The effects of sex-biased gene expression and X-linkage on rates of sequence evolution in Drosophila

A faster rate of adaptive evolution of X-linked genes compared with autosomal genes (the faster-X effect) can be caused by the fixation of recessive or partially recessive advantageous mutations. This effect should be largest for advantageous mutations that affect only male fitness, and least for mutations that affect only female fitness. We tested these predictions in Drosophila melanogaster by using coding and functionally significant noncoding sequences of genes with different levels of sex-biased expression. Consistent with theory, nonsynonymous substitutions in most male-biased and unbiased genes show faster adaptive evolution on the X. However, genes with very low recombination rates do not show such an effect, possibly as a consequence of Hill–Robertson interference. Contrary to expectation, there was a substantial faster-X effect for female-biased genes. After correcting for recombination rate differences, however, female-biased genes did not show a faster X-effect. Similar analyses of noncoding UTRs and long introns showed a faster-X effect for all groups of genes, other than introns of female-biased genes. Given the strong evidence that deleterious mutations are mostly recessive or partially recessive, we would expect a slower rate of evolution of X-linked genes for slightly deleterious mutations that become fixed by genetic drift. Surprisingly, we found little evidence for this after correcting for recombination rate, implying that weakly deleterious mutations are mostly close to being semidominant. This is consistent with evidence from polymorphism data, which we use to test how models of selection that assume semidominance with no sex-specific fitness effects may bias estimates of purifying selection

Comparative study of density functional theories of the exchange-correlation hole and energy in silicon

We present a detailed study of the exchange-correlation hole and exchange-correlation energy per particle in the Si crystal as calculated by the Variational Monte Carlo method and predicted by various density functional models. Nonlocal density averaging methods prove to be successful in correcting severe errors in the local density approximation (LDA) at low densities where the density changes dramatically over the correlation length of the LDA hole, but fail to provide systematic improvements at higher densities where the effects of density inhomogeneity are more subtle. Exchange and correlation considered separately show a sensitivity to the nonlocal semiconductor crystal environment, particularly within the Si bond, which is not predicted by the nonlocal approaches based on density averaging. The exchange hole is well described by a bonding orbital picture, while the correlation hole has a significant component due to the polarization of the nearby bonds, which partially screens out the anisotropy in the exchange hole.Comment: 16 pages, 5 figures, RevTeX, added conten

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Local authority intervention in the local economy The case of the A1 corridor campaign

SIGLEAvailable from British Library Document Supply Centre- DSC:DX175146 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Risk assessment for physical activity and exercise clearance In pregnant women without contraindications

Traditionally, exercise was advised with caution or not recommended for pregnant women. Women active before pregnancy were advised by physicians to reduce their habitual exercise levels, while previously inactive women were advised to refrain from initiating exercise programs.1 However, guidelines for exercise during pregnancy have evolved substantially during the past 30 years; recommendations have become less restrictive as evidence-based information becomes more readily available.2 Moreover, an increasing number of pregnant women wish to maintain prepregnancy physical fitness levels during the prenatal period, and others wish to initiate exercise for healthier pregnancies.2,3 The conservative nature of medical advice in the past was intended to safeguard the health of both the mother and the growing fetus.2,3 Advice was intentionally conservative because of concern that exercise might shift oxygenated blood and energy substrates away from the fetus to maternal skeletal muscle, as well as increase core body temperature during vulnerable developmental periods such as embryogenesis. Therefore, it was largely unknown whether exercise increased the risk of congenital abnormalities and caused disturbances in optimal fetal growth.2 There were also maternal concerns that excessive exercise might cause conditions such as chronic fatigue and hypoglycemia, or increase the risk of injury (eg, low back pain, musculoskeletal injury).4,5 A more contemporary view of exercise during pregnancy emphasizes that women and their care providers need to consider the risks of not participating in regular physical activities during the prenatal period.3 Previous work in prenatal exercise did not systematically evaluate the prevalence of adverse exercise-related events. This article provides an executive summary of findings from a systematic review of the risks of physical activity for pregnant women without contraindications.6 It is one in a comprehensive series about the risks of physical activity participation in patients with various medical conditions.7 The overall purpose of these systematic reviews was to provide evidence-based recommendations for tools to simplify exercise clearance and prescription: the new Physical Activity Readiness Questionnaire for Everyone (PAR-Q+)8 and the electronic Physical Activity Readiness Medical Examination (ePARmed-X+).9 The purpose of this summary is to present evidence-based information regarding adverse exercise-related events during uncomplicated pregnancy and discuss this information in relation to the family physician’s task of screening patients for physical activity participation