Biology subjects

Pagani, L.

Publications and source records attributed to Pagani, L..

33 records · Page 2Linked to original sources

bioRxiv2021

Regulatory dissection of the severe COVID-19 risk locus introgressed by Neanderthals

Individuals infected with the SARS-CoV-2 virus present with a wide variety of phenotypes ranging from asymptomatic to severe and even lethal outcomes. Past research has revealed a genetic haplotype on chromosome 3 that entered the human population via introgression from Neanderthals as the strongest genetic risk factor for the severe COVID-19 phenotype. However, the specific variants along this introgressed haplotype that contribute to this risk and the biological mechanisms that are involved remain unclear. Here, we assess the variants present on the risk haplotype for their likelihood of driving the severe COVID-19 phenotype. We do this by first exploring their impact on the regulation of genes involved in COVID-19 infection using a variety of population genetics and functional genomics tools. We then perform an locus-specific massively parallel reporter assay to individually assess the regulatory potential of each allele on the haplotype in a multipotent immune-related cell line. We ultimately reduce the set of over 600 linked genetic variants to identify 4 introgressed alleles that are strong functional candidates for driving the association between this locus and severe COVID-19. These variants likely drive the locus impact on severity by putatively modulating the regulation of two critical chemokine receptor genes: CCR1 and CCR5. These alleles are ideal targets for future functional investigations into the interaction between host genomics and COVID-19 outcomes.

genetics↗

bioRxiv2021

Genetics and material culture support repeated expansions into Paleolithic Eurasia from a population hub out of Africa

The population dynamics that followed the out of Africa expansion (OoA) and the whereabouts of the early migrants before the differentiation that ultimately led to the formation of Oceanian, West and East Eurasian macro populations have long been debated. Shedding light on these events may, in turn, provide clues to better understand cultural evolution in Eurasia between 50kya and 35kya. Here we analyze Eurasian Paleolithic DNA evidence to provide a comprehensive population model and validate it in light of available material culture. Leveraging on our integrated approach we propose the existence of a Eurasian population Hub, where Homo sapiens lived between the OoA and the broader colonization of Eurasia, which was characterized by multiple events of expansion and local extinction. A major population wave out of Hub, of which UstIshim, Bacho Kiro and Tianyuan are unadmixed representatives, is broadly associated with Initial Upper Paleolithic lithics and populated West and East Eurasia before or around 45 kya, before getting largely extinct in Europe. In this light, we suggest a parsimonious placement of Oase1 as an individual related to Bacho Kiro who experienced additional Neanderthal introgression. Another expansion, started before 38 kya, is broadly associated with Upper Paleolithic industries and repopulated Europe with sporadic admixtures with the previous wave (GoyetQ116-1) and more systematic ones while moving through Siberia (Yana, Malta).

evolutionary biology↗

bioRxiv2020

Continental-scale genomic analysis suggests shared post-admixture adaptation in Americas

American populations are one of the most interesting examples of recently admixed groups, where ancestral components from three major continental human groups (Africans, Eurasians and Native Americans) have admixed within the last 15 generations. Recently, several genetic surveys focusing on thousands of individuals shed light on the geography, chronology and relevance of these events. However, despite the fact that gene-flow could drive adaptive evolution, it is not clear whether and how natural selection acted on the resulting genetic variation in the Americas. In this study, we analysed the patterns of local ancestry of genomic fragments in genome-wide data for [~]6,000 admixed individuals from ten American countries. In doing so, we identified regions characterized by a Divergent Ancestry Profile (DAP), in which a significant over or under ancestral representation is evident. Our results highlighted a series of genomic regions with Divergent Ancestry Profiles (DAP) associated with immune system response and relevant medical traits, with the longest DAP region encompassing the Human Leukocyte Antigen locus. Furthermore, we found that DAP regions are enriched in genes linked to cancer-related traits and autoimmune diseases. Then, analyzing the biological impact of these regions, we showed that natural selection could have acted preferentially towards variants located in coding and non-coding transcripts, and characterized by a high deleteriousness score. Taken together, our analyses suggest that shared patterns of post admixture adaptation occurred at continental scale in the Americas, affecting more often functional and impactful genomic variants.

