Identifying the genetic basis of viral spillover using Lassa virus as a test case

The rate at which zoonotic viruses spill over into the human population varies significantly over space and time. Remarkably, we do not yet know how much of this variation is attributable to genetic variation within viral populations. This gap in understanding arises because we lack methods of genetic analysis that can be easily applied to zoonotic viruses, where the number of available viral sequences is often limited, and opportunistic sampling introduces significant population stratification. Here, we explore the feasibility of using patterns of shared ancestry to correct for population stratification, enabling genome-wide association methods to identify genetic substitutions associated with spillover into the human population. Using a combination of phylogenetically structured simulations and Lassa virus sequences collected from humans and rodents in Sierra Leone, we demonstrate that existing methods do not fully correct for stratification, leading to elevated error rates. We also demonstrate, however, that the Type I error rate can be substantially reduced by confining the analysis to a less-stratified region of the phylogeny, even in an already-small dataset. Using this method, we detect two candidate single-nucleotide polymorphisms associated with spillover in the Lassa virus polymerase gene and provide generalized recommendations for the collection and analysis of zoonotic viruses

Evaluation of serum CEA, CYFRA21-1 and CA125 for the early detection of colorectal cancer using longitudinal preclinical samples

Blood-borne biomarkers for early detection of colorectal cancer (CRC) could markedly increase screening uptake. The aim of this study was to evaluate serum carcinoembryonic antigen (CEA), CYFRA21-1 and CA125 for the early detection of CRC in an asymptomatic cohort

Searching for Speciation Genes: Molecular Evidence for Selection Associated with Colour Morphotypes in the Caribbean Reef Fish Genus Hypoplectrus

Closely related species that show clear phenotypic divergence, but without obvious geographic barriers, can provide opportunities to study how diversification can occur when opportunities for allopatric speciation are limited. We examined genetic divergence in the coral reef fish genus Hypoplectrus (family: Serranidae), which comprises of 10–14 morphotypes that are distinguished solely by their distinct colour patterns, but which show little genetic differentiation. Our goal was to detect loci that show clear disequilibrium between morphotypes and across geographical locations. We conducted Amplified Fragment Length Polymorphism molecular analysis to quantify genetic differentiation among, and selection between, morphotypes. Three loci were consistently divergent beyond neutral expectations in repeated pair-wise morphotype comparisons using two different methods. These loci provide the first evidence for genes that may be associated with colour morphotype in the genus Hypoplectrus

Proteasome Inhibition Induces Nuclear Translocation and Transcriptional Activation of the Dioxin Receptor in Mouse Embryo Primary Fibroblasts in the Absence of Xenobiotics

The aryl hydrocarbon receptor (AHR) is a transcription factor that is highly conserved during evolution and shares important structural features with the Drosophila developmental regulators Sim and Per. Although much is known about the mechanism of AHR activation by xenobiotics, little information is available regarding its activation by endogenous stimuli in the absence of exogenous ligand. In this study, using embryonic primary fibroblasts, we have analyzed the role of proteasome inhibition on AHR transcriptional activation in the absence of xenobiotics. Proteasome inhibition markedly reduced cytosolic AHR without affecting its total cellular content. Cytosolic AHR depletion was the result of receptor translocation into the nuclear compartment, as shown by transient transfection of a green fluorescent protein-tagged AHR and by immunoblot analysis of nuclear extracts. Gel retardation experiments showed that proteasome inhibition induced transcriptionally active AHR-ARNT heterodimers able to bind to a consensus xenobiotic-responsive element. Furthermore, nuclear AHR was transcriptionally active in vivo, as shown by the induction of the endogenous target gene CYP1A2. Synchronized to AHR activation, proteasome inhibition also induced a transient increase in AHR nuclear translocator (ARNT) at the protein and mRNA levels. Since nuclear levels of AHR and ARNT are relevant for AHR transcriptional activation, our data suggest that proteasome inhibition, through a transient increase in ARNT expression, could promote AHR stabilization and accumulation into the nuclear compartment. An elevated content of nuclear AHR could favor AHR-ARNT heterodimers able to bind to xenobiotic-responsive elements and to induce gene transcription in the absence of xenobiotics. Thus, depending on the cellular context, physiologically regulated proteasome activity could participate in the control of endogenous AHR functions