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Williams, R. W.

Publications and source records attributed to Williams, R. W..

At least 19 recordsLinked to original sources

An Expert-Curated Benchmark for Frontier and Local LLMs Querying a Biomedical Knowledge Graph

We combine GeneNetwork's 1TB structured database with its metadata as an RDF graph and an associated literature corpus. We benchmark frontier and local LLMs querying it through four architectures: document, graph and agentic retrieval-augmented generation (RAG), and a combination of the three. We evaluate them on 40 domain specific expert-curated questions with a new metric: the satisfaction frequency psi (psi, i.e, the share of questions answered with precision and recall of at least 70% or an f1 of at least 60%). psi ranks systems the same way precision, recall and f1 -- a machine learning metric built from the harmonic mean of precision and recall -- but is easier to read and assess for humans. System architecture had a large effect: with full use of Claude Opus 4.8 the plain document RAG of our earlier GNQA system had a psi of 36% against 86% for our new combined tools. Delegating most of the work from Claude Opus 4.8 to a local model halved query costs while still reaching a psi of 59%.

bioinformatics↗

BXD51: A Robust and Translational Mouse Model for Studying the Pathophysiology of Glaucoma

The aim of this study was to characterize the BXD51 mouse strain as a reproducible model of chronic progressive glaucoma. Unlike the highly susceptible DBA/2J (D2) mutant strain, BXD51 is a genetically stable recombinant inbred line derived from C57BL/6J (B6) and D2 parental lines. Longitudinal assessments of intraocular pressure (IOP), visual acuity (VA), contrast sensitivity (CS), and pattern electroretinogram (pERG) demonstrated that BXD51 mice undergo a delayed decline in visual and retinal ganglion cell (RGC) function. Their decline is biphasic, with a period of initial ocular stress followed by a late-onset, accelerated structural and functional deterioration of RGCs. Anterior segment structural analysis by optical coherence tomography (OCT) and histology demonstrated increasing pigment dispersion and subsequent iridocorneal angle closure. Immunofluorescence analysis of structural neuronal markers (TUBB3 and MAP1A/2) exhibited thinning of the ganglion cell layer (GCL) and inner plexiform layer (IPL) together with axonal degeneration, mirroring the laminar degeneration seen in human glaucoma patients. BXD51 also revealed marked spatial heterogeneity between peripheral and central retina. Multivariate analysis confirmed that BXD51 follows a distinct clinical trajectory that separates it from both wild-type (B6) and a severe glaucoma model (D2). By spanning the range between resistance and extreme susceptibility to glaucomatous neurodegeneration, this study establishes the BXD51 mouse as a translational platform for mechanistic studies and for evaluating long-term neuroprotective strategies.

neuroscience↗

MONICA: A Web Application for Automated Whole Optic Nerve Contour Extraction and Morphometric Analysis Validated Across Taxonomic Orders and Image Quality Levels

Quantitative assessment of optic nerve health requires metrics beyond axon counts alone. Axon density and glial coverage fraction correlate with clinical measures of visual function, yet no existing automated tool extracts optic nerve cross-sectional boundaries to enable their calculation. We developed MONICA (Morphometrics from Optic Nerve Imaging Contour Analysis), a web application that integrates AxonDeepSeg deep learning segmentation with a novel morphology-based contour extraction algorithm to automatically derive whole nerve boundaries alongside axon and myelin masks. The contour extraction algorithm was validated against manual ground truth annotations using 15 optic nerve cross-sections spanning two taxonomic orders (mouse, rabbit), two mouse strains (BXD29, BXD51), and varying preparation quality levels (modern and archival samples). Automated contour extraction demonstrated excellent agreement with manual annotations, achieving an overall Dice similarity coefficient (a measure of segmentation overlap) of 0.987 {+/-} 0.009. Balanced precision (0.985) and recall (0.989) values indicated that the algorithm neither systematically over-segments nor under-segments nerve boundaries. MONICA requires no local software installation and runs entirely in-browser, providing batch processing for high-throughput phenotyping alongside a full suite of per-axon morphometrics. MONICA provides researchers with an accessible tool for complete nerve cross-section morphometry.

neuroscience↗

Genome-Wide Annotation of Promoter-Enhancer Interactions via Chromatin Loops in the Hybrid Rat Diversity Panel

