Biology subjects

Kenney, C.

Publications and source records attributed to Kenney, C..

4 recordsLinked to original sources

bioRxiv2020

Evolutionary Conservation and Essential Function of Human and Maize RNA Binding Motif Protein 48 (RBM48) in U12-Type Intron Splicing

U12-type or minor introns are found in most multicellular eukaryotes and constitute [~]0.5% of all introns in species with a minor spliceosome. Although the biological significance for evolutionary conservation of U12-type introns is debated, mutations disrupting U12 splicing cause developmental defects in both plants and animals. In human hematopoietic stem cells, U12 splicing defects disrupt proper differentiation of myeloid lineages and are associated with myelodysplastic syndrome (MDS), predisposing individuals to acute myeloid leukemia. Mutants in the maize ortholog of RNA Binding Motif Protein48 (RBM48) have aberrant U12-type intron splicing. Human RBM48 was recently purified biochemically as part of the minor spliceosome and shown to recognize the 5 end of the U6atac snRNA. In this report, we use CRISPR/Cas9-mediated ablation of RBM48 in human K-562 cells to show the genetic function of RBM48. RNA-seq analysis comparing wild-type and mutant K-562 genotypes found that 48% of minor intron containing genes (MIGs) have significant U12-type intron retention in RBM48 mutants. Comparing these results to maize rbm48 mutants defined a subset of MIGs disrupted in both species. Mutations in the majority of these orthologous MIGs have been reported to cause developmental defects in both plants and animals. Our results provide genetic evidence that the primary defect of human RBM48 mutants is aberrant U12-type intron splicing, while a comparison of human and maize RNA-seq data identifies candidate genes likely to mediate mutant phenotypes of U12-type splicing defects.

evolutionary biology↗

bioRxiv2018

Preclinical Modeling of Exposure to a Global Marine Bio Contaminant: Effects of In Utero Domoic Acid Exposure on Neonatal Behavior and Infant Memory

Domoic Acid (DA) is a naturally-occurring marine neurotoxin that is increasingly recognized as an important public health issue. Prenatal DA exposure occurs through the maternal consumption of contaminated shellfish/finfish. To better understand the fetal risks associated with DA, we initiated a longitudinal, preclinical study focused on the reproductive and developmental effects of chronic, low-dose oral DA exposure. To this end, 32 adult female Macaca fascicularis monkeys were orally dosed with 0, 0.075 or 0.15 mg/kg/day DA on a daily basis prior to breeding and throughout breeding and pregnancy. The doses included the proposed human Tolerable Daily Intake (TDI) (0.075 mg/kg/day) for DA. Adult females were bred to nonexposed males. To evaluate development during early infancy, offspring were administered a Neonatal Assessment modeled after the human Neonatal Behavior Assessment Scale and a series of Visual Recognition Memory problems using the novelty paradigm. Results indicated that prenatal DA exposure did not impact early survival reflexes or responsivity to the environment. Findings from the recognition memory assessment, given between 1-2 months of age, showed that exposed and control infants demonstrated robust novelty scores when test problems were relatively easy to solve. Performance was not diminished by the introduction of delay periods. However, when more difficult recognition problems were introduced, the looking behavior of the 0.15 mg/kg DA group was random and infants failed to show differential visual attention to novel test stimuli. This finding suggests subtle but significant impairment in recognition memory and demonstrates that chronic fetal exposure to DA may impact developing cognitive processes.

pharmacology and toxicology↗

bioRxiv2017

Analysis of RAS as a tumor suppressor

The RAS GTPases are among the best-understood oncogenes that promote human cancer. Many have argued that non-mutated, wild-type, RAS also functions as a tumor suppressor. The arguments for RAS tumor suppressor activity often involve data that are claimed to be inconsistent with known principles of RAS biology. RAS tumor suppressor activity is invoked to explain these observations. Here, we consider an alternative hypothesis: these data are actually consistent with RAS biology. We investigate by using our previously developed mathematical model of RAS regulation. We find that three of five arguments for RAS having tumor suppressor activity are based upon data that the model demonstrates are actually consistent with known RAS biology. We also find that the other two types of data interpreted to indicate a tumor suppressor effect can be explained by our model with the additional assumption that RAS protein expression does not vary proportionally with gene dosage. Measurements of RAS protein expression as a function of gene dosage could help resolve whether or not RAS has tumor suppressor activity. Overall, we conclude that the evidence for RAS having tumor suppressor activity is much less strong that it has appeared.

cancer biology↗

bioRxiv2017

A computational panel of pathological RAS mutants with implications for personalized medicine and genetic medicine

The RAS proteins (KRAS, NRAS, and HRAS) play important roles in multiple diseases. This includes many types of cancer and the developmental syndromes collectively referred to as the RASopathies. There are many different RAS mutants that are found to drive these diseases. Mutant-to-mutant differences pose a challenge for personalized medicine. To investigate this problem, we extend our previously developed model of oncogenic RAS mutants to a total of 16 oncogenic mutants. We also extend our model to RASopathy associated mutants using data for 14 such RAS mutants. The model finds that the known biochemical defects of these mutants are typically sufficient to explain their elevated levels of RAS signaling. In general, our analysis finds that the oncogenic mutants are stronger than the RASopathy mutants. However, the model suggests that RAS signal intensities are spanned by the pathological variants; there does not appear to be a perfect separation between cancer promoting and developmental syndrome promoting mutants. Analysis of the panel also finds that the relative strengths of pathological RAS mutants is not absolute, but rather can vary depending on context. We discuss implications of this finding for personalized cancer medicine and for medical genetics. As genomics permeates clinical medicine, computational models that can resolve mutant specific differences, like the one presented here, may be useful for augmenting clinical thinking with their ability to logically translate biochemical knowledge into system level outputs of perceived clinical relevance.

pathology↗