genomics↗

bioRxiv2020

Revisiting the Out of Africa event with a novel Deep Learning approach

Anatomically modern humans evolved around 300 thousand years ago in Africa1. Modern humans started to appear in the fossil record outside of Africa about 100 thousand years ago though other hominins existed throughout Eurasia much earlier2-4. Recently, several researchers argued in favour of a single out of Africa event for modern humans based on whole-genome sequences analyses5-7. However, the single out of Africa model is in contrast with some of the findings from fossil records, which supports two out of Africa8,9, and uniparental data, which proposes back to Africa movement10,11. Here, we used a novel deep learning approach coupled with Approximate Bayesian Computation and Sequential Monte Carlo to revisit these hypotheses from the whole genome sequence perspective. Our results support the back to Africa model over other alternatives. We estimated that there are two successive splits between Africa and out of African populations happening around 60-80 thousand years ago and separated by 12-13 thousand years. One of the populations resulting from the more recent split has to a large extent replaced the older West African population while the other one has founded the out of Africa populations.

genetics↗

bioRxiv2020

Archaeogenomic Distinctiveness of the Isthmo-Colombian Area

The recently enriched genomic history of Indigenous groups in the Americas is still meagre concerning continental Central America. Here, we report ten pre-Hispanic (plus two early colonial) genomes and 84 genome-wide profiles from seven groups presently living in Panama. Our analyses reveal that pre-Hispanic demographic changes and isolation events contributed to create the extensive genetic structure currently seen in the area, which is also characterized by a distinctive Isthmo-Colombian Indigenous component. This component drives these populations on a specific variability axis and derives from the local admixture of different ancestries of northern North American origin(s). Two of these ancestries were differentially associated to Pleistocene Indigenous groups that also moved into South America leaving heterogenous footprints. An additional Pleistocene ancestry was brought by UPopI, a still unsampled population that remained restricted to the Isthmian area, expanded locally during the early Holocene, and left genomic traces up to the present.

genomics↗

bioRxiv2020

Early Alpine human occupation backdates westward human migration in Late Glacial Europe

The end of the Last Glacial Maximum (LGM) in Europe (~16.5 ka ago) set in motion major changes in human culture and population structure1. In Southern Europe, Early Epigravettian material culture was replaced by Late Epigravettian art and technology about 18-17 ka ago at the beginning of southern Alpine deglaciation, although available genetic evidence from individuals who lived ~14 ka ago2-5 opened up questions on the impact of migrations on this cultural transition only after that date. Here we generate new genomic data from a human mandible uncovered at the Late Epigravettian site of Riparo Tagliente (Veneto, Italy), that we directly dated to 16,980-16,510 cal BP (2{sigma}). This individual, affected by a low-prevalence dental pathology named focal osseous dysplasia, attests that the very emergence of Late Epigravettian material culture in Italy was already associated with migration and genetic replacement of the Gravettian-related ancestry. In doing so, we push back by at least 3,000 years the date of the diffusion in Southern Europe of a genetic component linked to Balkan/Anatolian refugia, previously believed to have spread during the later Bolling/Allerod warming event (~14 ka ago4,6). Our results suggest that demic diffusion from a genetically diverse population may have substantially contributed to cultural changes in LGM and post-LGM Southern Europe, independently from abrupt shifts to warmer and more favourable conditions.

genomics↗

bioRxiv2019

Creating Artificial Human Genomes Using Generative Models

Generative models have shown breakthroughs in a wide spectrum of domains due to recent advancements in machine learning algorithms and increased computational power. Despite these impressive achievements, the ability of generative models to create realistic synthetic data is still under-exploited in genetics and absent from population genetics.\n\nYet a known limitation of this field is the reduced access to many genetic databases due to concerns about violations of individual privacy, although they would provide a rich resource for data mining and integration towards advancing genetic studies. In this study, we demonstrated that deep generative adversarial networks (GANs) and restricted Boltzmann machines (RBMs) can be trained to learn the high dimensional distributions of real genomic datasets and create high quality artificial genomes (AGs) with none to little privacy loss. To illustrate the promising outcomes of our method, we showed that (i) imputation quality for low frequency alleles can be improved by augmenting reference panels with AGs, (ii) scores obtained from selection tests on AGs and real genomes are highly correlated and (iii) AGs can inherit genotype-phenotype associations. AGs have the potential to become valuable assets in genetic studies by providing high quality anonymous substitutes for private databases.

