Biology subjects

Gilbert, D.

Publications and source records attributed to Gilbert, D..

12 recordsLinked to original sources

bioRxiv2026

Genomic history and selection in Roman and early medieval Britain

Leading biomedical resources rely on genome variation in Britain1-3, but the historical processes that shaped present-day fine-scale diversity remain debated4-13. Here we sequenced 1039 ancient shotgun genomes from Britain (median 1.4-fold coverage), primarily dating to the first millennium CE. We imputed [~]660 million variants in the UK Biobank14-16 and employed genealogy-based ancestry reconstruction. We found an association between Iron Age consanguinity and matrilineal burial practices17, later disrupted following the Roman Conquest. Despite this societal impact, only 20% of Roman-period individuals carried detectable ancestry from outside Britain. In contrast, from the 6th century CE we detect widespread influx of ancestry in over 70% of individuals in southernAnglo-Saxon Britain, with limited local admixture. We find previously underappreciated heterogeneity, with ancestries associated with Central and Southern Europe rising in prevalence from the 7th century CE. We demonstrate distinct Scandinavian-related ancestry in many Viking-associated contexts, but show that the population-level impact of the Viking Age in Britain was limited. Finally, we detect pre-medieval selection on variants linked with key immunity genes TLR10-TLR1 and IRF8. These results identify population-level and selective processes that shape variation and disease risk in Britain today.

genomics↗

bioRxiv2026

Alpha oscillations are dysrhythmic in Fragile X syndrome

BackgroundAlpha oscillations are dominant rhythms in the human brain, supporting inhibitory control and coordination of neural activity. Altered alpha dynamics are observed across many neuropsychiatric and neurodevelopmental disorders, including Fragile X syndrome (FXS), the most common monogenic cause of autism and intellectual disability. FXS exhibits paradoxical alpha power: elevated absolute but reduced relative power. To resolve this incongruity, we considered that conventional power metrics, relying on averaging, may obscure the underlying critical temporal dynamics of such neural rhythms. MethodsHere, we investigate alpha oscillations in FXS as a model to decompose nonspecific alpha abnormalities into underlying temporal features. We used cycle-by-cycle (bycycle) alpha burst analysis from source-localized resting-state EEG of 70 individuals with FXS (20.5{+/-}10.0 years; 32 females, 38 males) and 71 age- and sex-matched typically developing controls (22.2{+/-}10.7 years; 30 females, 41 males). Statistical modeling examined group, sex, and regional differences in alpha burst features using generalized linear mixed-effects models. ResultsWe reveal that alpha bursts in FXS show reduced count only in males, prolonged periods across sexes, and elevated amplitudes, particularly in males. Spatial mapping identified differential circuit vulnerability: timing-associated dysregulation in cognitive-control regions and amplitude elevations in sensory cortices. Within the FXS group, global alpha burst amplitude correlated with hyperactivity symptoms and inversely with general intelligence scores, and burst count correlated with age. LimitationsThis study is limited by its resting-state design and cross-sectional nature. Future studies should explore task-based modulation of alpha burst features and longitudinal trajectories in FXS. Additionally, fragile X messenger ribonucleoprotein (FMRP) was not quantified for participants, limiting potential stratification by molecular severity. ConclusionsThese findings resolve paradoxical alpha power in FXS into features consistent with interneuron dysfunction, demonstrating the potential for burst-level decomposition in mechanistic hypothesis generation and biomarker development across neurodevelopmental and neuropsychiatric disorders.

neuroscience↗

bioRxiv2025

Do DNA and cytometric measures agree on genome sizes?

Measurement of DNA contents of genomes is valuable for understanding genome biology, including assessments of genome assemblies, but it is not a trivial problem. Measuring contents of DNA shotgun reads is complicated by several factors: biological contents of genomes, laboratory methods, sequencing technology and computational processing. This compares and shares complications with cytometric measures of genome size and contents. There is an obvious discrepancy between cytometry and current long-read assemblies: assemblies average significantly below cytometric sizes. Measures of population changes within a species will control some of these complications. This report examines five species population sets with published cytometric and DNA data sets: Arabidopsis thaliana and A. arenosa, Arctic plants of Cochlearia genus, clonal populations of a rotifer Brachionus asplanchnoidis, and Zea mays corn plants. Results of this are clear, if complicated: DNA and cytometry do measure the same genome sizes, when done carefully with controls or adjustments for errors. Population changes in genome sizes are found by assembly-mapped measures of DNA, including environment or regional effects of latitude and altitude. Copy numbers of repeats, transposons and genes are changing. Kmer-based measures of DNA generally fail to match cytometry, miss population changes, and are opaque to understanding measurement errors. Oxford Nanopore technology produces the least biased DNA for measurement, with recent ONT.R10 Simplex data a match to cytometric sizes for corn, tomato plants, zebra fish and zebra finch bird. Assemblies of these species DNA average 12% below measured sizes, incomplete for duplicated content. New assembly of this ONT Simplex DNA reaches the size measured by cytometry and Gnodes, in 4 of 5 species. rRNA gene duplications measure one aspect of this discrepancy: the genome assemblies examined all are missing many rRNA genes. New experiments that measure both cytometry and DNA, controlling error factors, are warranted to clarify these results and suggest improvements for genome projects.

