Author contributions M.K. co-designed and implemented the overall strategy for the creation of the knock-in fly lines, designed and implemented the bioassays, the RT-qPCR experiments and the RMO analysis, performed statistical analyses and co-wrote the manuscript. S.C.G. designed and implemented the overall strategy for the creation of the knock-in fly lines, prepared the sequence data and metadata for the phylogenetic analyses, co-designed all other experiments, and co-wrote the manuscript. F.S. performed the structural modelling and docking site analyses. J.N.P. performed the phylogenetic, ancestral state and co-evolutionary analyses. K.I.V. conducted crosses, genotyping, and feeding experiments, and co-designed the qPCR experiments. J.M.A. and S.L.B. conducted crosses and genotyping, and feeding and sequestration experiments. A.P.H. performed the in vitro physiological experiments and sequestration analyses. T.M. conducted feeding experiments M.A. performed the RMO analysis with M.K., and conducted genotyping and feeding experiments. G.G. completed the RMO and ouabain dietary survival analyses. F.R. supervised the structural modelling and docking site analyses. S.D. oversaw and interpreted in vitro cell line analyses, helped to design the overall project and co-wrote the manuscript. A.A.A. helped to design the overall project, oversaw the in vitro physiological and sequestration experiments, and co-wrote the manuscript. N.K.W. led the overall collaboration, the project design and its integration, creation of fly lines and statistical analyses, and co-wrote the manuscript. Peer review information Nature thanks Joseph W. Thornton and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.Online content Any methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at

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Background Multiple studies have implicated infections in glioma susceptibility, but the evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study we leveraged genetic predictors of antibody response to 10 viral antigens to investigate the relationship and glioma risk and survival. Methods Genetic reactivity scores (GRS) for each antigen were derived from genome-wide significant (p<5x10-8) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution using data from 3418 glioma patients and 8156 controls. Results Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were suggestively associated with glioma risk and survival (unadjusted p<0.05). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild type gliomas (Odds ratio ORZEBRA=0.91, p=0.007 / ORMCV=1.11, p=0.005). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR=1.09, p=0.04) and improved survival (Hazard ratio HR=0.86, p=0.01). HLA-DQA1*03:01 was significantly associated with decreased risk of glioma overall (OR=0.85, p=3.96x10-4) after multiple testing adjustment. Conclusion This first systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may also inform applications of antiviral based therapies in the treatment of glioma.

Background Lifetime exposure to the varicella-zoster virus (VZV) has been consistently inversely associated with glioma risk, however the relationship of VZV with survival in adults with glioma has not been investigated. In this study, we analyzed survival of adults with glioma in relation to their antibody measurements to 4 common herpes viral infections, including VZV, measured post-diagnosis. Materials and Methods We analyzed IgG antibody measurements to VZV, cytomegalovirus (CMV), herpes simplex virus 1/2 (HSV), and Epstein-Barr virus (EBV) collected from 1378 adults with glioma diagnosed between 1991 and 2010. Blood was obtained a median of 3 months after surgery. Associations of patient IgG levels with overall survival were estimated using Cox models adjusted for age, sex, self-reported race, surgery type, dexamethasone usage at blood draw, and tumor grade. Models were stratified by recruitment series and meta-analyzed to account for time-dependent treatment effects. Results VZV antibody seropositivity was associated with improved survival outcomes in adults with glioma (Hazard ratio, HR=0.70, 95% Confidence Interval 0.54-0.90, p=0.006). Amongst cases who were seropositive for VZV antibodies, survival was significantly improved for those above the 25th percentile of continuous reactivity measurements versus those below (HR=0.76, 0.66-0.88, p=0.0003). Antibody seropositivity to EBV was separately associated with improved survival (HR=0.71, 0.53-0.96, p=0.028). Antibody positivity to two other common viruses (CMV, HSV) was not associated with altered survival. Conclusions Low levels of VZV or EBV antibodies are associated with poorer survival outcomes for adults with glioma. Differential immune response rather than viral exposure may explain these findings.

The multi-species coalescent (MSC) provides a theoretical foundation for modern phylogenetics and comparative population genetics. Its theoretical properties have been heavily studied but there are still aspects of the MSC that are largely unknown, including the covariances in pairwise coalescence times, which are fundamental for understanding the properties of statistics that combine data from multiple species, such as the fixation index ( F ST ). The major contribution of this study is the derivation and implementation of exact expressions for the covariances of pairwise coalescence times under phylogenetic models with piecewise constant changes in population size, assuming no gene flow after species divergence. We use these expressions to derive the variance in average pairwise differences within and between populations. We then derive approximations for the expectation and bias of a sequence-based estimator of F ST , a commonly used genetic measurement of population differentiation, when it is applied to a non-recombining region of the genome. We show that the estimator of F ST is generally biased downward. A freely available software package is provided, STCov, to calculate the mean, variances and covariances in coalescence times presented here under user-defined piecewise-constant species trees. This article is part of the theme issue ‘Celebrating 50 years since Lewontin's apportionment of human diversity’.

