors, allelic patterns, observed and expected heterozygosity, discriminatory powers, number of mismatching pairs, and probability of identity. The optimal marker set was selected evaluating the low molecular weight, the high discriminatory power, and the low occurrence of genotyping errors of each primer. We calibrated allele calls and verified matches among genotypes obtained in previous studies using the complete set of 13 STRs (Short Tandem Repeats), analyzing six invasive DNA samples from distinct individuals. Differences in allele-sizing between labs were consistent, showing a substantial overlap of the individual genotyping. CONCLUSIONS: The proposed marker set comprises 11 Ursus specific markers with the addition of cxx20, the canid-locus less prone to genotyping errors, in order to prevent underestimation (maximizing the discriminatory power) and overestimation (minimizing the genotyping errors) of the number of Apennine brown bears. The selected markers allow saving time and costs with the amplification in multiplex of all loci thanks to the same annealing temperature. Our work optimizes the available resources by identifying a shared panel and a uniform methodology capable of improving comparisons between past and future studies.

Y-chromosome variability and genetic history of Commons from Northern Italy.

OBJECTIVES: Genetic drift and admixture are driving forces in human evolution, but their concerted impact to population evolution in historical times and at a micro-geographic scale is poorly assessed. In this study we test a demographic model encompassing both admixture and drift to the case of social-cultural isolates such as the so-called "Commons." MATERIALS AND METHODS: Commons are peculiar institutions of medieval origins whose key feature is the tight relationship between population and territory, mediated by the collective property of shared resources. Here, we analyze the Y-chromosomal genetic structure of four Commons (for a total of 366 samples) from the Central and Eastern Padana plain in Northern Italy. RESULTS: Our results reveal that all these groups exhibit patterns of significant diversity reduction, peripheral/outlier position within the Italian/European genetic space and high frequency of Common-specific haplogroups. By explicitly testing different drift-admixture models, we show that a drift-only model is more probable for Central Padana Commons, while additional admixture (~20%) from external population around the same time of their foundation cannot be excluded for the Eastern ones. DISCUSSION: Building on these results, we suggest central Middle Ages as the most probable age of foundation for three of the considered Commons, the remaining one pointing to late antiquity. We conclude that an admixture-drift model is particularly useful for interpreting the genetic structure and recent demographic history of small-scale populations in which social-cultural features play a significant role.

Genomic history of the Italian population recapitulates key evolutionary dynamics of both Continental and Southern Europeans.

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.

The surname structure of Trentino (Italy) and its relationship with dialects and genes.

BACKGROUND: Thanks to the availability of rich surname, linguistic and genetic information, together with its geographic and cultural complexity, Trentino (North-Eastern Italy) is an ideal place to test the relationships between genetic and cultural traits. AIM: We provide a comprehensive study of population structures based on surname and dialect variability and evaluate their relationships with genetic diversity in Trentino. SUBJECTS AND METHODS: Surname data were collected for 363 parishes, linguistic data for 57 dialects and genetic data for different sets of molecular markers (Y-chromosome, mtDNA, autosomal) in 10 populations. Analyses relied on different multivariate methods and correlation tests. RESULTS: Besides the expected isolation-by-distance-like patterns (with few local exceptions, likely related to sociocultural instances), we detected a significant and geography-independent association between dialects and surnames. As for molecular markers, only Y-chromosomal STRs seem to be associated with the dialects, although no significant result was obtained. No evidence for correlation between molecular markers and surnames was observed. CONCLUSION: Surnames act as cultural markers as do other words, although in this context they cannot be used as reliable proxies for genetic variability at a local scale.

Dissecting the Pre-Columbian Genomic Ancestry of Native Americans along the Andes-Amazonia Divide.

