Wasl is crucial to maintain microglial core activities during glioblastoma initiation stages

Microglia actively promotes the growth of high‐grade gliomas. Within the glioma microenvironment an amoeboid microglial morphology has been observed, however the underlying causes and the related impact on microglia functions and their tumor promoting activities is unclear. Using the advantages of the larval zebrafish model, we identified the underlying mechanism and show that microglial morphology and functions are already impaired during glioma initiation stages. The presence of pre‐neoplastic HRasV12 expressing cells induces an amoeboid morphology of microglia, increases microglial numbers and decreases their motility and phagocytic activity. RNA sequencing analysis revealed lower expression levels of the actin nucleation promoting factor wasla in microglia. Importantly, a microglia specific rescue of wasla expression restores microglial morphology and functions. This results in increased phagocytosis of pre‐neoplastic cells and slows down tumor progression. In conclusion, we identified a mechanism that de‐activates core microglial functions within the emerging glioma microenvironment. Restoration of this mechanism might provide a way to impair glioma growth

A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics

Response to the commentary on ' A genome-wide association study in Caucasian women suggests the involvement of HLA gene in the severity of facial solar lentigines'

Response to the commentary on ' A genome-wide association study in Caucasian women suggests the involvement of [i]HLA[/i] gene in the severity of facial solar lentigines

Validation of Genetic Case-Control Studies in AIDS and Application to the CX3CR1 Polymorphism

New polymorphisms have been recently identified in CX3CRI, a coreceptor for some HIV-1 strains, one of which was associated with a strong acceleration of HIV disease progression. This effect was observed both by a case-control study involving 63 nonprogressors (NP) from the asymptomatic long-term (ALT) cohort and Kaplan-Meier analysis of 426 French seroconverters (SEROCO cohort). These results prompted us to analyze these polymorphisms in 244 nonprogressors (NPs) and 80 rapid progressors (RPs) from the largest case-control cohort known to date, the GRIV cohort. Surprisingly, the genetic frequencies found were identical for both groups under all genetic models (p \u3e .8). The discrepancy with the previous work stemmed only from the difference between GRIV NPs versus ALT NPs. We hypothesized this might be due to the limited number of NPs in ALT (n = 63) and in this line we reanalyzed the data previously collected on GRIV for over 100 different genetic polymorphisms: we effectively observed that the genetic frequencies of some polymorphisms could vary by as much as 10% (absolute percentage) when computing them on the first 50 NP subjects enrolled, on the first 100, or on all the NPs tested (240 study subjects). This observation emphasizes the need for caution in case-control studies involving small numbers of subjects: p values should be low or other control groups should be used. However, the association of the CX3CR1 polymorphism with progression seems quite significant in the Kaplan-Meier analysis of the SEROCO cohort (426 individuals), and the difference observed with GRIV might be explained by a delayed effect of the polymorphism on disease. Further studies on other seroconverter cohorts are needed to confirm the reported association with disease progression

New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS

The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and 75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I and class II genes in this highly informative cohort has identified HLA alleles associated with fast or slow progression, including several not described previously. A quantitative analysis shows an overall HLA influence independent of and equal in magnitude (for the protective effect) to the effect of the CCR5-�32 mutation. Among HLA class I genes, A29 ( p � 0.001) and B22 ( p < 0.0001) are significantly associated with rapid progression, whereas B14 ( p � 0.001) and C8 ( p � 0.004) are significantly associated with nonprogression. The class I alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are also influential, but their effects are less robust. Influence of class II alleles was only observed for DR11. These results confirm the influence of the immune system on disease progression and may have implications on peptide-based vaccine development. The Journal of Immunology, 1999, 162: 6942–6946. Human MHC (HLA) is a fundamental component of the immune system, but the extent of its role in the control of HIV-1 infection and disease progression remains unclear (1–3). During an infection, binding of peptides from the infectious pathogens to HLA proteins is the first step for the initiatio

G6PD and HBB polymorphisms in the Senegalese population: prevalence, correlation with clinical malaria

