Biology subjects

Funderburk, K.

Publications and source records attributed to Funderburk, K..

3 recordsLinked to original sources

bioRxiv2025

Functional characterization of the 9q34.13 locus identifies RAPGEF1 as modulating risk for melanoma and nevi via RAS activation

Genome-wide association studies identified a melanoma- and nevus count-associated locus on chromosome band 9q34.13. Fine-mapping and melanocyte expression data collectively suggest two potential causal genes with opposite association with risk: higher levels of Rap guanine nucleotide exchange factor 1 (RAPGEF1) and lower levels of uridine-cytidine kinase 1 (UCK1). Colocalization analyses and conditional TWAS suggest multiple causal cis-regulatory sequence variants in partial linkage disequilibrium (LD) to each other. Melanocyte capture-HiC and CRISPR-inhibition demonstrated regulatory interactions between fine-mapped variants and the RAPGEF1 and UCK1 promoters. Focusing on RAPGEF1, we demonstrate RAPGEF1 expression promotes melanocyte growth and drives malignant transformation of human immortalized melanocytes. Following treatment with human EGF, RAPGEF1 overexpression activated both RAP1 and RAS. Further, we show RAPGEF1 expression is significantly enriched in melanomas lacking strongly activating RAS-MAPK mutations, suggesting that RAPGEF1 may promote oncogenic RAS-MAPK signaling in melanomas. Furthermore, in these tumors, we provide preliminary evidence to support the prognostic relevance of RAPGEF1 expression in patients lacking RAS or BRAF mutations. Together with other recent studies, these data suggest that germline variation influencing RAS activation may play a key role in nevus development and melanoma risk.

genetics↗

bioRxiv2021

Investigating the genetic architecture of eye colour in a Canadian cohort

The main factors that determine eye colour are the amount of melanin concentrated in iris melanocytes, as well as the shape and distribution of melanosomes. Eye colour is highly variable in populations with European ancestry, in which eye colour categories cover a continuum of low to high quantities of melanin accumulated in the iris. A few polymorphisms in the HERC2/OCA2 locus in chromosome 15 have the largest effect on eye colour in these populations, although there is evidence of other variants in the locus and across the genome also influencing eye colour. To improve our understanding of the genetic loci determining eye colour, we performed a meta-analysis of genome-wide association studies in a Canadian cohort of European ancestry (N= 5,641) and investigated putative causal variants. Our fine-mapping results indicate that there are several candidate causal signals in the HERC2/OCA2 region, whereas other significant loci in the genome likely harbour a single causal signal (TYR, TYRP1, IRF4, SLC24A4). Furthermore, a short subset of the associated eye colour regions was colocalized with the gene expression or methylation profiles of cultured melanocytes (HERC2, OCA2), and transcriptome-wide association studies highlighted the expression of two genes associated with eye colour: SLC24A4 and OCA2. Finally, genetic correlations of eye and hair colour from the same cohort suggest high pleiotropy at the genome level, but locus-level evidence hints at several differences in the genetic architecture of both traits. Overall, we provide a better picture of how polymorphisms modulate eye colour variation, particularly in the HERC2/OCA2 locus, which may be a consequence of specific molecular processes in the iris melanocytes. Author SummaryEye colour differences among humans are the result of different amounts of melanin produced, as well as due to differences in the shape and distribution of the organelles in charge of producing melanin. Eye colour is a highly heritable trait, where several genes across the genome are involved in the process, but we currently do not fully understand which are the causal variants and how they modulate eye colour variation. By performing genome-wide association studies of eye colour across Canadian individuals of European ancestry, we identify several candidate causal signals in and near the gene OCA2, and one candidate signal in other genes, such as TYR, TYRP1, IRF4 and SLC24A4. Furthermore, we provide insights about how significant loci may modulate eye colour variation by testing for shared signals with polymorphisms associated with the expression of genes and DNA methylation. Overall, we provide a better picture of the genetic architecture of eye colour and the molecular mechanisms contributing to its variation.

genetics↗

bioRxiv2019

The Rising Prevalence of Weapons in Unsafe Arming Configurations Discovered in American Airports: the Increasing Practice of Storage and Carry of Firearms with a Round Chambered

BackgroundRecent studies have shown that Americans appear to be increasingly owning and carrying firearms for personal protection, and are increasingly storing their firearms loaded. However, the prevalence of firearm carry and/or storage with a round chambered has not hitherto been studied; in this arming configuration the weapon is loaded, with a bullet resting against the firing pin, ready to fire if the trigger is pulled. Ostensibly this decreases reaction time in a threat situation, but carries an increased risk of accidental discharge. It is unknown what fraction of firearm owners typically carry or store their firearms in this configuration, and if there have been significant temporal trends in the practice.\n\nObjectiveWe examine firearms detected at Transportation Security Administration (TSA) airport security checkpoints between 2012 to 2017, to examine geospatial and temporal trends in the prevalence of unsafe arming configuration in detected firearms.\n\nResultsThe fraction of detected firearms found to be loaded has risen significantly since 2012 (Beta Binomial logistic regression p = 0.011). States with firearm child access prevention laws have significantly fewer firearms found by the TSA to be loaded (p = 0.039).\n\nThe fraction of loaded firearms found by the TSA to also have a round chambered has also risen significantly since 2012 (Beta Binomial logistic regression p < 0.001). By 2017, 36% of firearms found loaded were also found to have a round chambered, representing an apparent concerning trend in unsafe arming configurations during carry and storage.\n\nConclusionsAmericans appear to be increasingly using and storing firearms in unsafe arming configurations. TSA firearm detection data can potentially provide a key source of data when researching trends in firearm injury.

epidemiology↗