genomics↗

bioRxiv2025

An extended β-finger motif is a near-universal feature of kinase fusion proteins

Kinase fusion proteins (KFPs) are immune receptors that confer disease resistance in wheat (Triticum aestivum) and barley (Hordeum vulgare). We discovered that KFPs with a confirmed function share an extended {beta}-finger motif, a Poaceae-specific feature that originated [~]98 million years ago. The genes encoding these receptors are among the most highly expressed within the plant KFP repertoire, suggesting that elevated transcript abundance is a hallmark of their disease resistance function.

plant biology↗

bioRxiv2024

Exposure to low doses of Batrachochytrium dendrobatidis reveals variation in resistance in the Critically Endangered southern corroboree frog

Chytridiomycosis poses a significant extinction threat to many amphibians, including the critically endangered southern corroboree frog (Pseudophryne corroboree). Captive breeding programs have become essential to maintain populations while effective long-term conservation strategies are developed. Understanding the variation in susceptibility to chytridiomycosis within this species is essential in exploring the potential for selective breeding to enhance disease resistance. In this study, we conducted a large-scale Batrachochytrium dendrobatidis (Bd) exposure experiment involving 972 juvenile P. corroboree selected to ensure a broad genetic representation of the species. Three replicate experiments were conducted under uniform conditions, to assess individual susceptibility and compare results across replicate experiments. Significant variation was observed within and between experiments, with individual survival rates ranging from 44-74% across experiments, influenced notably by the zoo in which frogs were bred. Remarkably, 21-47% of exposed frogs remained Bd-negative, suggesting potential innate resistance. Infection intensity correlated positively with body condition, in one experiment, while age and size showed inconsistent effects on survival and infection rates across experiments, but younger and smaller frogs were more susceptible to infection and had lower survival. Among frogs that became infected, none cleared infection, with most progressing to terminal stages within an average of 69 days (ranging from 33 to 97 days). However, a few individuals maintained stable infection loads without displaying clinical signs of chytridiomycosis. This observed phenotypic variation in P. corroboree responses to Bd highlights the potential for selective breeding to improve survival outcomes in this species. The dataset generated from this study will be instrumental in guiding breeding strategies that strengthen conservation efforts for this critically endangered species.

zoology↗

bioRxiv2024

Measuring DNA contents of animal and plant genomes with Gnodes, the long and short of it.

Measurement of DNA contents of genomes is valuable for understanding genome biology, including assessments of genome assemblies, but it is not a trivial problem. Measuring contents of DNA shotgun reads is complicated by several factors: biological contents of genomes at species, individual and tissue or cell levels, laboratory methods, sequencing technology and computational processing for measurement and assembly. This compares, and shares, complications with cytometric (Cym) and related molecular measurements of genome size and contents. There is an obvious discrepancy between cytometric measurements and current long-read genome assemblies (Asm): genome assemblies average 12% below Cym measured sizes, differing in amounts of duplicated content. This report examines five DNA read types to see if they can be used for more precise and reliable discrimination of major genome contents and sizes. The read types are short, accurate Illumina, long Pacific Biosciences, of low and high accuracy, and long Oxford Nanopore Technology of low and high accuracy. Gnodes is the measurement tool used, which maps DNA to assembly, and measures DNA copy numbers for major genome contents of genes, transposons, repeats, and others, using as a measurement unit the single copies of unique conserved genes. Public data of five well studied genomes, human, corn, zebrafish, sorghum and rice, are used for the primary evidence of this work. Results of this are mixed and open to interpretations: In broad terms, all DNA types measure about the same genome contents, at or below 90% agreement, which is a level that the other complications can contribute. For precision above a 90% level, long read types differ in supporting larger cytometric sizes (low accuracy reads), or smaller assembly sizes (high accuracy reads), with accurate short-reads roughly between. The weight of evidence suggests that low accuracy long reads are less biased for genome measurement, that high accuracy long reads have a bias of reduced duplications introduced by computational averaging or filtering. The several complicating factors noted can produce discrepancies larger than this average Cym - Asm difference, and are a problem to control.

genomics↗

bioRxiv2024

Complete sequencing of ape genomes

We present haplotype-resolved reference genomes and comparative analyses of six ape species, namely: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan, and siamang. We achieve chromosome-level contiguity with unparalleled sequence accuracy (<1 error in 500,000 base pairs), completely sequencing 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, providing more in-depth evolutionary insights. Comparative analyses, including human, allow us to investigate the evolution and diversity of regions previously uncharacterized or incompletely studied without bias from mapping to the human reference. This includes newly minted gene families within lineage-specific segmental duplications, centromeric DNA, acrocentric chromosomes, and subterminal heterochromatin. This resource should serve as a definitive baseline for all future evolutionary studies of humans and our closest living ape relatives.

genomics↗

bioRxiv2024

Frontal Cortex Hyperactivation and Gamma Desynchrony in Fragile X Syndrome: Correlates of Auditory Hypersensitivity

Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in top-down modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.

neuroscience↗

bioRxiv2023

Measure of major contents in animal and plant genomes, using Gnodes, finds under assemblies of model plant, Daphnia, fire ant and others.

