Biology subjects

Pagani, L.

Publications and source records attributed to Pagani, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Covariate-aware genomic prediction of blood metabolite profiles using multi-task neural networks

Predictive models of quantitative traits can combine genetic and covariate information, but overall predictive performance alone does not reveal whether differences between models arise from covariate, genetic or joint covariate-genetic effects. Circulating metabolites provide a high-dimensional set of clinically relevant quantitative traits in which these effects can be examined systematically. Although their genetic determinants are well characterised through genome-wide association studies, marginal associations do not establish how accurately metabolomic profiles can be predicted or whether nonlinear models can improve prediction by capturing complex and potentially interactive structure. Here, we developed a multi-task neural network (NN) for simultaneously predicting metabolomic profiles with a three-stage architecture separating covariate, genetic and joint contributions. In comparative analyses, the multi-task NN demonstrated the strongest mean performance across metabolites (R2=0.219), followed by the single-task NN (R2=0.211), elastic net (R2=0.207), and an activation-free multi-task model (R2=0.191). Decomposition analyses indicated that gains were mainly driven by nonlinear covariate modelling, consistent with improved prediction after incorporating nonlinear age effects into a linear model. Together, these analyses provide a framework for identifying sources of predictive differences between different models, which may be applicable to other collections of quantitative traits.

genomics↗

bioRxiv2026

Effects of introgressed Neanderthal alleles on present-day brain morphology

Neanderthal introgression contributed a small fraction of genetic variants to present-day non-African genomes. While differences in cranial globularity between Neanderthal and modern humans are well documented from endocasts, the phenotypic consequences of these introgressed alleles can illuminate otherwise inaccessible genetically divergent brain structures. We analyzed 370 MRI-derived brain traits--including cortical and subcortical regional measurements, cortical folding metrics, diffusion tracts--in nearly 40,000 UK Biobank participants. To quantify the impact of Neanderthal ancestry, we intersected trait-associated loci with Neanderthal-derived variants identified from introgressed segments imputed in the same subjects. Low-frequency introgressed variants were depleted for detectable effects on brain phenotypes, whereas common introgressed variants showed no comparable depletion. Conversely, Neanderthal deserts were consistently enriched for functional effects. Eight associations were fine-mapped to Neanderthal-derived variants: one locus near the gene DAAM1 was especially prominent across multiple traits, including opposite effects in the cuneus and precuneus mediated by introgressed regulatory variants. Genome-wide directional alignment of Neanderthal effects was limited but became evident when focusing on suggestive loci: frontal and parietal areas were the most consistently affected traits, though not in a direction that obviously mirrors known modern-archaic morphology divergence. Several of these loci also influenced neuropsychiatric traits, with detectable polygenic consequences against schizophrenia and towards major depression, linking neuroanatomical and neuropsychiatric impact of Neanderthal introgression. These findings suggest that while introgressed alleles affecting divergent neuroanatomy between modern humans and Neanderthals were largely purged, a subset of tolerated alleles continues to shape human brain morphology and mental health.

genomics↗

bioRxiv2026

The Neanderthal population history and the introgression landscape inferred from the UK Biobank

Neanderthal haplotypes in present-day Eurasians are unevenly distributed across the genome, forming introgression deserts and high-frequency segments consistent with adaptive introgression, with additional random variation affected by genetic drift. However, current estimates are limited by modest sample sizes and analyses restricted to subsets of the genome, given that any individual carries only 1-2% Neanderthal ancestry. Here we extract and analyse Neanderthal haplotypes from 45,000 imputed and phased genomes in the UK Biobank. Even at this scale, the number of sites overlapping Neanderthal haplotypes approaches--but does not reach--saturation, with rare haplotypes still being discovered. Using the derived allele frequency spectrum within the surviving Neanderthal segments, we infer a divergence time of 2,061 generations between the introgressed lineage and the Vindija Neanderthal, and estimate the effective population size of the introgressed lineage to Ne = 6,564. Individual-level resolution allows identification of 545 independent loci with excess Neanderthal homozygosity, consistent with ongoing selection. Despite the extensive dataset, a substantial portion of the genome remains a Neanderthal desert. Within these regions, we detect seven Human Accelerated Regions affected by recent human selective sweeps (TMRCA <650 kya), four located within introns of cerebellum-expressed genes, providing further support for their potential as modern human-specific adaptation.