Despite the prominence of laboratory rats in behavioral neuroscience and complex trait genetics, a significant gap exists in the functional rat genomics database that explains the regulation of gene expression at the genome level. To address this, we analyzed genome-wide Hi-C data from the frontal cortex of ten strains in the Hybrid Rat Diversity Panel. While originally generated to improve the rat genome assembly, these data provided a unique opportunity to characterize the regulatory landscape of the adult rat brain. We identified an average of 5,899 {+/-} 1,997 (STD) loops per sample and integrated these with over 3 million curated CTCF binding sites, which serve as architectural anchors for chromatin loops. Our multi-stage filtering workflow identified 15,085 unique, high-confidence regulatory interactions throughout the genome. As a validation of our approach, we observed that genes with the highest loop counts, including Foxo1, Gja1, and Spry2, were significantly enriched for developmental processes, reflecting the role of 3D genome structure in maintaining adult neuronal identity. The resulting resource addresses a critical deficiency in rat functional genomics and provides a foundation for dissecting the genetic architecture of complex traits.

genomics↗

Identity-by-descent captures Shared Environmental Factors at Biobank Scale

Genealogical ties leave traces beyond shared genetic material: relatives tend to share environmental exposures and cultural practices that persist across generations. Using genomic and electronic health record data from 13,143 individuals in the Biorepository for Integrative Genomics, we applied a hierarchical community detection algorithm to group individuals into four major communities and 17 subcommunities based on the proportion of their genome shared identical by descent (IBD). This approach captured a fine-scale demographic structure beyond traditional ancestry classifications. By integrating neighborhood-level geographic data with census-derived environmental metrics, we revealed unequal exposure to environmental stressors between subcommunities, which correlated with differential rates of health conditions, including elevated respiratory condition prevalence in subcommunities under greater pollution burden. Through an interventional mediation analysis we found that excess risk at the subcommunity-level substantially exceeded what measured environmental factors alone could explain. thus showing the contribution of unmeasured shared exposures that IBD-based grouping captures. Subcommunity-level disparities persisted in sensitivity analyses adjusting for self-reported race, indicating that IBD-based clustering captures health-relevant information beyond demographic categories commonly used as proxies for social determinants of health. We implemented an open-source dashboard for interactive exploration of IBD-defined communities, disease prevalence, and environmental exposures. Together, we demonstrate that IBD-based clustering jointly captures genetic and environmental determinants of health, offering a scalable framework for precision health and population genetics that translates biobank data into actionable insights.

genomics↗

Genetic Modulation of Lifespan: Dynamic Effects, Sex Differences, and Body Weight Trade-offs

The dynamics of lifespan are shaped by DNA variants that exert effects at different ages. We have mapped genetic loci that modulate age-specific mortality using an actuarial approach. We started with an initial population of 6,438 pubescent siblings and ended with a survivorship of 559 mice that lived to at least 1100 days. Twenty-nine Vita loci dynamically modulate the mean lifespan of survivorships with strong age- and sex-specific effects. Fourteen have relatively steady effects on mortality while other loci act forcefully only early or late in life and with polarities of effects that invert. A distinct set of 19 Soma loci shape the negative correlation between weights of young adults with their life expectancies--much more strongly so in males than females. Another set of 11 Soma loci shape the positive correlation between weights at older ages with life expectancies. The Vita and Soma loci share 289 age-dependent epistatic interactions (LODs [≥]3.8) but fewer than 4% are common to both sexes. We provide two examples of how to move from maps toward potential mechanisms. Our findings provide an empirical bridge between evolutionary theories on aging and genetic and molecular causes. These loci and their interactions are key to begin to understand the impact of interventions that may extend healthy lifespan in mice and even in humans.

genetics↗

Hi-C sequencing data from cortex laboratory rats

The three-dimensional conformation and packaging of chromosomes modulates the spatial organization of the nucleus, orchestrating DNA replication and repair, maintaining genome stability and integrity, and regulating gene expression. Hi-C methods provide high-resolution data on chromatin-to-chromatin interactions both within and among chromosomes at a genome-wide scale. Hi-C resolves topologically-associated domains (TADs) and chromatin loops that are linked to cell-specific transcriptional control. We present a comprehensive Hi-C dataset generated from the frontal cortex of laboratory rats, encompassing a diverse group of inbred strains (SHR/OlaIpcv, BN-Lx/Cub, BXH6/Cub, HXB2/Ipcv, HXB10/Ipcv, HXB23/Ipcv, HXB31/Ipcv, LE/Stm, F344/Stm) and an F1 hybrid (SHR/Olalpcv x BN/NHsdMcwi). This dataset serves as a valuable resource for studying the mechanisms by which three-dimensional chromatin architecture governs gene expression in the brain. Strain-specific variations in genome organization can illuminate the influence of chromatin structure on gene expression, neuronal functionality, and the predisposition to neurological and behavioral disorders.