International audienceBackground Host genetic factors contribute to the variability of malaria phenotypes and can allow a better understanding of mechanisms involved in susceptibility and/or resistance to Plasmodium falciparum infection outcomes. Several genetic polymorphisms were reported to be prevalent among populations living in tropical malaria-endemic regions and induce protection against malaria. The present study aims to investigate the prevalence of HBB (chr11) and G6PD (chrX) deficiencies polymorphisms among Senegalese populations and their associations with the risk for severe Plasmodium falciparum malaria occurrence. Methods We performed a retrospective study with 437 samples, 323 patients recruited in hospitals located in three different endemic areas where malaria episodes were confirmed and 114 free malaria controls. The patients enrolled were classified into two groups: severe malaria (SM) (153 patients) and uncomplicated malaria (UM) (170 patients). PCR and DNA sequencing assessed host genetic polymorphisms in HBB and G6PD . Using a multivariate regression and additive model, estimates of the impact of human HBB and G6PD polymorphisms on malaria incidence were performed. Results Six frequent SNPs with minor allele frequencies (MAF) > 3% were detected in the HBB gene ( rs7946748 , rs7480526 , rs10768683 , rs35209591 , HbS ( rs334 ) and rs713040 ) and two in the G6PD gene ( rs762515 and rs1050828 ( G6PD -202 G > A). Analysis of selected HbS polymorphism showed significant association with protective effect against severe malaria with a significant p-value = 0.033 (OR 0.38, 95% CI [0.16–0.91]) for SM vs. UM comparison. Surprisingly, our study did not identify the protective effect of variant HbC polymorphism against severe malaria. Finally, we found some of the polymorphisms, like HbS ( rs334 ), are associated with age and biological parameters like eosinophils, basophils, lymphocytes etc. Conclusion Our data report HBB and G6PD polymorphisms in the Senegalese population and their correlation with severe/mild malaria and outcome. The G6PD and HBB deficiencies are widespread in West Africa endemic malaria regions such as The Gambia, Mali, and Burkina Faso. The study shows the critical role of genetic factors in malaria outcomes. Indeed, genetic markers could be good tools for malaria endemicity prognosis

Distinctive Effects of CCR5, CCR2, and SDF1 Genetic Polymorphisms in AIDS Progression

The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor (Fastprog) HIV-1-infected patients. Using this unique assembly, we performed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDFI, which have been shown to slow the rate of disease progression. The increased prevalence of mutant alleles among Slowprogs from the GRIV cohort was significant for CCR5 (p \u3c .0001) but not for CCR2 (p = .09) or SDF1 (p = .12), emphasizing the predominant role of CCR5 as the major HIV-1 coreceptor. However, the prevalence of the CCR2 mutant allele (64I) was significantly increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .04). The prevalence of double mutants SDF1- 3\u27A/3\u27A genotypes was also increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations are overshadowed by the protective effects of the CCR5 deletion. Predictive biologic markers such as CD4 cell counts or viral load in the Slowprog population did not show significant differences between Slowprog groups with wild-type or mutant alleles for the three genes. Thus, our data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average duration of HIV infection is 12 years. We conclude that these genes, whose products serve as viral coreceptors or their ligands, may play a role early in infection and delay the onset of disease. However, among Slowprogs, whose duration of infection is \u3e8 years, they are no longer influential for maintenance of their longterm nonprogression status. Other genetic determinants may be responsible for late protective effects

DRAM triggers lysosomal membrane permeabilization and cell death in CD4(+) T cells infected with HIV.

Productive HIV infection of CD4(+) T cells leads to a caspase-independent cell death pathway associated with lysosomal membrane permeabilization (LMP) and cathepsin release, resulting in mitochondrial outer membrane permeabilization (MOMP). Herein, we demonstrate that HIV infection induces damage-regulated autophagy modulator (DRAM) expression in a p53-dependent manner. Knocking down the expression of DRAM and p53 genes with specific siRNAs inhibited autophagy and LMP. However, inhibition of Atg5 and Beclin genes that prevents autophagy had a minor effect on LMP and cell death. The knock down of DRAM gene inhibited cytochrome C release, MOMP and cell death. However, knocking down DRAM, we increased viral infection and production. Our study shows for the first time the involvement of DRAM in host-pathogen interactions, which may represent a mechanism of defense via the elimination of infected cells