evolutionary biology↗

bioRxiv2025

Ancient genomes from the siege and destruction of Middle Bronze Age Roca Vecchia (Apulia, Italy) shed light on Aegean contacts and conflicts

BackgroundRoca Vecchia, an iconic Bronze Age stronghold in Apulia, Southern Italy, was completely destroyed during a siege between the end of the 15th century BCE and the beginning of the 14th century BCE. During the siege, seven of the local people hid within the stronghold walls. Two others, who could have been as well attackers as defenders, were found under the ruins of the main gate. The material culture found at Roca Vecchia and associated with the period of the siege includes Minoan-type pottery produced from local clay, imported Aegean pottery and an Aegean-type dagger, pointing to an established relationship between the site and the Minoan civilization. Therefore, the site offers an unprecedented opportunity to characterise the genetic components of the population inhabiting an indigenous settlement with increasing contacts with the Aegean world, and to shed light on the demic or cultural modes of the Minoan presence in the central Mediterranean. ResultsWith our work, we sampled six out of nine available unburied Middle Bronze Age individuals, contemporary with the siege and destruction of the site, and obtained genome-wide information for two individuals. When compared with available Minoan, Apulian and broadly Mediterranean genomes, the individuals showed a characteristic Bronze/Iron Age Italian peninsula genetic signature, with limited contribution from Minoans. ConclusionsWe conclude that the local population of Roca Vecchia, at the moment of the siege, was predominantly autochthonous, with a minoritarian Minoan component. A Minoan genetic signal is indeed likely present in one out of two analysed individuals who were certainly part of the dwellers of Roca Vecchia. This confirms previous hypotheses supposing that a nucleus of "foreigners" coming from the Minoan world was living in the site and mixed with locals. Archaeological data suggest that the Roca Vecchia Aegean population component probably increased in the following centuries.

genetics↗

bioRxiv2025

Cross-scale effect of microbiota dynamics on resistance

Antimicrobial resistance (AMR) is often carried asymptomatically in the human gut microbiota, yet the role of this carriage in AMR persistence and transmission remains poorly understood. To address this gap, we developed a cross-scale model that links within-host microbiota dynamics of extended-spectrum beta-lactamase (ESBL)-producing and non-ESBL-producing bacteria with transmission across hospital and community settings. The model incorporates plasmid exchange, antibiotic effects, and host heterogeneity. It integrates diverse data sources, including microbiota dynamics, community antibiotic consumption, and detailed surveillance data from a large university hospital, complemented by literature estimates. This model identifies mechanisms that enable coexistence of resistant and sensitive strains at both individual and population levels, revealing host heterogeneity as a critical driver of resistance persistence. Unlike classic epidemiological models, our analysis finds a continuum of colonization states within individuals rather than discrete resistant or sensitive categories, and highlights that realistic detection thresholds may substantially underestimate resistance prevalence. Finally, we use this framework to evaluate interventions such as hospital screening and isolation, showing that their impact strongly depends on local transmission dynamics and resistance prevalence. By bridging within-host and population processes, our model provides a novel tool for investigating AMR spread and optimizing prevention strategies in healthcare and community environments.

ecology↗

bioRxiv2025

Parental haplotypes reconstruction in up to 440,209 individuals reveals recent assortative mating dynamics