Extensive European and African admixture coupled with loss of Amerindian lineages makes the reconstruction of pre-Columbian history of Native Americans based on present-day genomes extremely challenging. Still open questions remain about the dispersals that occurred throughout the continent after the initial peopling from the Beringia, especially concerning the number and dynamics of diffusions into South America. Indeed, if environmental and historical factors contributed to shape distinct gene pools in the Andes and Amazonia, the origins of this East-West genetic structure and the extension of further interactions between populations residing along this divide are still not well understood. To this end, we generated new high-resolution genome-wide data for 229 individuals representative of one Central and ten South Amerindian ethnic groups from Mexico, Peru, Bolivia, and Argentina. Low levels of European and African admixture in the sampled individuals allowed the application of fine-scale haplotype-based methods and demographic modeling approaches. These analyses revealed highly specific Native American genetic ancestries and great intragroup homogeneity, along with limited traces of gene flow mainly from the Andes into Peruvian Amazonians. Substantial amount of genetic drift differentially experienced by the considered populations underlined distinct patterns of recent inbreeding or prolonged isolation. Overall, our results support the hypothesis that all non-Andean South Americans are compatible with descending from a common lineage, while we found low support for common Mesoamerican ancestors of both Andeans and other South American groups. These findings suggest extensive back-migrations into Central America from non-Andean sources or conceal distinct peopling events into the Southern Continent.

Inferring patterns of folktale diffusion using genomic data.

Observable patterns of cultural variation are consistently intertwined with demic movements, cultural diffusion, and adaptation to different ecological contexts [Cavalli-Sforza and Feldman (1981) Cultural Transmission and Evolution: A Quantitative Approach; Boyd and Richerson (1985) Culture and the Evolutionary Process]. The quantitative study of gene-culture coevolution has focused in particular on the mechanisms responsible for change in frequency and attributes of cultural traits, the spread of cultural information through demic and cultural diffusion, and detecting relationships between genetic and cultural lineages. Here, we make use of worldwide whole-genome sequences [Pagani et al. (2016) Nature 538:238-242] to assess the impact of processes involving population movement and replacement on cultural diversity, focusing on the variability observed in folktale traditions (n = 596) [Uther (2004) The Types of International Folktales: A Classification and Bibliography. Based on the System of Antti Aarne and Stith Thompson] in Eurasia. We find that a model of cultural diffusion predicted by isolation-by-distance alone is not sufficient to explain the observed patterns, especially at small spatial scales (up to [Formula: see text]4,000 km). We also provide an empirical approach to infer presence and impact of ethnolinguistic barriers preventing the unbiased transmission of both genetic and cultural information. After correcting for the effect of ethnolinguistic boundaries, we show that, of the alternative models that we propose, the one entailing cultural diffusion biased by linguistic differences is the most plausible. Additionally, we identify 15 tales that are more likely to be predominantly transmitted through population movement and replacement and locate putative focal areas for a set of tales that are spread worldwide.

Disentangling Timing of Admixture, Patterns of Introgression, and Phenotypic Indicators in a Hybridizing Wolf Population.

Hybridization is a natural or anthropogenic process that can deeply affect the genetic make-up of populations, possibly decreasing individual fitness but sometimes favoring local adaptations. The population of Italian wolves (Canis lupus), after protracted demographic declines and isolation, is currently expanding in anthropic areas, with documented cases of hybridization with stray domestic dogs. However, identifying admixture patterns in deeply introgressed populations is far from trivial. In this study, we used a panel of 170,000 SNPs analyzed with multivariate, Bayesian and local ancestry reconstruction methods to identify hybrids, estimate their ancestry proportions and timing since admixture. Moreover, we carried out preliminary genotype-phenotype association analyses to identify the genetic bases of three phenotypic traits (black coat, white claws, and spur on the hind legs) putative indicators of hybridization. Results showed no sharp subdivisions between nonadmixed wolves and hybrids, indicating that recurrent hybridization and deep introgression might have started mostly at the beginning of the population reexpansion. In hybrids, we identified a number of genomic regions with excess of ancestry in one of the parental populations, and regions with excess or resistance to introgression compared with neutral expectations. The three morphological traits showed significant genotype-phenotype associations, with a single genomic region for black coats and white claws, and with multiple genomic regions for the spur. In all cases the associated haplotypes were likely derived from dogs. In conclusion, we show that the use of multiple genome-wide ancestry reconstructions allows clarifying the admixture dynamics even in highly introgressed populations, and supports their conservation management.

Correction to: Transposable Elements Activity is Positively Related to Rate of Speciation in Mammals.

The original version of the article unfortunately contained tagging error in Given and Surname of all the authors.

Transposable Elements Activity is Positively Related to Rate of Speciation in Mammals.