bioinformatics↗

bioRxiv2019

West Asian sources of the Eurasian component in Ethiopians: a reassessment

Previous genome-scale studies of populations living today in Ethiopia have found evidence of recent gene flow from an Eurasian source, dating to the last 3,000 years1,2,3,4. Haplotype1 and genotype data based analyses of modern2,4 and ancient data (aDNA)3,5 have considered Sardinia-like proxy2, broadly Levantine1,4 or Neolithic Levantine3 populations as a range of possible sources for this gene flow. Given the ancient nature of this gene flow and the extent of population movements and replacements that affected West Asia in the last 3000 years, aDNA evidence would seem as the best proxy for determining the putative population source. We demonstrate, however, that the deeply divergent, autochthonous African component which accounts for [~]50% of most contemporary Ethiopian genomes, affects the overall allele frequency spectrum to an extent that makes it hard to control for it and, at once, to discern between subtly different, yet important, Eurasian sources (such as Anatolian or Levant Neolithic ones). Here we re-assess pattern of allele sharing between the Eurasian component of Ethiopians (here called \"NAF\" for Non African) and ancient and modern proxies area after having extracted NAF from Ethiopians through ancestry deconvolution, and unveil a genomic signature compatible with population movements that affected the Mediterranean area and the Levant after the fall of the Minoan civilization.

evolutionary biology↗

bioRxiv2019

DNA energy constraints shape biological evolutionary trajectories

Most living systems rely on double-stranded DNA (dsDNA) to store their genetic information and perpetrate themselves. Thus, the biological information contained within a dsDNA molecule, in terms of a linear sequence of nucleotides, has been considered the main target of the evolution. However, in this information-centred perspective, certain DNA sequence symmetries are difficult to explain. Here we show that these patterns can emerge from the physical peculiarities of the dsDNA molecule itself and the maximum entropy principle alone, rather than from biological or environmental evolutionary pressure. Our predictions are valid for both prokaryotes and eukaryotes, and also inform the interpretation of observed codon biases and context-dependent mutation patterns in human populations. Our results suggest that the double helix energy constraints and, more generally, the physical properties of the dsDNA are the hard drivers of the overall DNA sequence architecture, whereas the biological selective processes act as soft drivers, which only under extraordinary circumstances overtake the overall entropy content of the genome.

molecular biology↗

bioRxiv2019

Inter-individual genomic heterogeneity within European population isolates

A number of studies carried out since the early 70s has investigated the effects of isolation on genetic variation within and among human populations in diverse geographical contexts. However, no extensive analysis has been carried out on the heterogeneity among genomes within isolated populations. This issue is worth exploring since events of recent admixture and/or subdivision could potentially disrupt the genetic homogeneity which is to be expected when isolation is prolonged and constant over time. Here, we analyze literature data relative to 87,818 autosomal single-nucleotide polymorphisms, which were obtained from a total of 28 European populations. Our results challenge the traditional paradigm of population isolates as genetically (and genomically) uniform entities. In fact, focusing on the distribution of variance of intra-population diversity measures across individuals, we show that the inter-individual heterogeneity of isolated populations is at least comparable to the open ones. More in particular, three small and highly inbred isolates (Sappada, Sauris and Timau in Northeastern Italy) were found to be characterized by levels of this parameter largely exceeding that of all other populations, possibly due to relatively recent events of genetic introgression. Finally, we propose a way to monitor the effects of inter-individual heterogeneity in disease-gene association studies.

genomics↗

bioRxiv2018

Population structure of modern-day Italians reveals patterns of ancient and archaic ancestries in Southern Europe

European populations display low genetic diversity as the result of long term blending of the small number of ancient founding ancestries. However it is still unclear how the combination of ancient ancestries related to early European foragers, Neolithic farmers and Bronze Age nomadic pastoralists can fully explain genetic variation across Europe. Populations in natural crossroads like the Italian peninsula are expected to recapitulate the overall continental diversity, but to date have been systematically understudied. Here we characterised the ancestry profiles of modern-day Italian populations using a genome-wide dataset representative of modern and ancient samples from across Italy, Europe and the rest of the world. Italian genomes captured several ancient signatures, including a non-steppe related substantial ancestry contribution ultimately from the Caucasus. Differences in ancestry composition as the result of migration and admixture generated in Italy the largest degree of population structure detected so far in the continent and shaped the amount of Neanderthal DNA present in modern-day populations.\n\nOne sentence summaryAncient and historical admixture events shaped the genetic structure of modern-day Italians, the ancestry profile of Southern European populations and the continental distribution of Neanderthal legacy.

genomics↗

bioRxiv2018

The genetic legacy of continental scale admixture in Indian Austroasiatic speakers