genomics↗

Global dissection of the impact of Alzheimer's disease on brain architecture and behavior: High resolution MRH resolves robust regional effects

Alzheimers disease (AD) affects brain regions with remarkable heterogeneity, but the precise impact of this disease on hundreds of small cortical, subcortical, and brainstem regions remains poorly defined. Here, as a prelude to testing preclinical models to prevent AD, we systematically quantified effects of human AD mutations in APP and PSEN1 on 231 regions and comprehensively evaluated changes in volume with unprecedented resolution in genetically diverse mice as a function of sex and genetic background. We studied 34 5XFAD F1 hybrids and 23 sibling controls at 14 months, evaluating learning and memory behaviors, followed by ex vivo diffusion tensor images (DTI) at 25 {micro}m resolution. We delineated 231 regions of interest (ROIs) bilaterally with high precision. Remarkably, we found bidirectional changes: marked volume increases (up to 10%) in neocortex, hippocampus, amygdala, and sensory nuclei, contrasted with decreases in striatum, pallidum, thalamus, hypothalamus, and most fiber tracts. These opposing effects are unrelated to amyloid load and are likely to reflect temporal gradients in susceptibility of ROIs. Effects are similar in both sexes but far more prominent in females. Genetic background strongly modulates penetrance of the human mutations with the AD-BXD77 F1 type having the greatest sensitivity. Light sheet microscopy and stereological analysis of NeuN+ neurons and amyloid {beta} aggregates in 22 regions revealed up to 20% loss of cells in CA3 and in anterior and intralaminar parts of the thalamus. Volumetric changes correlated with impaired fear acquisition and memory, with cases and controls often showing opposite relations between performance and regional volumes. These findings reveal unprecedented regional heterogeneity in AD progression and suggest therapeutic efficacy may vary substantially across genetic backgrounds and between sexes.

neuroscience↗

Creating a biomedical knowledge base by addressing GPT inaccurate responses and benchmarking context

We created GNQA, a generative pre-trained transformer (GPT) knowledge base driven by a performant retrieval augmented generation (RAG) with a focus on aging, dementia, Alzheimers and diabetes. We uploaded a corpus of three thousand peer reviewed publications on these topics into the RAG. To address concerns about inaccurate responses and GPT hallucinations, we implemented a context provenance tracking mechanism that enables researchers to validate responses against the original material and to get references to the original papers. To assess the effectiveness of contextual information we collected evaluations and feedback from both domain expert users and citizen scientists on the relevance of GPT responses. A key innovation of our study is automated evaluation by way of a RAG assessment system (RAGAS). RAGAS combines human expert assessment with AI-driven evaluation to measure the effectiveness of RAG systems. When evaluating the responses to their questions, human respondents give a "thumbs-up" 76% of the time. Meanwhile, RAGAS scores 90% on answer relevance on questions posed by experts. And when GPT-generates questions, RAGAS scores 74% on answer relevance. With RAGAS we created a benchmark that can be used to continuously assess the performance of our knowledge base. Full GNQA functionality is embedded in the free GeneNetwork.org web service, an open-source system containing over 25 years of experimental data on model organisms and human. The code developed for this study is published under a free and open-source software license at https://git.genenetwork.org/gn-ai/tree/README.md.

scientific communication and education↗

An Open Resource: MR and light sheet microscopy stereotaxic atlas of the mouse brain

We have combined MR histology and light sheet microscopy (LSM) of five postmortem C57BL/6J mouse brains in a stereotaxic space based on micro-CT yielding a multimodal 3D atlas with the highest spatial and contrast resolution yet reported. Brains were imaged in situ with multi gradient echo (mGRE) and diffusion tensor imaging (DTI) at 15 m resolution ([~] 2.4 million times that of clinical MRI). Scalar images derived from the average DTI and mGRE provide unprecedented contrast in 14 complementary 3D volumes, each highlighting distinct histologic features. The same tissues scanned with LSM and registered into the stereotaxic space provide 17 different molecular cell type stains. The common coordinate framework labels (CCFv3) complete the multimodal atlas. The atlas has been used to correct distortions in the Allen Brain Atlas and harmonize it with Franklin Paxinos. It provides a unique resource for stereotaxic labeling of mouse brain images from many sources.