Significant discrepancies in genome sizes measured by cytometric methods versus DNA sequence estimates are frequent, including recent long-read DNA assemblies of plant and animal genomes. A new DNA sequence measure using a baseline of unique conserved genes, Gnodes, finds the larger cytometric measures are often accurate. DNA-informatic measures of size, as well as assembly methods, have errors in methodology that under-measure duplicated genome spans. Major contents of several model and discrepant genomes are assessed here, including human, corn, chicken, insects, crustaceans, and the model plant. Transposons dominate larger genomes, structural repeats are often a major portion of smaller ones. Gene coding sequences are found in similar amounts across the taxonomic spread. The largest contributors to size discrepancies are higher-order repeats, but duplicated coding sequences are a significant missed content, and transposons in some examined species. Informatics of measuring DNA and producing assemblies, including recent long-read telomere to telomere approaches, are subject to mistakes in operation and/or interpretation that are biased against repeats and duplications. Mistaken aspects include alignment methods that are inaccurate for high-copy duplicated spans; misclassification of true repetitive sequence as heterozygosity and artifact; software default settings that exclude high-copy DNA; and overly conservative data processing that reduces duplicated genomic spans. Re-assemblies with balanced methods recover the missing portions of problem genomes including model plant, water fleas and fire ant.

genomics↗

bioRxiv2023

The wheat powdery mildew resistance gene Pm4 also confers resistance to wheat blast

Wheat blast, caused by the fungus Magnaporthe oryzae, threatens global cereal production since its emergence in Brazil in 1985 and recently spread to Bangladesh and Zambia. Here we demonstrate that the AVR-Rmg8 effector, common in wheat-infecting isolates, is recognised by the gene Pm4, previously shown to confer resistance to specific races of Blumeria graminis f.sp. tritici, the cause of powdery mildew of wheat. We show that Pm4 alleles differ in their recognition of different AVR-Rmg8 alleles, and some confer resistance only in seedling leaves but not spikes making it important to select for those alleles that function in both tissues. This study has identified a gene recognising an important virulence factor present in wheat blast isolates in Bangladesh and Zambia and represents an important first step towards developing durably resistant wheat cultivars for these regions.

plant biology↗

bioRxiv2021

Evolution of the bread wheat D-subgenome and enriching it with diversity from Aegilops tauschii

Aegilops tauschii, the diploid wild progenitor of the D-subgenome of bread wheat, constitutes a reservoir of genetic diversity for improving bread wheat performance and environmental resilience. To better define and understand this diversity, we sequenced 242 Ae. tauschii accessions and compared them to the wheat D-subgenome. We characterized a rare, geographically-restricted lineage of Ae. tauschii and discovered that it contributed to the wheat D-subgenome, thereby elucidating the origin of bread wheat from at least two independent hybridizations. We then used k-mer-based association mapping to identify discrete genomic regions with candidate genes for disease and pest resistance and demonstrated their functional transfer into wheat by transgenesis and wide crossing, including the generation of a library of synthetic hexaploids incorporating diverse Ae. tauschii genomes. This pipeline permits rapid trait discovery in the diploid ancestor through to functional genetic validation in a hexaploid background amenable to breeding.

plant biology↗

bioRxiv2019

An integrative ENCODE resource for cancer genomics

ENCODE comprises thousands of functional genomics datasets, and the encyclopedia covers hundreds of cell types, providing a universal annotation for genome interpretation. However, for particular applications, it may be advantageous to use a customized annotation. Here, we develop such a custom annotation by leveraging advanced assays, such as eCLIP, Hi-C, and whole-genome STARR-seq on a number of data-rich ENCODE cell types. A key aspect of this annotation is comprehensive and experimentally derived networks of both transcription factors and RNA-binding proteins (TFs and RBPs). Cancer, a disease of system-wide dysregulation, is an ideal application for such a network-based annotation. Specifically, for cancer-associated cell types, we put regulators into hierarchies and measure their network change (rewiring) during oncogenesis. We also extensively survey TF-RBP crosstalk, highlighting how SUB1, a previously uncharacterized RBP, drives aberrant tumor expression and amplifies the effect of MYC, a well-known oncogenic TF. Furthermore, we show how our annotation allows us to place oncogenic transformations in the context of a broad cell space; here, many normal-to-tumor transitions move towards a stem-like state, while oncogene knockdowns show an opposing trend. Finally, we organize the resource into a coherent workflow to prioritize key elements and variants, in addition to regulators. We showcase the application of this prioritization to somatic burdening, cancer differential expression and GWAS. Targeted validations of the prioritized regulators, elements and variants using siRNA knockdowns, CRISPR-based editing, and luciferase assays demonstrate the value of the ENCODE resource.

genomics↗