Surrounded by speakers of Indo-European, Dravidian and Tibeto-Burman languages, around 11 million Munda (a branch of Austroasiatic language family) speakers live in the densely populated and genetically diverse South Asia. Their genetic makeup holds components characteristic of South Asians as well as Southeast Asians. The admixture time between these components has been previously estimated on the basis of archaeology, linguistics and uniparental markers. Using genome-wide genotype data of 102 Munda speakers and contextual data from South and Southeast Asia, we retrieved admixture dates between 2000 - 3800 years ago for different populations of Munda. The best modern proxies for the source populations for the admixture with proportions 0.78/0.22 are Lao people from Laos and Dravidian speakers from Kerala in India, while the South Asian population(s), with whom the incoming Southeast Asians intermixed, had a smaller proportion of West Eurasian component than contemporary proxies. Somewhat surprisingly Malaysian Peninsular tribes rather than the geographically closer Austroasiatic languages speakers like Vietnamese and Cambodians show highest sharing of IBD segments with the Munda. In addition, we affirmed that the grouping of the Munda speakers into North and South Munda based on linguistics is in concordance with genome-wide data.

genetics↗

bioRxiv2017

Impact of non-LTR retrotransposons in the differentiation and evolution of Anatomically Modern Humans

Transposable Elements are biologically important components of eukaryote genomes. In particular, non-LTR retrotransposons (N-LTRrs) extensively shaped the human genome throughout evolution. In this study, we compared retrotransposon insertions differentially present in the genomes of Anatomically Modern Humans, Neanderthals, Denisovans and Chimpanzees, in order to assess the possible impact of retrotransposition in the differentiation of the human lineage. Briefly, we first identified species-specific N-LTRrs and established their distribution in present day human populations. These analyses shortlisted a group of N-LTRr insertions that were found exclusively in Anatomically Modern Humans. Notably, these insertions targeted genes more frequently than randomly expected and are associated with an increase in the number of transcriptional/splicing variants of those genes they inserted in. The analysis of the functionality of genes targeted by human-specific N-LTRr insertions seems to reflect phenotypic changes that occurred during human evolution. Furthermore, the expression of genes containing the most recent N-LTRr insertions is enriched in the brain, especially in undifferentiated neurons, and these genes associate in networks related to neuron maturation and migration. Additionally, we also identified candidate N-LTRr insertions that have likely produced new functional variants exclusive to modern humans, which show traces of positive selection and are now fixed in all present-day human populations. In sum, our results strongly suggest that N-LTRr impacted our differentiation as a species and have been a constant source of genomic variability all throughout the evolution of the human lineage.

genomics↗

bioRxiv2017

Extensive farming in Estonia started through a sex-biased migration from the Steppe

Farming-based economies appear relatively late in Northeast Europe and the extent to which they involve genetic ancestry change is still poorly understood. Here we present the analyses of low coverage whole genome sequence data from five hunter-gatherers and five farmers of Estonia dated to 4,500 to 6,300 years before present. We find evidence of significant differences between the two groups in the composition of autosomal as well as mtDNA, X and Y chromosome ancestries. We find that Estonian hunter-gatherers of Comb Ceramic Culture are closest to Eastern hunter-gatherers. The Estonian first farmers of Corded Ware Culture show high similarity in their autosomes with Steppe Belt Late Neolithic/Bronze Age individuals, Caucasus hunter-gatherers and Iranian farmers while their X chromosomes are most closely related with the European Early Farmers of Anatolian descent. These findings suggest that the shift to intensive cultivation and animal husbandry in Estonia was triggered by the arrival of new people with predominantly Steppe ancestry, but whose ancestors had undergone sex-specific admixture with early farmers with Anatolian ancestry.

evolutionary biology↗

bioRxiv2016

The Tell-Tale Genome

Observable patterns of cultural variation are consistently intertwined with demic movements, cultural diffusion, and adaptation to different ecological contexts (Cavalli-Sforza and Feldman 1981; Boyd and Richerson 1985). The quantitative study of gene-culture co-evolution has focused in particular on the mechanisms responsible for change in frequency and attributes of cultural traits, on the spread of cultural information through demic and cultural diffusion, and on detecting relationships between genetic and cultural lineages. Here, for the first time, we make use of worldwide whole-genome sequences (Pagani et al. 2016) to assess the impact of demic diffusion on cultural diversity, focusing on the variability observed in folktale traditions (N=596) (Uther 2004) in Eurasia and Africa. We show that at small geographic scales (<=5000 km) there is a strong correlation between folktale and genomic distance when the effect of geography is corrected, while geographic distance has no independent effect on the distribution of folkloric narratives at the same spatial scale. This points to demic processes (i.e. population movement and replacement) as the main driver of folktale transmission at limited geographic ranges. The role of population movements becomes more apparent when regions characterized by episodes of directional expansions, such as the Neolithization of West Eurasia, are examined. Furthermore, we identify 89 individual tales which are likely to be predominantly transmitted through demic diffusion, and locate putative focal areas for a subset of them.

evolutionary biology↗