Assortative mating (AM), the tendency for individuals to choose partners with similar traits, plays an important role in social stratification and has a wide-spread impact on the genetic architecture of complex human traits. A genetic footprint of this behaviour, genetic assortative mating (GAM), has been documented for many traits. However, most existing approaches to estimate GAM either rely on genotyped couples - rare in large biobanks - or on estimates based on gametic phase disequilibrium (GPD), which reflect cumulative effects over multiple generations and cannot detect short-term events. We introduce a novel, scalable approach that infers genetic data for the parental generation to boost statistical power and improve interpretability when estimating GAM in biobank cohorts. Our method reconstructs the two parental haplotypes of biobank individuals by leveraging state-of-the-art inter-chromosomal phasing based on close relative information. By correlating polygenic scores computed separately on maternally and paternally inherited haplotypes, we infer the extent of GAM. Applied to 245,884 individuals from the UK Biobank and 194,325 individuals from the Estonian Biobank, our haplotype-based estimates showed strong concordance with GAM estimates from genotyped mate pairs across 69 traits and improved performance compared to existing GPD-based methods. We replicated previously identified patterns of GAM for many traits (educational attainment, height, BMI, and alcohol consumption), and revealed new ones (overall health and sedentary lifestyle). Temporal and geographic stratification revealed accelerated assortment in recent generations -- particularly for education and height -- and modest differences between urban and rural contexts. Our method enables scalable, interpretable, and generation-specific estimation of GAM in large biobank cohorts, providing new insights into the dynamic nature of mate choice and its impact on the genetic makeup of populations.

genetics↗

bioRxiv2025

Worldwide patterns in mythology echo the human expansion out of Africa

Similarities between geographically distant mythological and folkloric traditions have been noted for a long time. With the elaboration of large banks of data describing the presence and absence of narrative motifs around the world, scholars have been able to statistically investigate their potential routes and mechanisms of diffusion. However, despite genetic data allowing for increasingly refined demographic movement inferences, few have integrated it into their models, and none at a global scale. In this work, we capitalise on the augmenting availability of modern and ancient genetic data and on Yuri E. Berezkins database of more than 2000 mythological motifs worldwide to investigate the mechanisms involved in generating their present-day distribution at a global scale. The direct combination of both kinds of evidence allows us to explore in more depth the respective influences of population movement and replacement versus cultural diffusion on motif transmission. Our results show that both processes have played important roles in shaping their present-day distribution. By leveraging available ancient DNA (aDNA) and deepening the temporal scale of the detected signals, we reveal that correlations between mythemes and genetic patterns can be traced back to population movements that pre-date the Last Glacial Maximum and go back to at least 38,000 years ago, and possibly even earlier to the human expansion out of Africa some 60,000 years ago. Our work shows the earliest evidence for the transmission of stories and storytelling in human history, and supports the joint use of cultural evolutionary theory and population genetics to illuminate the biocultural processes that shaped our species.

evolutionary biology↗

bioRxiv2025

HoloMoA: Fast holography and deep-learning-based tool for the novelty detection of mechanism of action of antimicrobial candidates

We propose an innovative technology to classify the Mechanism of Action (MoA) of antimicrobials and predict their novelty, called HoloMoA. HoloMoA is a rapid, robust, inexpensive, and versatile tool based on the combination of time-lapse Digital Inline Holographic Microscopy (DIHM) and Deep Learning (DL). In combination with proper image reconstruction, DIHM enables a label-free, time-resolved visualization of bacterial cell morphology and phase map (i.e. refractive index x thickness) to reveal phenotypic responses to antimicrobials, while DL techniques are powerful tools to extract discriminative features from image sequences and classify them. We assessed the performance of HoloMoA technology on Escherichia coli (E. coli) ATCC 25922 treated for up to 2 hours with 22 antibiotic molecules representing 5 functional classes (i.e. Cell Wall synthesis inhibitors, Cell Membrane inhibitors, Protein synthesis inhibitors, DNA and RNA synthesis inhibitors). First, using reconstructed phase images as input to a 3D Convolutional Neural Network classifier, we detected the MoA of known antibiotics with 89% accuracy. Secondly, we showed how our CNN models combined with a Siamese neural network architecture can be used for the novelty assessment of the MoA of a candidate antibiotic. The HoloMoA novelty detection tool succeeded in detecting trimethoprim-sulfamethoxazole (Folic Acid synthesis inhibitors) as belonging to a novel functional class (i.e. different from the 5 aforementioned classes). We demonstrated that combining DHIM and DL gives a promising tool for determining the MoA of new antimicrobial candidates provided that a large image database for known antimicrobials is available.

