Biology subjects

Morris, N.

Publications and source records attributed to Morris, N..

3 recordsLinked to original sources

bioRxiv2018

Translation elongation and mRNA stability are coupled through the ribosomal A-site

Messenger RNA (mRNA) degradation plays a critical role in regulating transcript levels in eukaryotic cells. Previous work by us and others has shown that codon identity exerts a powerful influence on mRNA stability. In Saccharomyces cerevisiae, studies using a handful of reporter mRNAs show that optimal codons increase translation elongation rate, which in turn increase mRNA stability. However, a direct link between elongation rate and mRNA stability has not been established across the entire yeast transcriptome. In addition, there is evidence from work in higher eukaryotes that amino acid identity influences mRNA stability, raising the question as to whether the impact of translation elongation on mRNA decay is at the level of tRNA decoding, amino acid incorporation, or some combination of each. To address these questions, we performed ribosome profiling of wildtype yeast. In good agreement with other studies, our data showed faster codon-specific elongation over optimal codons and faster transcript-level elongation correlating with transcript optimality. At both the codon-level and transcript-level, faster elongation correlated with increased mRNA stability. These findings were reinforced by showing increased translation efficiency and kinetics for a panel of 11 HIS3 reporter mRNAs of increasing codon optimality. While we did observe that elongation measured by ribosome profiling is composed of both amino acid identity and synonymous codon effects, further analyses of these data establish that A-site tRNA decoding rather than other steps of translation elongation is driving mRNA decay in yeast.

molecular biology↗

bioRxiv2017

Spatial distribution of extensively drug-resistant tuberculosis (XDR-TB) patients in KwaZulu-Natal, South Africa

BackgroundKwaZulu-Natal province, South Africa, has among the highest burden of XDR-TB worldwide with the majority of cases occurring due to transmission. Poor access to health facilities can be a barrier to timely diagnosis and treatment of TB, which can contribute to ongoing transmission. We sought to determine the geographic distribution of XDR-TB patients and proximity to health facilities in KwaZulu-Natal.\n\nMethodsWe recruited adults and children with XDR-TB diagnosed in KwaZulu-Natal. We calculated distance and time from participants home to the closest hospital or clinic, as well as to the actual facility that diagnosed XDR-TB, using tools within ArcGIS Network analyst. Speed of travel was assigned to road classes based on Department of Transport regulations. Results were compared to guidelines for the provision of social facilities in South Africa: 5km to a clinic and 30km to a hospital.\n\nResultsDuring 2011-2014, 1027 new XDR-TB cases were diagnosed throughout all 11 districts of KwaZulu-Natal, of whom 404 (39%) were enrolled and had geospatial data collected. Participants would have had to travel a mean distance of 2.9 km (CI 95%: 1.8-4.1) to the nearest clinic and 17.6 km (CI 95%: 11.4-23.8) to the nearest hospital. Actual distances that participants travelled to the health facility that diagnosed XDR-TB ranged from <10 km (n=143, 36%) to >50 km (n=109, 27%). The majority (77%) of participants travelled farther than the recommended distance to a clinic (5 km) and 39% travelled farther than the recommended distance to a hospital (30 km). Nearly half (46%) of participants were diagnosed at a health facility in eThekwini district, of whom, 36% resided outside the Durban metropolitan area.\n\nConclusionsXDR-TB cases are widely distributed throughout KwaZulu-Natal province with a denser focus in eThekwini district. Patients travelled long distances to the health facility where they were diagnosed with XDR-TB, suggesting a potential role for migration or transportation in the XDR-TB epidemic.

epidemiology↗

bioRxiv2017

Widespread Inter-Chromosomal Epistasis Regulates Glucose Homeostasis And Gene Expression

The relative contributions of additive versus non-additive interactions in the regulation of complex traits remains controversial. This may be in part because large-scale epistasis has traditionally been difficult to detect in complex, multi-cellular organisms. We hypothesized that it would be easier to detect interactions using mouse chromosome substitution strains that simultaneously incorporate allelic variation in many genes on a controlled genetic background. Analyzing metabolic traits and gene expression levels in the offspring of a series of crosses between mouse chromosome substitution strains demonstrated that inter-chromosomal epistasis was a dominant feature of these complex traits. Epistasis typically accounted for a larger proportion of the heritable effects than those due solely to additive effects. These epistatic interactions typically resulted in trait values returning to the levels of the parental CSS host strain. Due to the large epistatic effects, analyses that did not account for interactions consistently underestimated the true effect sizes due to allelic variation or failed to detect the loci controlling trait variation. These studies demonstrate that epistatic interactions are a common feature of complex traits and thus identifying these interactions is key to understanding their genetic regulation.

genetics↗