Biology subjects

Hodgkinson, A.

Publications and source records attributed to Hodgkinson, A..

3 recordsLinked to original sources

bioRxiv2018

Time Dependent Stochastic mRNA and Protein Synthesis in Piecewise-deterministic Models of Gene Networks.

We discuss piecewise-deterministic approximations of gene networks dynamics. These approximations capture in a simple way the stochasticity of gene expression and the propagation of expression noise in networks and circuits. By using partial omega expansions, piecewise deterministic approximations can be formally derived from the more commonly used Markov pure jump processes (chemical master equation). We are interested in time dependent multivariate distributions that describe the stochastic dynamics of the gene networks. This problem is difficult even in the simplified framework of piecewise-determinisitic processes. We consider three methods to compute these distributions: the direct Monte-Carlo, the numerical integration of the Liouville-master equation and the push-forward method. This approach is applied to multivariate fluctuations of gene expression, generated by gene circuits. We find that stochastic fluctuations of the proteome and much less those of the transcriptome can discriminate between various circuit topologies.

systems biology↗

bioRxiv2017

Genomic and Environmental Contributions to Chronic Diseases in Urban Populations

Uncovering the interaction between genomes and the environment is a principal challenge of modern genomics and preventive medicine. While theoretical models are well defined, little is known of the GxE interactions in humans. We used a system biology approach to comprehensively assess the interactions between 1.6 million environmental exposure data, health, and expression phenotypes, together with whole genome genetic variation, for [~]1000 individuals from a founder-population in Quebec. We reveal a substantial impact of the urbanization gradient on the transcriptome and clinical endophenotypes, overpowering that of genetic ancestry. In detail, air pollution impacts gene expression and pathways affecting cardio-metabolic and respiratory traits when controlling for genetic ancestry. Finally, we capture 34 clinically associated expression quantitative trait loci that interact with the environment (air pollution). Our findings demonstrate how the local environment directly affects chronic disease development, and that genetic variation, including rare variants, can modulate individuals response to environmental challenges.\n\nHighlightsO_LIFine scale environmental effects overpower those of ancestry on gene expression\nC_LIO_LIAir pollution (geographic and temporal) is associated with transcriptional response\nC_LIO_LIGene-by-environment interactions with air pollution include asthma associated loci\nC_LIO_LIInflammatory pathways and cardio-respiratory clinical traits are among those affected\nC_LI

genomics↗

bioRxiv2016

Integrated Genomic Analysis of Mitochondrial RNA Processing in Human Cancers

Alterations to mitochondrial function and mutations in mitochondrial genes have been reported for a wide variety of cancers, however the mitochondrial transcriptome remains largely unexplored in cancer despite an emerging appreciation of the role that post-transcriptional regulation plays in the etiology of these diseases. Here, we quantify and assess changes to mitochondrial RNA processing in human cancers using integrated genomic analysis of RNA Sequencing and genotyping data from 1226 samples across 12 different cancer types. We find significant changes to m1A and m1G post-transcriptional methylation rates at functionally important positions in mitochondrial tRNAs in tumor tissues across all cancers. Pathways of RNA processing are strongly associated with methylation rates in normal tissues (P=2.85x10-27), yet these associations are lost in tumors. Furthermore, we report 18 gene-by-disease-state interactions where altered methylation rates occur under cancer status conditional on genotype, implicating genes associated with mitochondrial function or cancer (e.g. CACNA2D2, LMO2 and FLT3) and suggesting that nuclear genetic variation can potentially modulate an individuals ability to maintain unaltered rates of mitochondrial RNA processing under cancer status. Finally, we report a significant association between the magnitude of methylation rate changes in tumors and patient survival outcomes. These results highlight mitochondrial post-transcriptional events as a clinically relevant mechanism and as a theme for the further investigation of cancer processes, biomarkers and therapeutic interventions.

genomics↗