microbiology↗

bioRxiv2024

Partitioning the genomic journey to becoming Homo sapiens

What makes us human? Homo sapiens diverged from its ancestors in fundamental ways, as reflected in recent genomic acquisitions, such as the PAR2-Y chromosome translocation. Here we show that despite morphological and cultural differences between modern and archaic humans, these human groups share these recent acquisitions. Our modern lineage shows recent functional variants in only 56 genes, of which 24 are linked to brain functions and skull morphology. Nevertheless, these acquisitions failed to introgress into Neanderthals when archaic and modern populations admixed after 350 kya, suggesting their exclusive link to the modern human niche or that Neanderthals small population size hindered their spread. Taken together, our results point to a scenario where Modern and Archaic should be regarded as populations of an otherwise common human species, which independently accumulated mutations and cultural innovations.

evolutionary biology↗

bioRxiv2024

2500 Years of Human Betaherpesvirus 6A and 6B Evolution Revealed by Ancient DNA

Human betaherpesviruses 6A and 6B are double-stranded DNA viruses, specialised in infecting humans and are best known as the main causative pathogens of the common childhood infection "sixth disease". Despite only being discovered in the 1980s, these viruses are speculated to have a much longer and more complex history within the human population than available modern data make clear. The viruses are carried by large fractions of the human population and can integrate into the human genome, leading to a wide range of clinical manifestations of varied severity. Here, we present the first nine full and two partial ancient genomes of HHV-6A and 6B, dating as far back as the Italian Iron Age (ca. 1100-600 BCE). We demonstrate that large fractions of the current HHV-6 diversity were already well established in the human population by the 14th century CE. Our data suggests that HHV-6B integrated into the human genome at the latest before the 1st-6th century CE, with two integrated clades being populated by ancient DNA genomes in our phylogeny, which further supports that they originated from likely much older ancient founder events. Additionally, we show that all known inherited chromosomally integrated (ici-)HHV-6A clades were already represented in European historical populations, confirming that ici-HHV-6A no longer integrates into the human germline within populations of European ancestry and likely endogenized in early human history. Finally, our results demonstrate the unique suitability of archaeological remains and ancient DNA for the study of the evolution of integrated viruses in human populations.

evolutionary biology↗

bioRxiv2024

Fast and reliable ancestral reconstruction on ancient genotype data with non-negative Least square and Principal Component Analysis

The history of human populations has been strongly shaped by admixture events, contributing to the patterns of observed genetic diversity across populations. Given its significance for evolutionary and medical studies, many algorithms focusing on the inference of the genetic composition of admixed populations have been developed. In particular, the recent development of new ancestry estimation methods that consider the fragmentary nature of ancient genotype data, such as the f-statistics family and its derivations, have radically changed our understanding of the past. F-statistics capture similar genetic similarity information as Principal Component Analysis (PCA), which is widely used in population genetics to quantify genetic affinity between populations or individuals. In this study, we introduce ASAP (ASsessing ancestry proportions through Principal component Analysis) method that leverages PCA and Non-Negative Least Square (NNLS) to assess the ancestral compositions of admixed individuals given a large set of populations. We tested ASAP on different simulated models, incorporating high levels of missingness. Our results show its ability to reliably estimate ancestry across numerous scenarios, even those with a significant proportion of missing genotypes, in a fraction of the time required when using other tools. When harnessed on Eurasias genotype data, ASAP helped replicate and extend findings from previous studies proving to be a fast, efficient, and straightforward new ancestry estimation tool.

genomics↗

bioRxiv2024

Setting Climate Targets: The Case of Higher Education and Research

The carbon footprint and low-carbon strategies of higher education and research organizations have been the subject of scientific articles and reports. However, these provide few details on the reduction targets themselves, leaving the question of how should higher education and research organizations define and construct their climate targets and trajectories unanswered. The present paper fills this gap. We first review and analyze the documents describing the climate strategies of 53 higher education and research organizations coming from 11 countries, based on their detailed GreenHouse Gas emissions (GHGs) reporting. The selected reports include at least one target re-duction for at least one target year. Then, on the basis of this analysis we propose guidelines to encourage and help higher education and research organizations set rele-vant climate targets.