Transposable elements (TEs) play an essential role in shaping eukaryotic genomes and generating variability. Speciation and TE activity bursts could be strongly related in mammals, in which simple gradualistic models of differentiation do not account for the currently observed species variability. In order to test this hypothesis, we designed two parameters: the Density of insertion (DI) and the Relative rate of speciation (RRS). DI is the ratio between the number of TE insertions in a genome and its size, whereas the RRS is a conditional parameter designed to identify potential speciation bursts. Thus, by analyzing TE insertions in mammals, we defined the genomes as "hot" (high DI) and "cold" (low DI). Then, comparing TE activity among 29 taxonomical families of the whole Mammalia class, 16 intra-order pairs of mammalian species, and four superorders of Eutheria, we showed that taxa with high rates of speciation are associated with "hot" genomes, whereas taxa with low ones are associated with "cold" genomes. These results suggest a remarkable correlation between TE activity and speciation, also being consistent with patterns describing variable rates of differentiation and accounting for the different time frames of the speciation bursts.

Ripples on the surface. Surnames and genes in Sicily and Southern Italy.

BACKGROUND: Southern Italy and Sicily played a key role in the peopling history of the Mediterranean. While genetic research showed the remarkable homogeneity of these regions, surname-based studies instead suggested low population mobility, hence potential structuring. AIM: In order to better understand these different patterns, this study (1) thoroughly analysed the surname structure of Sicily and Southern Italy and (2) tested its relationships with a wide set of molecular markers. SUBJECTS AND METHODS: Surname data were collected from 1213 municipalities and compared to uniparental and autosomal genetic markers typed in ∼300 individuals from 8-10 populations. Surname analyses were performed using different multivariate methods, while comparisons with genetic data relied on correlation tests. RESULTS: Surnames were clearly structured according to regional geographic patterns, which likely emerged because of recent isolation-by-distance-like population dynamics. In general, genetic markers, hinting at a pervasive homogeneity, did not correlate with surname distribution. However, long autosomal haplotypes (>5 cM) that compared to genotypic (SNPs) data identify more "recent" relatedness, showing a clear association with surname patterns. CONCLUSION: The apparent contradiction between surname structure and genetic homogeneity was resolved by figuring surnames as recent "ripples" deposited on a vast and ancient homogeneous genetic "surface".

Positive selection of lactase persistence among people of Southern Arabia.

OBJECTIVE: Frequency patterns of the lactase persistence (LP)-associated -13,915 G allele and archaeological records pointing to substantial role played by southern regions in the peopling and domestication processes that involved the Arabian Peninsula suggest that Southern Arabia plausibly represented the center of diffusion of such adaptive variant. Nevertheless, a well-defined scenario for evolution of Arabian LP is still to be elucidated and the burgeoning archaeological picture of complex human migrations occurred through the peninsula is not matched by an equivalent high-resolution description of genetic variation underlying this adaptive trait. To fill this gap, we investigated diversity at a wide genomic interval surrounding the LCT gene in different Southern Arabian populations. METHODS: 40 SNPs were genotyped to characterize LCT profiles of 630 Omani and Yemeni individuals to perform population structure, linkage disequilibrium, population differentiation-based and haplotype-based analyses. RESULTS: Typical Arabian LP-related variation was found in Dhofaris and Yemenis, being characterized by private haplotypes carrying the -13,915 G allele, unusual differentiation with respect to northern groups and conserved homozygous haplotype-blocks, suggesting that the adaptive allele was likely introduced in the Arabian gene pool in southern populations and was then subjected to prolonged selective pressure. CONCLUSION: By pointing to Yemen as one of the best candidate centers of diffusion of the Arabian-specific adaptive variant, obtained results indicate the spread of indigenous groups as the main process underlying dispersal of LP along the Arabian Peninsula, supporting a refugia model for Arabian demic movements occurred during the Terminal Pleistocene and Early Holocene.

Tracing Behçet's disease origins along the Silk Road: an anthropological evolutionary genetics perspective.

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.

Inferring the genetic history of lactase persistence along the Italian peninsula from a large genomic interval surrounding the LCT gene.

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.

Between Andes and Amazon: the genetic profile of the Arawak-speaking Yanesha.