Measures of Varicella-Zoster virus (VZV) have been consistently inversely associated with glioma risk, but the association with glioma survival has not been investigated. In this study we analyzed overall survival of individuals with glioma in relation to measured levels of antibodies to 4 common viral infections, measured post-diagnosis. METHODS We utilized immunoglobulin G (IgG) antibody measurements to VZV, Epstein-Barr virus (EBV), herpes simplex virus (HSV), and cytomegalovirus (CMV), collected from 1378 patients newly enrolled in the UCSF Adult Glioma Study between 1991-2010. Blood was obtained a median of 3 months post diagnostic surgery. Subject follow-up for survival is ongoing. The associations of IgG levels with overall survival were estimated using Cox models adjusted for age, sex, race, type of surgery, dexamethasone usage, and stratified by tumor grade. RESULTS The 1378 glioma patients studied had median survival of 2.1 years. VZV antibody seropositivity was associated with improved survival outcomes (Hazard ratio, HR = 0.70, 95% Confidence Interval 0.54-0.90, p = 0.0061), with a grade-IV specific association (HR=0.65, 0.48-0.87, p=0.0046). Amongst VZV seropositive cases, those in the bottom quartile of measured seroreactivity had significantly worse survival outcomes as compared to the upper three quartiles (HR = 1.31, 1.13-1.52, p = 0.0003). Antibody seropositivity to EBV was also associated with improved survival times (HR = 0.71, 0.53-0.96, p = 0.028). Antibody response to two other common viruses (CMV, HSV) were not associated with glioma survival (p = 0.213, p = 0.215, respectively). CONCLUSION This is the first study, to our knowledge, to associate virus-specific antibody levels with survival amongst glioma patients. These associations do not appear to be due to general tumor-induce immune suppression. Our results controlled for dexamethasone usage, a known immunosuppressor. IgG measurements were taken post-glioma diagnosis, therefore further study is needed to determine the direction of causation, and if anti-herpesvirus treatment, such as VZV vaccination, might be beneficial for glioma prognosis.

2AbstractGenome-scale data are increasingly being used to infer phylogenetic trees. A major challenge in such inferences is that different regions of the genome may have local topologies that differ from the species tree due to incomplete lineage sorting (ILS). Another source of gene tree discrepancies is estimation errors arising from the randomness of the mutational process during sequence evolution. There are two major groups of methods for estimating species tree from whole-genome data: a set of full likelihood methods, which model both sources of variance, but do not scale to large numbers of independent loci, and a class of faster approximation methods which do not model the mutational variance.To bridge the gap between these two classes of methods, we present COAL_PHYRE (COmposite Approximate Likelihood for PHYlogenetic REconstruction), a composite likelihood based method for inferring population size and divergence time estimates of rooted species trees from aligned gene sequences. COAL_PHYRE jointly models coalescent variation across loci using the MSC and variation in local gene tree reconstruction using a normal approximation. To evaluate the accuracy and speed of the method, we compare against BPP, a powerful MCMC full-likelihood method, as well as ASTRAL-III, a fast approximate method. We show that COAL_PHYRE’s divergence time and population size estimates are more accurate than ASTRAL, and comparable to those obtained using BPP, with an order of magnitude decrease in computational time. We also present results on previously published data from a set of Gibbon species to evaluate the accuracy in topology and parameter inference on real data, and to illustrate the method’s ability to analyze data sets which are prohibitively large for MCMC methods.

BACKGROUND Meningioma treatments are limited due to incomplete understanding of meningioma biology. To address this, we performed multiplatform molecular profiling on 565 meningiomas with comprehensive clinical data to define genomic drivers and identify therapeutic vulnerabilities. METHODS DNA methylation profiling was performed on meningiomas from UCSF (n=200, discovery) and Hong Kong University (n=365, validation). Median follow-up was 5.6 years, and there were 388/142/35 WHO grade I/II/III meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on UCSF meningiomas. Cell type deconvolution, metagenomics, CRISPR, and pharmacology were used for mechanistic and functional validation. RESULTS Unsupervised hierarchical clustering of differentially methylated DNA probes revealed that meningiomas were comprised of 3 epigenetic subgroups associated with good, intermediate, and poor outcomes, with representation from all WHO grades in each subgroup. Meningiomas from the subgroup with the best outcomes (52% WHO grade I) were distinguished by recurrent gain of Chr5. Meningiomas from the subgroup with intermediate outcomes (31% WHO grade II) were distinguished by genomic stability, enrichment of innate immune genes, and immune infiltration in the setting of endogenous retroviral gene re-expression, a mechanism of immune recruitment. The most aggressive subgroup of meningiomas (57% WHO grade III) was distinguished by genomic instability, including recurrent loss of Chr22q harboring NF2, and decreased immune infiltration. Consistently, NF2 suppression in primary meningioma cells derived from immunogenic meningiomas decreased expression of innate immune genes critical for immune recruitment, suggesting a novel immunostimulatory function of NF2. The most aggressive subgroup of meningiomas were further distinguished by activation of the mitogenic FOXM1 transcriptional program, and recurrent loss of Chr9p harboring CDKN2A/B, which rendered primary meningioma cells from this subgroup susceptible to CDK4/6 inhibitors. CONCLUSIONS Meningiomas are comprised of 3 epigenetic subgroups defined by genetic mechanisms driving immune infiltration in the tumor microenvironment and meningioma cell proliferation.