Biology subjects

Cavalleri, G. L.

Publications and source records attributed to Cavalleri, G. L..

13 recordsLinked to original sources

bioRxiv2026

Genomic impact of the second plague pandemic on three human populations

The second plague pandemic (early 14th-early 19th centuries), which was caused by Yersinia pestis, had a profound demographic, socio-economic and cultural impact across Eurasia and North Africa. Many regions in Europe and the Middle East are estimated to have lost 40-60% of their human populations, with some areas suffering even higher mortality. Whether exposure to Y. pestis drove strong positive selection on protective genetic variants in the human genome, and how it shaped migration patterns, remains debated, despite several recent studies based on ancient DNA. Here, we analyse a markedly larger, higher coverage, and geographically diverse dataset based on shotgun sequencing of genomes from 529 ancient individuals to a mean depth 8.8x dating to either before or after the arrival of the pandemic at three sites in northern Europe: Trondheim (Norway), Lund (Sweden) and Vilnius (Lithuania). Genome-wide scans for signatures of selection provide no evidence for strong positive selection acting on specific genetic variants driven by Y. pestis exposure: we neither replicate selection signatures reported by previous studies nor identify new genome-wide significant candidates. However, for all three sites, we observe evidence for a reduction in long-range immigration, indicated by a drop in the diversity of ancestry that followed the arrival of Y. pestis and broadly coincided with the end of the Viking Age, Christianisation and the onset of the Little Ice Age. Our results shed important light on the demographic impact of major sociohistorical changes that occurred during the late Medieval period in Scandinavia and the Baltic region and link Christianisation to increased diversity in ancestry before the pandemic.

genomics↗

bioRxiv2025

Long-Read Sequencing of the MUC1 VNTR: Genomic Variation, Mutational Landscape, and Its Impact on ADTKD Diagnosis and Progression

BackgroundADTKD-MUC1 is caused by frameshift mutations in MUC1 gene that produce a frameshifted protein (MUC1fs) toxic to kidney cells. The genes variable number of tandem repeats (VNTR), with high GC content, makes it largely inaccessible to standard sequencing. As a result, both the reference sequence and natural variation in this region remain poorly defined, complicating mutation detection and data interpretation. Standard methods also fail to pinpoint the exact VNTR unit affected, limiting insight into mutation mechanisms and genotype-phenotype correlations. MethodsWe employed Single Molecule, Real-Time (SMRT) sequencing and characterized the genomic sequence of MUC1 in 300 individuals including 279 individuals from 143 families suspected of having ADTKD-MUC1. We compared these results to those obtained using the CLIA-approved mass spectrometry-based probe extension (PE) assay, which specifically detect the most prevalent 59dupC mutation. We correlated the structural features of the MUC1 VNTR with the rate of kidney function decline in affected individuals. ResultsWe identified MUC1 consensus sequences for 205 unique VNTR alleles, with 9 distinct types of frameshift mutations present on 52 distinct mutated VNTR alleles. MUC1 frameshift mutations were identified in 71 of 143 families (50%) with suspected ADTKD, comprising 135 genetically affected individuals (48%). The SMRT assay exhibited complete concordance and revealed that the PE assay is capable of detecting frameshift mutations in approximately 85% of affected families. The constellation of VNTR structures supports a genotype-progression model, in which fast progressors exhibit a significantly lower number of repeat units on the wild-type allele and a higher number of repeats on the mutation-bearing allele, including an increased number of frameshifted repeat units. ConclusionsSMRT sequencing outperforms current diagnostic methods for ADTKD-MUC1 and reveals the prognostic value of VNTR structures. Although their contribution to disease progression is modest ([~]6% variance explained), it remains biologically and clinically meaningful. Key Points 3O_LISingle Molecule, Real-Time (SMRT) sequencing of MUC1 outperforms existing genetic and immunohistochemical methods for ADTKD-MUC1 diagnosis. C_LIO_LICLIA-approved mass spectrometry-based genotyping assay, complemented by SMRT sequencing, can detect nearly all ADTKD-MUC1 patients. C_LIO_LIDisease progression correlates with VNTR pattern: fast progressors have fewer WT repeats and more mutant/frameshifted repeats C_LI

genetics↗

bioRxiv2025

Predicting Drug Response with Multi-Task Gradient-Boosted Trees in Epilepsy

MotivationDespite the availability of numerous anti-seizure medications (ASMs), drug resistance remains a major issue for people with epilepsy. The probability of achieving seizure freedom diminishes with each unsuccessful drug trial, and the impact of genetic and clinical markers on ASM response remains unclear. To address this issue, we used state-of-the-art machine learning (ML) methods to predict the response of people with epilepsy to individual ASMs based on their clinical and genomic information. ResultsTo overcome data sparsity for less common drugs, we implement a multi-task (MT) learning approach for gradient-boosted trees (GBTs), assuming that predicting responses to different ASMs involves similar tasks. This strategy allows models for less prevalent drugs to leverage the more abundant data available for other drugs during training. The proposed model outperforms individual and combined drug-response predictions for most drugs. Our findings identify key genomic and clinical features influencing drug response, enhancing understanding of individual drug responses in people with epilepsy, and aiding clinicians in making informed treatment decisions. Availability and ImplementationDue to privacy reasons data is not publically available. The code will be made available upon acceptance under https://github.com/pfeiferAI/MT-GBT