scientific communication and education↗

bioRxiv2024

Mutant fate in spatially structured populations on graphs: connecting models to experiments

In nature, most microbial populations have complex spatial structures that can affect their evolution. Evolutionary graph theory predicts that some spatial structures modelled by placing individuals on the nodes of a graph affect the probability that a mutant will fix. Evolution experiments are beginning to explicitly address the impact of graph structures on mutant fixation. However, the assumptions of evolutionary graph theory differ from the conditions of modern evolution experiments, making the comparison between theory and experiment challenging. Here, we aim to bridge this gap by using our new model of spatially structured populations. This model considers connected subpopulations that lie on the nodes of a graph, and allows asymmetric migrations. It can handle large populations, and explicitly models serial passage events with migrations, thus closely mimicking experimental conditions. We analyze recent experiments in light of this model. We suggest useful parameter regimes for future experiments, and we make quantitative predictions for these experiments. In particular, we propose experiments to directly test our recent prediction that the star graph with asymmetric migrations suppresses natural selection and can accelerate mutant fixation or extinction, compared to a well-mixed population. Author SummaryPredicting how mutations spread through a population and eventually take over is important for understanding evolution. Complex spatial structures are ubiquitous in natural microbial populations, and can impact the fate of mutants. Theoretical models have been developed to describe this effect. They predict that some spatial structures have mutant fixation probabilities that differ from those of well-mixed populations. Experiments are beginning to probe these effects in the laboratory. However, there is a disconnect between models and experiments, because they consider different conditions. In this work, we connect them through a new model that closely matches experimental conditions. We analyze recent experiments and propose new ones that should allow testing the effects of complex population spatial structures on mutant fate.

biophysics↗

bioRxiv2023

Assessing the impact of 20th century internal migrations on the genetic structure of Estonia

There is emerging evidence that migration behaviour can be selective with respect to individuals genotypes. As a result, it can generate genotype-environment correlations at migration-associated loci that cannot be corrected by standard methods used in genetic association studies. Here, we explore this phenomenon by looking into the dynamics of the spatial distribution of polygenic scores (PGSs) in the Estonian Biobank. We show that contemporary migrations intensify inter-regional differences in PGSs for many traits, with the effect of educational attainment (EA) PGS being the strongest and, to a large extent, explaining inter-regional differences in other PGSs. This differentiation is mainly driven by the migration of individuals with relatively high PGS for EA to the two largest cities from the rest of the country. Importantly, we replicate this pattern within families: individuals migrating to the major cities have, on average, higher PGS for EA relative to their siblings residing in other regions of Estonia. This trend is observed for the period starting from the mid-20th century to the present, despite substantial changes in Estonian society during this period. Thus, we show that there is increasing genetic differentiation at trait-associated loci between most urbanized regions of Estonia versus the rest of the country, leading to genotype-environment correlations that cannot be fully corrected using standard approaches. We also provide evidence for direct genetic effects on migration behaviour based on sibling analysis and discuss potential links between migration and EA.

genetics↗

bioRxiv2023

Ancestral genetic components are consistently associated with the complex trait landscape in European biobanks

The genetic structure in Europe was mostly shaped by admixture between the Western Hunter-Gatherer, Anatolian Neolithic and Steppes Yamnaya ancestral components. Such structure is regarded as a confounder in GWAS and follow-up studies, and gold-standard methods exist to correct for it. However, it is still poorly understood to which extent these ancestral components contribute to complex trait variation in present-day Europe. In this work we harness the UK Biobank to address this question. By extensive demographic simulations and incorporating previous results obtained using the Estonian Biobank, we carefully evaluate the significance and scope of our findings. Heart rate, platelet count, monocyte percentage and many other traits show stratification similar to height and pigmentation traits, likely targets of selection and divergence across ancestral groups. The consistency of our results across biobanks indicates that these ancestry-specific genetic predispositions act as a source of variability and as potential confounders in Europe as a whole.

