The Impact of Recombination on Nucleotide Substitutions in the Human Genome

Unraveling the evolutionary forces responsible for variations of neutral substitution patterns among taxa or along genomes is a major issue for detecting selection within sequences. Mammalian genomes show large-scale regional variations of GC-content (the isochores), but the substitution processes at the origin of this structure are poorly understood. We analyzed the pattern of neutral substitutions in 1 Gb of primate non-coding regions. We show that the GC-content toward which sequences are evolving is strongly negatively correlated to the distance to telomeres and positively correlated to the rate of crossovers (R2 = 47%). This demonstrates that recombination has a major impact on substitution patterns in human, driving the evolution of GC-content. The evolution of GC-content correlates much more strongly with male than with female crossover rate, which rules out selectionist models for the evolution of isochores. This effect of recombination is most probably a consequence of the neutral process of biased gene conversion (BGC) occurring within recombination hotspots. We show that the predictions of this model fit very well with the observed substitution patterns in the human genome. This model notably explains the positive correlation between substitution rate and recombination rate. Theoretical calculations indicate that variations in population size or density in recombination hotspots can have a very strong impact on the evolution of base composition. Furthermore, recombination hotspots can create strong substitution hotspots. This molecular drive affects both coding and non-coding regions. We therefore conclude that along with mutation, selection and drift, BGC is one of the major factors driving genome evolution. Our results also shed light on variations in the rate of crossover relative to non-crossover events, along chromosomes and according to sex, and also on the conservation of hotspot density between human and chimp

Circadian Disruption Accelerates Tumor Growth and Angio/Stromagenesis through a Wnt Signaling Pathway

Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more “normal” 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway

Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters

Background: Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. Methodology/Principal Findings: In the present study, we investigated whether experimental ‘jet lag ’ (i.e., phase advances of the light:dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. Conclusions/Significance: Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learnin

cGMP-Phosphodiesterase Inhibition Enhances Photic Responses and Synchronization of the Biological Circadian Clock in Rodents

The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions

Effects of circadian disruption on physiology and pathology: from bench to clinic (and back)

Nested within the hypothalamus, the suprachiasmatic nuclei (SCN) represent a central biological clock that regulates daily and circadian (i.e., close to 24 h) rhythms in mammals. Besides the SCN, a number of peripheral oscillators throughout the body control local rhythms and are usually kept in pace by the central clock. In order to represent an adaptive value, circadian rhythms must be entrained by environmental signals or zeitgebers, the main one being the daily light?dark (LD) cycle. The SCN adopt a stable phase relationship with the LD cycle that, when challenged, results in abrupt or chronic changes in overt rhythms and, in turn, in physiological, behavioral, and metabolic variables. Changes in entrainment, both acute and chronic, may have severe consequences in human performance and pathological outcome. Indeed, animal models of desynchronization have become a useful tool to understand such changes and to evaluate potential treatments in human subjects. Here we review a number of alterations in circadian entrainment, including jet lag, social jet lag (i.e., desynchronization between body rhythms and normal time schedules), shift work, and exposure to nocturnal light, both in human subjects and in laboratory animals. Finally, we focus on the health consequences related to circadian/entrainment disorders and propose a number of approaches for the management of circadian desynchronization.Fil: Chiesa, Juan José. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Duhart, José Manuel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Casiraghi, Leandro Pablo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Paladino, Natalia. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bussi, Ivana Leda. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Golombek, Diego Andrés. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Updating the landscape of direct-to-consumer pharmacogenomic testing

Kelly K Filipski, John D Murphy, Kathy J Helzlsouer Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Rockville, MD, USA Abstract: Pharmacogenomics has identified important drug–gene interactions that affect the safety and efficacy of medications. Direct-to-consumer genetic testing, when first introduced, included some pharmacogenomic-related genes. The current landscape of pharmacogenomic direct-to-consumer testing is reviewed. Prior published reviews of the literature were updated through February 2017 and a scan of the current availability of direct-to-consumer genomic testing by companies was conducted. Results of the review demonstrate a shift toward physician-approved ordering. Keywords: pharmacogenomics, direct-to-consumer testing&nbsp