bioinformatics↗

bioRxiv2024

A genetic perspective on the recent demographic history of Ireland and Britain

BackgroundWhile subtle yet discrete clusters of genetic identity across Ireland and Britain have been identified, their demographic history is unclear. MethodsUsing genotype data from 6,574 individuals with associated regional Irish or British ancestry, we identified Irish-like and British-like genetic communities using network community detection. We segregated Identity-by-Descent (IBD) and Runs-of-Homozygosity (ROH) segments by length and approximated their corresponding time periods. Through this, we inferred the regional Irish and British demographic histories in these time periods by (1) estimating genetic relatedness between communities, (2) estimating changes in effective population sizes, (3) inferring recent migration rates across Ireland and Britain, and (4) estimating changing affinities to regional European populations. For a subset of the Irish communities, we determined the enrichment/depletion of surnames within the genetic communities. ResultsThrough patterns of IBD-sharing and ROH, we find evidence of recent population bottlenecks in the Orcadian, Manx and Welsh communities. While the structure in Ireland is subtler, the communities share relatively more IBD segments that are shorter in length, and the genetic differences between the Irish communities are more subtle on average, when compared to the British communities. Regional effective population size trajectories indicate a similar demographic history throughout the island of Ireland. Further, we observe a stable migration corridor between north-east Ireland and south-west Scotland while there is a recent migration barrier between South-Eastern Ireland and Western Ireland. We observed an enrichment of Anglo-Norman and English surnames in the Wexford community while within the West Ulster-Argyll community, we saw an enrichment of Gallowglass and Scottish surnames. ConclusionsUsing well-annotated Irish and British reference genotypes, we observed temporal changes in genetic affinities within and between genetic communities in Ireland and Britain. In addition, using effective population size estimates and levels of haplotype-sharing, we detected varying degrees of genetic isolation in some Irish and British genetic communities across time. Using these new insights into the regional demographic history of Ireland and Britain across different time periods, we hope to understand the driving forces of rare allele frequencies and disease risk association within these populations.

genetics↗

bioRxiv2024

A worldwide ENIGMA study on epilepsy-related gray and white matter compromise across the adult lifespan

ObjectivesTemporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. MethodsWe studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. ResultsIn TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. ConclusionsThis study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.

neuroscience↗

bioRxiv2022

Characterization of the Y Chromosome in Newfoundland and Labrador: Evidence of a Founder Effect

The population of Newfoundland and Labrador (NL) is largely derived from settlers who migrated primarily from England and Ireland in the 1700-1800s. Previously described as an isolated founder population, based on historical and demographic studies, data on the genetic ancestry of this population remains fragmentary. Here we describe the largest investigation of patrilineal ancestry in NL. To determine the paternal genetic structure of the population, 1,110 Y chromosomes from an NL based cohort were analyzed using 5,761 Y-specific markers. We identified 160 distinct paternal haplotypes, the majority of which (71.4%) belong to the R1b haplogroup. When NL is compared with global reference populations, the haplotype composition and frequencies of the NL paternal lineages primarily resemble the English and Irish ancestral source populations. There is also evidence for genetic contributions from Basque, French, Portuguese, and Spanish fishermen and early settlers that frequented NL. The population structure shows geographical and religious clustering that can be associated with the settlement of ancestral source populations from England and Ireland. For example, the R1b-M222 haplotype, seen in people of Irish descent, is found clustered in the Irish-settled Southeast region of NL. The clustering and expansion of Y haplotypes in conjunction with the geographical and religious clusters illustrate that limited subsequent in-migration, geographic isolation and societal factors have contributed to the genetic substructure of the NL population and its designation as a founder population.

genomics↗

bioRxiv2022

Newfoundland and Labrador: A mosaic founder population of an Irish and British diaspora from 300 years ago.

The founder population of Newfoundland and Labrador (NL) is a unique genetic resource, in part due to geographic and cultural isolation, where historical records describe a migration of European settlers primarily from Ireland and England to NL in the 18th and 19th centuries. Whilst its historical isolation, and increase prevalence of certain monogenic disorders, have been appreciated, the fine-scale genetic structure and ancestry of the population has not been well described. Understanding the genetic background on which functional, disease causing, genetic variation resides on would aid informed genetic mapping efforts in the Province. Here, we leverage dense genome-wide SNP data on 1,807 NL individuals to reveal fine-scale genetic structure in NL that is clustered around coastal communities and correlated with Christian denomination. We show that the majority of NL European ancestry can be traced back to the south-east and south-west of Ireland and England, respectively. We date a substantial population size bottleneck approximately 10-15 generations ago in NL, associated with increased haplotype sharing and autozygosity. Our results elucidate novel insights into the population history of NL and demonstrate evidence of a population conducive to further genetic studies and biomarker discovery. Significance StatementNewfoundland and Labrador (NL) has been identified as a founder population, though evidence of its magnitude and subsequent isolation is unclear. Here, analysis of 1,807 NL individuals demonstrates population structure associated with geographical isolation in coastal communities and religious denomination (Catholic or Protestant Christian). Further, NL European ancestry primarily descends from settlers from south-east Ireland and south-west England. This history is associated with increased sharing of longer haplotypes in NL, and NL-specific drift in some communities more than others, providing strong evidence of a founder event occurring about 10-15 generations ago. This study elucidates the detailed population structure of NL and shows enrichment for otherwise low frequency functional variants due to genetic drift useful for potential future biomarker discovery studies.