neuroscience↗

Male and female variability in response to chronic stress and morphine in C57BL/6J, DBA/2J, and their BXD progeny

Drug addiction is a multifactorial syndrome in which genetic predispositions and exposure to environmental stressors constitute major risk factors for the early onset, escalation, and relapse of addictive behaviors. While it is well known that stress plays a key role in drug addiction, the genetic factors that make certain individuals particularly sensitive to stress and thereby more vulnerable to becoming addicted are unknown. In an effort to test a complex set of gene x environment interactions--specifically gene x chronic stress--here we leveraged a systems genetics resource: BXD recombinant inbred mice (BXD5, BXD8, BXD14, BXD22, BXD29, and BXD32) and their parental mouse lines, C57BL/6J and DBA/2J. Utilizing the chronic social defeat stress (CSDS) and chronic variable stress (CVS) paradigms, we first showed sexual dimorphism in the behavioral stress response between the mouse strains. Further, we observed an interaction between genetic background and vulnerability to prolonged exposure to non-social stressors. Finally, we found that DBA/2J and C57BL/6J mice pre-exposed to stress displayed differences in morphine sensitivity. Our results support the hypothesis that genetic variation in predisposition to stress responses influences morphine sensitivity and is likely to modulate the development of drug addiction.

neuroscience↗

Pangenome reconstruction in rats enhances genotype-phenotype mapping and novel variant discovery

The HXB/BXH family of recombinant inbred rat strains is a unique genetic resource that has been extensively phenotyped over 25 years, resulting in a vast dataset of quantitative molecular and physiological phenotypes. We built a pangenome graph from 10x Genomics Linked-Read data for 31 recombinant inbred rats to study genetic variation and association mapping. The pangenome includes 0.2Gb of sequence that is not present the reference mRatBN7.2, confirming the capture of substantial additional variation. We validated variants in challenging regions, including complex structural variants resolving into multiple haplotypes. Phenome-wide association analysis of validated SNPs uncovered variants associated with glucose/insulin levels and hippocampal gene expression. We propose an interaction between Pirl1l1, chromogranin expression, TNF- levels, and insulin regulation. This study demonstrates the utility of linked-read pangenomes for comprehensive variant detection and mapping phenotypic diversity in a widely used rat genetic reference panel.

genomics↗

BulkLMM: Real-time genome scans for multiple quantitative traits using linear mixed models

Genetic studies often collect data using high-throughput phenotyping. That has led to the need for fast genomewide scans for large number of traits using linear mixed models (LMMs). Computing the scans one by one on each trait is time consuming. We have developed new algorithms for performing genome scans on a large number of quantitative traits using LMMs, BulkLMM, that speeds up the computation by orders of magnitude compared to one trait at a time scans. On a mouse BXD Liver Proteome data with more than 35,000 traits and 7,000 markers, BulkLMM completed in a few seconds. We use vectorized, multi-threaded operations and regularization to improve optimization, and numerical approximations to speed up the computations. Our soft-ware implementation in the Julia programming language also provides permutation testing for LMMs and is available at https://github.com/senresearch/BulkLMM.jl.

bioinformatics↗

Polyglucosan body density in the aged mouse hippocampus is controlled by a novel modifier locus on chromosome 1

In aged humans and mice, aggregates of hypobranched glycogen molecules called polyglucosan bodies (PGBs) accumulate in hippocampal astrocytes. PGBs are known to drive cognitive decline in neurological diseases but remain largely unstudied in the context of typical brain aging. Here, we show that PGBs arise in autophagy-dysregulated astrocytes of the aged C57BL/6J mouse hippocampus. To map the genetic cause of age-related PGB accumulation, we quantified PGB burden in 32 fully sequenced BXD-recombinant inbred mouse strains, which display a 400-fold variation in hippocampal PGB burden at 16-18 months of age. A major modifier locus was mapped to chromosome 1 at 72-75 Mb, which we defined as the Pgb1 locus. To evaluate candidate genes and downstream mechanisms by which Pgb1 controls the aggregation of glycogen, extensive hippocampal transcriptomic and proteomic datasets were produced for aged mice of the BXD family. We utilized these datasets to identify Smarcal1 and Usp37 as potential regulators of PGB accumulation. To assess the effect of PGB burden on age-related cognitive decline, we performed phenome-wide association scans, transcriptomic analyses as well as conditioned fear memory and Y-maze testing. Importantly, we did not find any evidence suggesting a negative impact of PGBs on cognition. Taken together, our study demonstrates that the Pgb1 locus controls glycogen aggregation in astrocytes of the aged hippocampus without affecting age-related cognitive decline.

