Biomedical subjects

Kim C Worley

Publications and source records attributed to Kim C Worley.

3 recordsLinked to original sources

PubMed2026

Long-read Sequences Mapped to a Complete Reference Genome Uncover Uncaptured Structural Variants across the Beta-globin Cluster in Africans with Sickle Cell Disease.

African genomes are marked by extensive complexity in the number and distribution of variants, yet remain under-represented in genetic databases and the human reference genome. This gap in representation limits the broad application of genomic medicine. Sickle cell disease (SCD) - one of the most common monogenic diseases - has its highest prevalence in Africa, and variation in disease severity has consistently been linked to the beta-globin locus, including levels of fetal hemoglobin (HbF). Modulation of HbF is central to current SCD gene therapies; however, the inherent complexity and variation at the locus in African genomes presents a challenge to translating these advances to Africa. Here, we align long-read single molecule sequences (LRS) targeted to the beta-globin region to the hg38 and T2T-CHM13v2 genome references in 40 individuals with SCD, predominantly recruited from three African countries. We demonstrate that the expanded T2T-CHM13v2 reference sequence at this locus reduces Structural Variant (SV) calls by 70% and uncovers uncaptured single nucleotide variants (SNVs). Across the cluster we report 343 SVs and 196 SNVs that have not been previously reported, including in LRS data from the All of Us project. By including African populations from ethnolinguistic groups that have not been previously surveyed we improve variant resolution and bolster evidence for observed variation. Finally, we identify a common ∼4kb insertion locus overlapping the HBB promoter among individuals with high HbF. These results demonstrate the utility of combining a comprehensive reference genome with LRS in African populations to uncover genomic variation at disease-associated loci.

SNV↗

PubMed2025

Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP levels indicative of uncoupled oxidative phosphorylation as a pathophysiologic mechanism. Our findings contrast with the previously reported ATP5F1A variant, p.Arg207His, indicating a different pathological mechanism. This study expands the phenotypic and genotypic spectrum of ATP5F1A-associated conditions and highlights how functional studies can provide an understanding of the genetic, molecular, and cellular mechanisms of ATP5F1A variants of uncertain significance. With 12 heterozygous individuals now reported, ATP5F1A is the most frequent nuclear genome cause of complex V deficiency.

Humans↗

PubMed2025

Implementing a training resource for large-scale genomic data analysis in the All of Us Researcher Workbench.

A lack of representation in genomic research and limited access to computational training create barriers for many researchers seeking to analyze large-scale genetic datasets. The All of Us Research Program provides an unprecedented opportunity to address these gaps by offering genomic data from a broad range of participants, but its impact depends on equipping researchers with the necessary skills to use it effectively. The All of Us Biomedical Researcher (BR) Scholars Program at Baylor College of Medicine aims to break down these barriers by providing early-career researchers with hands-on training in computational genomics through the All of Us Evenings with Genetics Research Program. The year-long program begins with the faculty summit, an in-person computational boot camp that introduces scholars to foundational skills for using the All of Us dataset via a cloud-based research environment. The genomics tutorials focus on genome-wide association studies (GWASs), utilizing Jupyter Notebooks and the Hail computing framework to provide an accessible and scalable approach to large-scale data analysis. Scholars engage in hands-on exercises covering data preparation, quality control, association testing, and result interpretation. By the end of the summit, participants will have successfully conducted a GWAS, visualized key findings, and gained confidence in computational resource management. This initiative expands access to genomic research by equipping early-career researchers from a variety of backgrounds with the tools and knowledge to analyze All of Us data. By lowering barriers to entry and promoting the study of representative populations, the program fosters innovation in precision medicine and advances equity in genomic research.

Humans↗