genetics↗

bioRxiv2021

Structural network alterations in focal and generalized epilepsy follow axes of epilepsy risk gene expression: An ENIGMA study

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-genetic signatures could guide diagnosis, and ultimately, tailor therapeutic approaches to specific epilepsy syndromes.

neuroscience↗

bioRxiv2021

Topographic divergence of atypical cortical asymmetry and regional atrophy patterns in temporal lobe epilepsy: a worldwide enigma study

AO_SCPLOWBSTRACTC_SCPLOWTemporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter pathology in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity, and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.

neuroscience↗

bioRxiv2020

Network-based atrophy modelling in the common epilepsies: a worldwide ENIGMA study

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy co-localized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Indices of progressive atrophy further revealed a strong influence of connectome architecture on disease progression in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients, and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided novel insights into the macroscale features that shape the pathophysiology of common epilepsies.

neuroscience↗

bioRxiv2019

White matter abnormalities across different epilepsy syndromes in adults: an ENIGMA Epilepsy study

The epilepsies are commonly accompanied by widespread abnormalities in cerebral white matter. ENIGMA-Epilepsy is a large quantitative brain imaging consortium, aggregating data to investigate patterns of neuroimaging abnormalities in common epilepsy syndromes, including temporal lobe epilepsy, extratemporal epilepsy, and genetic generalized epilepsy. Our goal was to rank the most robust white matter microstructural differences across and within syndromes in a multicentre sample of adult epilepsy patients. Diffusion-weighted MRI data were analyzed from 1,069 non-epileptic controls and 1,249 patients: temporal lobe epilepsy with hippocampal sclerosis (N=599), temporal lobe epilepsy with normal MRI (N=275), genetic generalized epilepsy (N=182) and nonlesional extratemporal epilepsy (N=193). A harmonized protocol using tract-based spatial statistics was used to derive skeletonized maps of fractional anisotropy and mean diffusivity for each participant, and fiber tracts were segmented using a diffusion MRI atlas. Data were harmonized to correct for scanner-specific variations in diffusion measures using a batch-effect correction tool (ComBat). Analyses of covariance, adjusting for age and sex, examined differences between each epilepsy syndrome and controls for each white matter tract (Bonferroni corrected at p<0.001). Across "all epilepsies" lower fractional anisotropy was observed in most fiber tracts with small to medium effect sizes, especially in the corpus callosum, cingulum and external capsule. Less robust effects were seen with mean diffusivity. Syndrome-specific fractional anisotropy and mean diffusivity differences were most pronounced in patients with hippocampal sclerosis in the ipsilateral parahippocampal cingulum and external capsule, with smaller effects across most other tracts. Those with temporal lobe epilepsy and normal MRI showed a similar pattern of greater ipsilateral than contralateral abnormalities, but less marked than those in patients with hippocampal sclerosis. Patients with generalized and extratemporal epilepsies had pronounced differences in fractional anisotropy in the corpus callosum, corona radiata and external capsule, and in mean diffusivity of the anterior corona radiata. Earlier age of seizure onset and longer disease duration were associated with a greater extent of microstructural abnormalities in patients with hippocampal sclerosis. We demonstrate microstructural abnormalities across major association, commissural, and projection fibers in a large multicentre study of epilepsy. Overall, epilepsy patients showed white matter abnormalities in the corpus callosum, cingulum and external capsule, with differing severity across epilepsy syndromes. These data further define the spectrum of white matter abnormalities in common epilepsy syndromes, yielding new insights into pathological substrates that may be used to guide future therapeutic and genetic studies.

neuroscience↗

bioRxiv2019

Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

genetics↗

bioRxiv2017

Mapping Cortical Brain Asymmetry in 17,141 Healthy Individuals Worldwide via the ENIGMA Consortium

Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here the ENIGMA consortium presents the largest ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and brain size (indexed by intracranial volume). Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (N = 1,443 and 1,113, respectively), we found several asymmetries showing modest but highly reliable heritability. The structural asymmetries identified, and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders.\n\nSignificance StatementLeft-right asymmetry is a key feature of the human brain's structure and function. It remains unclear which cortical regions are asymmetrical on average in the population, and how biological factors such as age, sex and genetic variation affect these asymmetries. Here we describe by far the largest ever study of cerebral cortical brain asymmetry, based on data from 17,141 participants. We found a global anterior-posterior 'torque' pattern in cortical thickness, together with various regional asymmetries at the population level, which have not been previously described, as well as effects of age, sex, and heritability estimates. From these data, we have created an on-line resource that will serve future studies of human brain anatomy in health and disease.

neuroscience↗