Biology subjects

Keenan, K.

Publications and source records attributed to Keenan, K..

4 recordsLinked to original sources

bioRxiv2025

Beyond reference bias: Making pangenomes accessible with PangyPlot

Linear reference genomes have standardized genomics research but remain limited by reference bias, which skews read mapping and variant discovery. This bias can distort the interpretation of genetic variation, particularly for populations that are genetically distant from the reference. Pangenome graphs, such as those generated by the Human Pangenome Reference Consortium (HPRC), mitigate this limitation by integrating diverse haplotypes into a unified representation of human genetic variation. However, the complexity of graph-based data and the lack of intuitive visualization tools have hindered broader adoption. Here we introduce PangyPlot, a genome browser that simplifies exploration of pangenome graphs by retaining linear-style navigation, integrating gene annotations, abstracting complex variation into interpretable structures, and employing a dynamic, physics-based layout optimization engine. We demonstrate its utility by constructing a chromosome 7 graph from 101 individuals with cystic fibrosis (CF), capturing a broad spectrum of genetic variation. Using PangyPlot, we visualized CF-relevant loci and compared results with existing graph viewers, highlighting its ability to display both base-level and large structural variation. With an additional 64 PacBio HiFi assemblies, we fine-mapped a repeat-dense CF modifier locus on chromosome 5, where PangyPlot was used in conjunction with graph-based analysis to identify a repeat expansion in the 5' end of EXOC3 that may promote G-quadruplex formation and affect gene expression. Together, these examples demonstrate PangyPlot s capacity to make populationlevel variation interpretable. To support broader use of graph-based resources, we also released a live public instance of PangyPlot preloaded with HPRC data (https://pangyplot.research.sickkids.ca/).

genomics↗

bioRxiv2025

GWAS SVatalog: a visualization tool to aid fine-mapping of GWAS loci with structural variations

BackgroundGenome-wide association studies (GWAS) have been successful in identifying single nucleotide polymorphisms (SNPs) associated with phenotypic traits. However, SNPs form an incomplete set of variation across the genome and since a large percentage of GWAS-significant SNPs lie in non-coding regions, their impact on a given trait is difficult to decipher. Recognizing whether these SNPs are tagging other polymorphisms, like structural variations (SV), is an important step towards understanding the putative causal variation at GWAS loci. ResultsHere, we develop GWAS SVatalog (https://svatalog.research.sickkids.ca/), a novel open-source web tool that computes and visualizes linkage disequilibrium (LD) between SVs and GWAS-associated SNPs throughout the human genome. The tool combines GWAS Catalogs SNP-trait association data across 14,479 phenotypes with LD statistics calculated between 35,732 SVs and 116,870 SNPs identified in 101 whole-genome long-read sequences. We use GWAS SVatalog to identify SVs that may explain GWAS loci for iron levels, refractive error, and Alzheimers disease, where previously SNPs were unable to provide a causal explanation. ConclusionsGWAS SVatalog advances the fine-mapping of GWAS loci with structural variations, enabling researchers to associate 35,732 common SVs with 14,479 phenotypes, accelerating the understanding of disease etiology.

bioinformatics↗

bioRxiv2022

High Quality Phasing Using Linked-Read Whole Genome Sequencing of Patient Cohorts Informs Genetic Understanding of Complex Traits

Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. For population studies, phase is often inferred from external data but read-based phasing approaches that span long genomic distances would be more accurate because they enable both genotype and phase to be obtained from a single dataset. To demonstrate how read-based phasing can provide functional insights, we sequenced 477 individuals with Cystic Fibrosis (CF) using linked-read sequencing. We benchmark read-based phasing with different short- and long-read sequencing technologies, prioritize linked-read technology as the most informative and produce a benchmark phase call set from reference sample HG002 for the community. The 477 samples display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, which facilitates understanding of complex CF alleles. Fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus demonstrates a 20 kb deletion and a PRSS2 missense variant p.Thr8Ile (rs62473563) independently contribute to meconium ileus risk (p=0.0028, p=0.011, respectively) and are PRSS2 pancreas eQTLs (p=9.5e-7 and p=1.4e-4, respectively), explaining the mechanism by which these polymorphisms contribute to CF. Phase enables access to haplotypes that can be used for genome graph or reference panel construction, identification of cis-effects, and for understanding disease associated loci. The phase information from linked-reads provides a causal explanation for variation at a CF-relevant locus which also has implications for the genetic basis of non-CF pancreatitis to which this locus has been reported to contribute.

genetics↗

bioRxiv2020

The longitudinal stability of fMRI activation during reward processing in adolescents and young adults

BackgroundThe use of functional neuroimaging has been an extremely fruitful avenue for investigating the neural basis of human reward function. This approach has included identification of potential neurobiological mechanisms of psychiatric disease and examination of environmental, experiential, and biological factors that may contribute to disease risk via effects on the reward system. However, a central and largely unexamined assumption of much of this research is that neural reward function is an individual difference characteristic that is relatively stable over time. MethodsIn two independent samples of adolescents and young adults studied longitudinally (Ns = 145 & 153, 100% female & 100% male, ages 15-21 & 20-22, 2-4 scans & 2 scans respectively), we tested within-person stability of reward-task BOLD activation, with a median of 1 and 2 years between scans. We examined multiple commonly used contrasts of active states and baseline in both the anticipation and feedback phases of a card-guessing reward task. We examined the effects of cortical parcellation resolution, contrast, network (reward regions and resting-state networks), region-size, and activation strength and variability on the stability of reward-related activation. ResultsOverall, stability (ICC; intra-class correlation) across 1-2 years was modest. In both samples, contrasts of an active state relative to a baseline were more stable (e.g., Win>Baseline; mean ICC = 0.13 - 0.33) than contrasts of two active states (e.g., Win>Loss; mean ICC = 0.048 - 0.05). Additionally, activation in reward regions was less stable than in many non-task networks (e.g., dorsal attention), and activation in regions with greater between-subject variability showed higher stability in both samples. ConclusionsThese results show that functional neuroimaging activation to reward has modest stability over 1-2 years. Notably, results suggest that contrasts intended to map cognitive function and show robust group-level effects (i.e. Win > Loss) may be less effective in studies of individual differences and disease risk. The robustness of group-level activation should be weighed against other factors when selecting regions of interest in individual difference fMRI studies.

neuroscience↗