genomics↗

bioRxiv2022

Assessing temporal and geographic contacts across the Adriatic Sea through the analysis of genome-wide data from Southern Italy

Southern Italy was characterised by a complex prehistory that started with different Palaeolithic cultures, later followed by the Neolithic transition and the demic dispersal from the Pontic-Caspian Steppe during the Bronze Age. Archaeological and historical evidence points to demic and cultural influences between Southern Italians and the Balkans, starting with the initial Palaeolithic occupation until historical and modern times. To shed light on the dynamics of these contacts, we analysed a genome-wide SNP dataset of more than 700 individuals from the South Mediterranean area (102 from Southern Italy), combined with ancient DNA from neighbouring areas. Our findings revealed high affinities of South-Eastern Italians with modern Eastern Peloponnesians, and a closer affinity of ancient Greek genomes with those from specific regions of South Italy than modern Greek genomes. The higher similarity could be associated with the presence of a Bronze Age component ultimately originating from the Caucasus and characterised by high frequencies of Iranian and Anatolian Neolithic ancestries. Furthermore, to reveal possible signals of natural selection, we looked for extremely differentiated allele frequencies among Northern and Southern Italy, uncovering putatively adapted SNPs in genes involved in alcohol metabolism, nevi features and immunological traits, such as ALDH2, NID1 and CBLB.

genomics↗

bioRxiv2021

Ancestral contributions to contemporary European complex traits

The contemporary European genetic makeup formed in the last 8000 years as the combination of three main genetic components: the local Western Hunter-Gatherers, the incoming Neolithic Farmers from Anatolia and the Bronze Age component from the Pontic Steppes. When meeting into the post-Neolithic European environment, the genetic variants accumulated during their three distinct evolutionary histories mixed and came into contact with new environmental challenges. Here we investigate how this genetic legacy reflects on the complex trait landscape of contemporary European populations, using the Estonian Biobank as a case study. For the first time we directly connect the phenotypic information available from biobank samples with the genetic similarity to these ancestral groups, both at a genome-wide level and focusing on genomic regions associated with each of the 27 complex traits we investigated. We also found SNPs connected to pigmentation, cholesterol, sleep, diastolic blood pressure, and body mass index (BMI) to show signals of selection following the post Neolithic admixture events. We recapitulate existing knowledge about pigmentation traits, corroborate the connection between Steppe ancestry and height and highlight novel associations. Among others, we report the contribution of Hunter Gatherer ancestry towards high BMI and low blood cholesterol levels. Our results show that the ancient components that form the contemporary European genome were differentiated enough to contribute ancestry-specific signatures to the phenotypic variability displayed by contemporary individuals in at least 11 out of 27 of the complex traits investigated here.

genomics↗

bioRxiv2021

The genetic origin of Daunians and the Pan-Mediterranean southern Italian Iron Age context

The geographical location and shape of Apulia, a narrow land stretching out in the sea at the South of Italy, made this region a Mediterranean crossroads connecting Western Europe and the Balkans. Such movements culminated at the beginning of the Iron Age with the Iapygian civilization which consisted of three cultures: Peucetians, Messapians and Daunians. Among them, the Daunians left a peculiar cultural heritage, with one-of-a-kind stelae and pottery, but, despite the extensive archaeological literature, their origin has been lost to time. In order to shed light on this and to provide a genetic picture of Iron Age Southern Italy, we collected and sequenced human remains from three archaeological sites geographically located in Northern Apulia (the area historically inhabited by Daunians) and radiocarbon dated between 1157 and 275 calBCE. We find that Iron Age Apulian samples are still distant from the genetic variability of modern-day Apulians, they show a remarkable genetic heterogeneity, even though a few kilometers and centuries separate them, and they are well inserted into the Iron Age Pan-Mediterranean genetic landscape. Our study provides for the first time a window on the genetic make-up of pre-imperial Southern Italy, whose increasing connectivity within the Mediterranean landscape, would have contributed to laying the foundation for modern genetic variability. In this light, the genetic profile of Daunians may be compatible with an autochthonous origin, with plausible contributions from the Balkan peninsula.

genetics↗