Biology subjects

Marnetto, D.

Publications and source records attributed to Marnetto, D..

14 recordsLinked to original sources

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↗

bioRxiv2026

Co-expression-based models improve eQTL predictions and highlightnovel transcriptome-wide genes associated with schizophrenia

Non-coding genetic variants statistically associated with complex heritability phenotypes are thought to act primarily through transcriptome regulatory mechanisms. Predictions of gene expression in tissue like the human brain traditionally rely primarily on cis-eQTLs. Here, we introduce INGENE and MODULE, trans-eQTLs models designed to enhance the prediction of gene expression by capturing the collective impact of candidate trans-eQTLs acting within co-expression networks. Exploiting RNA-seq data in six post-mortem brain regions (amygdala, caudate nucleus, dorsal/subgenual anterior cingulate cortex, dorsolateral prefrontal cortex, and hippocampus), we validate our models on two testing datasets, demonstrating increased gene predictability compared to both an original cis-based model and to EpiXcan, the leading benchmark in cis-model performance. Integration of cis- and trans-predictions significantly improves gene-level expression imputation (MLE = 0.05) for 18,744 genes across the six brain regions considered. Applying cis and trans models to PGC wave 3 genotypes identifies 766 SCZ-associated genes across brain regions (pFDR < .01), emphasizing the complementary nature of cis and trans predictions in trait association discovery. Of these genes, 641 represent novel transcriptome-wide associations with schizophrenia, highlighting the role of trans-heritability and genetic interactions underlying risk for this disorder, in addition to further supporting 125 previous candidates.

genomics↗

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↗

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

Differential selective regimes identify categories of transposable elements with regulatory function

Transposable elements (TEs) are powerful drivers of genome evolution, in part through their ability to rapidly rewire the host regulatory network by creating transcription factor binding sites that can potentially be turned to the hosts advantage in a process called exaptation. However, the effects on the host phenotype vary widely among different TEs. Here, we classify TEs based on their contribution to the human host phenotypes at both molecular and macroscopic scales. TE contributions to chromatin accessibility, gene expression, and the heritability of complex traits are strongly correlated to each other, confirming that the main mechanism through which TEs affect the host phenotype is through the rewiring of the regulatory network. TE sequence and evolutionary features are able to explain a large fraction of the variance in phenotypic relevance, and in particular more than 50% of the variance of their contribution to the heritability of complex traits. A conspicuous exception to this pattern is represented by TEs of the ERV1 family, whose phenotypic impact cannot be explained by our model: In particular, this family includes a set of relatively young TEs whose phenotypic relevance is much larger than would be expected based on their sequence and evolutionary parameters. These TEs are involved in fast-evolving biological processes related to the interaction of the organism with its environment. In conclusion, our results confirm quantitatively that TE insertions affect the host phenotype mostly through the rewiring of its regulatory network; identify a signature of phenotypic relevance based on sequence and conservation properties; and highlight several TEs as promising candidates for functional studies.

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↗

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

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↗

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↗

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

The genomic impact of European colonization of the Americas

The human genetic diversity of the Americas has been shaped by several events of gene flow that have continued since the Colonial Era and the Atlantic slave trade. Moreover, multiple waves of migration followed by local admixture occurred in the last two centuries, the impact of which has been largely unexplored.\n\nHere we compiled a genome-wide dataset of [~]12,000 individuals from twelve American countries and [~]6,000 individuals from worldwide populations and applied haplotype-based methods to investigate how historical movements from outside the New World affected i) the genetic structure, ii) the admixture profile, iii) the demographic history and iv) sex-biased gene-flow dynamics, of the Americas.\n\nWe revealed a high degree of complexity underlying the genetic contribution of European and African populations in North and South America, from both geographic and temporal perspectives, identifying previously unreported sources related to Italy, the Middle East and to specific regions of Africa.

genomics↗

bioRxiv2017

Evolutionary rewiring of the human regulatory network by waves of genome expansion

Genome expansion is believed to be an important driver of the evolution of gene regulation. To investigate the role of newly arising sequence in rewiring the regulatory network we estimated the age of each region of the human genome by applying maximum parsimony to genome-wide alignments with 100 vertebrates. We then studied the age distribution of several types of functional regions, with a focus on regulatory elements. The age distribution of regulatory elements reveals the extensive use of newly formed genomic sequence in the evolution of regulatory interactions. Many transcription factors have expanded their repertoire of targets through waves of genomic expansions that can be traced to specific evolutionary times. Repeated elements contributed a major part of such expansion: many classes of such elements are enriched in binding sites of one or a few specific transcription factors, whose binding sites are localized in specific portions of the element and characterized by distinctive motif words. These features suggest that the binding sites were available as soon as the new sequence entered the genome, rather than being created later by accumulation of point mutations. By comparing the age of regulatory regions to the evolutionary shift in expression of nearby genes we show that rewiring through genome expansion played an important role in shaping the human regulatory network.

evolutionary biology↗

bioRxiv2016

Selection on the FADS region in Europeans

AbstractFADS genes encode fatty acid desaturases that are important for the conversion of short chain polyunsaturated fatty acids (PUFAs) to long chain fatty acids. Prior studies indicate that the FADS genes have been subjected to strong positive selection in Africa, South Asia, Greenland, and Europe. By comparing FADS sequencing data from present-day and Bronze Age (5-3k years ago) Europeans, we identify possible targets of selection in the European population, which suggest that selection has targeted different alleles in the FADS genes in Europe than it has in South Asia or Greenland. The alleles showing the strongest changes in allele frequency since the Bronze Age show associations with expression changes and multiple lipid-related phenotypes. Furthermore, the selected alleles are associated with a decrease in linoleic acid and an increase in arachidonic and eicosapentaenoic acids among Europeans; this is an opposite effect of that observed for selected alleles in Inuit from Greenland. We show that multiple SNPs in the region affect expression levels and PUFA synthesis. Additionally, we find evidence for a gene-environment interaction influencing low-density lipoprotein (LDL) levels between alleles affecting PUFA synthesis and PUFA dietary intake: carriers of the selected, derived allele have diminished increases in LDL cholesterol with a higher intake of PUFAs. We hypothesize that the selective patterns observed in Europeans were driven by a change in dietary composition of fatty acids following the transition to agriculture, resulting in a lower intake of arachidonic acid and eicosapentaenoic acid, but a higher intake of linoleic acid and -linolenic acid.

genetics↗