genetics↗

GenomeMUSter mouse genetic variation service enables multi-trait, multi-population data integration and analyses

Hundreds of inbred laboratory mouse strains and intercross populations have been used to functionalize genetic variants that contribute to disease. Thousands of disease relevant traits have been characterized in mice and made publicly available. New strains and populations including the Collaborative Cross, expanded BXD and inbred wild-derived strains add to set of complex disease mouse models, genetic mapping resources and sensitized backgrounds against which to evaluate engineered mutations. The genome sequences of many inbred strains, along with dense genotypes from others could allow integrated analysis of trait - variant associations across populations, but these analyses are not feasible due to the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense data resource by harmonizing multiple variant datasets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extensible to other model organism species. The result is a web- and programmatically-accessible data service called GenomeMUSter (https://muster.jax.org), comprising allelic data covering 657 strains at 106.8M segregating sites. Interoperation with phenotype databases, analytic tools and other resources enable a wealth of applications including multi-trait, multi-population meta-analysis. We demonstrate this in a cross-species comparison of the meta-analysis of Type 2 Diabetes and of substance use disorders, resulting in the more specific characterization of the role of human variant effects in light of mouse phenotype data. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.

genetics↗

RNA Strain-Match: A tool for matching single-nucleus, single-cell, or bulk RNA-sequencing alignment data to its corresponding genotype

When next generation sequencing is performed in large batches, there are several stages at which samples can be swapped or mislabeled. It is therefore helpful, when possible, to integrate measures into analysis pipelines to confirm that samples match their assigned metadata. Here, we introduce RNA Strain-Match (GitHub: https://github.com/jon-willcox/RNA-strain-match), a quality control tool developed to match RNA data in the form of sequence alignment files (i.e. SAM or BAM files) to their corresponding genotype without the use of an RNA variant call format file. We successfully used RNA Strain-Match in tandem with assessment of markers for sex and transgene status to identify and correct sample mismatches in 50/379 samples (13%) from two distinct recombinant inbred mouse models (BXD and Collaborative Cross). We believe this tool will be beneficial to any research group working with similar data.

bioinformatics↗

A rapid workflow for neuron counting in combined light sheet microscopy and magnetic resonance histology

Information on regional variation in cell numbers and densities in the CNS provides critical insight into structure, function, and the progression of CNS diseases. However, variability can be real or can be a consequence of methods that do not account for technical biases, including morphologic deformations, errors in the application of cell type labels and boundaries of regions, errors of counting rules and sampling sites. We address these issues of by introducing a workflow that consists of the following steps: 1. Magnetic resonance histology (MRH) to establish the size, shape, and regional morphology of the mouse brain in situ. 2. Light-sheet microscopy (LSM) to selectively label all neurons or other cells in the entire brain without sectioning artifacts. 3. Register LSM volumes to MRH volumes to correct for dissection errors and morphological deformations. 4. Implement novel protocol for automated sampling and counting of cells in 3D LSM volumes. This workflow can analyze the cells density of one brain region in less than 1 min and is highly replicable to cortical and subcortical gray matter regions and structures throughout the brain. We report deformation-corrected neuron (NeuN) counts and neuronal density in 13 representative regions in 5 C57B6/6J and 2 BXD strains. The data represent the variability among cases for the same brain region and across regions within case. Our data are consistent with previous studies. We demonstrate the application of our workflow to a mouse model of aging. This workflow improves the accuracy of neuron counting and the assessment of neuronal density on a region-by-region basis, with broad applications in how genetics, environment, and development across the lifespan impact brain structure.

neuroscience↗

Building pangenome graphs

Pangenome graphs can represent all variation between multiple reference genomes, but current approaches to build them exclude complex sequences or are based upon a single reference. In response, we developed the PanGenome Graph Builder (PGGB), a pipeline for constructing pangenome graphs without bias or exclusion. PGGB uses all-to-all alignments to build a variation graph in which we can identify variation, measure conservation, detect recombination events, and infer phylogenetic relationships.

bioinformatics↗