The Yanesha are a Peruvian population who inhabit an environment transitional between the Andes and Amazonia. They present cultural traits characteristic of both regions, including in the language they speak: Yanesha belongs to the Arawak language family (which very likely originated in the Amazon/Orinoco lowlands), but has been strongly influenced by Quechua, the most widespread language family of the Andes. Given their location and cultural make-up, the Yanesha make for an ideal case study for investigating language and population dynamics across the Andes-Amazonia divide. In this study, we analyze data from high and mid-altitude Yanesha villages, both Y chromosome (17 STRs and 16 SNPs diagnostic for assigning haplogroups) and mtDNA data (control region sequences and 3 SNPs and one INDEL diagnostic for assigning haplogroups). We uncover sex-biased genetic trends that probably arose in different stages: first, a male-biased gene flow from Andean regions, genetically consistent with highland Quechua-speakers and probably dating back to Inca expansion; and second, traces of European contact consistent with Y chromosome lineages from Italy and Tyrol, in line with historically documented migrations. Most research in the history, archaeology and linguistics of South America has long been characterized by perceptions of a sharp divide between the Andes and Amazonia; our results serve as a clear case-study confirming demographic flows across that 'divide'.

mtDNA variation in East Africa unravels the history of Afro-Asiatic groups.

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.

Comparative analysis of bats and rodents' genomes suggests a relation between non-LTR retrotransposons, cancer incidence, and ageing.

The presence in nature of species showing drastic differences in lifespan and cancer incidence has recently increased the interest of the scientific community. In particular, the adaptations and the genomic features underlying the evolution of cancer-resistant and long-lived organisms have recently focused on transposable elements (TEs). In this study, we compared the content and dynamics of TE activity in the genomes of four rodent and six bat species exhibiting different lifespans and cancer susceptibility. Mouse, rat, and guinea pig genomes (short-lived and cancer-prone organisms) were compared with that of naked mole rat (Heterocephalus glaber) which is a cancer-resistant organism and the rodent with the longest lifespan. The long-lived bats of the genera Myotis, Rhinolophus, Pteropus and Rousettus were instead compared with Molossus molossus, which is one of the organisms with the shortest lifespan among the order Chiroptera. Despite previous hypotheses stating a substantial tolerance of TEs in bats, we found that long-lived bats and the naked mole rat share a marked decrease of non-LTR retrotransposons (LINEs and SINEs) accumulation in recent evolutionary times.

Evolutionarily recent retrotransposons contribute to schizophrenia.

Transposable Elements (TEs) are mobile genetic elements that constitute half of the human genome. Recent studies suggest that polymorphic non-reference TEs (nrTEs) may contribute to cognitive diseases, such as schizophrenia, through a cis-regulatory effect. The aim of this work is to identify sets of nrTEs putatively linked to an increased risk of developing schizophrenia. To do so, we inspected the nrTE content of genomes from the Dorsolateral Prefrontal Cortex of schizophrenic and control individuals, and identified 38 nrTEs which possibly contribute to the emergence of this psychiatric disorder. Furthermore, we performed in silico functional inferences and found, for instance, that 9 of the 38 nrTEs act as expression/alternative splicing quantitative trait loci (eQTLs/sQTLs) in the brain, suggesting a possible role in shaping the human cognitive genome structure. Therefore, to our knowledge, this is the first attempt at identifying polymorphic nrTEs that can contribute to the functionality of the brain. Finally, we suggest that a neurodevelopmental genetic mechanism, which involves evolutionarily young nrTEs, can be the key to understanding the ethiopathogenesis of this complex disorder.

Evolutionarily recent retrotransposons contribute to schizophrenia.

Transposable elements (TEs) are mobile genetic elements that constitute half of the human genome. Recent studies suggest that polymorphic non-reference TEs (nrTEs) may contribute to cognitive diseases, such as schizophrenia, through a cis-regulatory effect. The aim of this work is to identify sets of nrTEs putatively linked to an increased risk of developing schizophrenia. To do so, we inspected the nrTE content of genomes from the dorsolateral prefrontal cortex of schizophrenic and control individuals and identified 38 nrTEs that possibly contribute to the emergence of this psychiatric disorder, two of them further confirmed with haplotype-based methods. We then performed in silico functional inferences and found that 9 of the 38 nrTEs act as expression/alternative splicing quantitative trait loci (eQTLs/sQTLs) in the brain, suggesting a possible role in shaping the human cognitive genome structure. To our knowledge, this is the first attempt at identifying polymorphic nrTEs that can contribute to the functionality of the brain. Finally, we suggest that a neurodevelopmental genetic mechanism, which involves evolutionarily young nrTEs, can be key to understanding the ethio-pathogenesis of this complex disorder.