Highlights d 102 genes implicated in risk for autism spectrum disorder (ASD genes, FDR % 0.1) d Most are expressed and enriched early in excitatory and inhibitory neuronal lineages d Most affect synapses or regulate other genes; how these roles dovetail is unknown d Some ASD genes alter early development broadly, others appear more specific to ASD

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Heritability and polygenic predictionIn the EUR sample, the SNP-based heritability (h 2 SNP ) (that is, the proportion of variance in liability attributable to all measured SNPs)

The main forces directing long-term molecular evolution remain obscure. A sizable fraction of amino-acid substitutions seem to be fixed by positive selection, but it is unclear to what degree long-term protein evolution is constrained by epistasis, that is, instances when substitutions that are accepted in one genotype are deleterious in another. Here we obtain a quantitative estimate of the prevalence of epistasis in long-term protein evolution by relating data on amino-acid usage in 14 organelle proteins and 2 nuclear-encoded proteins to their rates of short-term evolution. We studied multiple alignments of at least 1,000 orthologues for each of these 16 proteins from species from a diverse phylogenetic background and found that an average site contained approximately eight different amino acids. Thus, without epistasis an average site should accept two-fifths of all possible amino acids, and the average rate of amino-acid substitutions should therefore be about three-fifths lower than the rate of neutral evolution. However, we found that the measured rate of amino-acid substitution in recent evolution is 20 times lower than the rate of neutral evolution and an order of magnitude lower than that expected in the absence of epistasis. These data indicate that epistasis is pervasive throughout protein evolution: about 90 per cent of all amino-acid substitutions have a neutral or beneficial impact only in the genetic backgrounds in which they occur, and must therefore be deleterious in a different background of other species. Our findings show that most amino-acid substitutions have different fitness effects in different species and that epistasis provides the primary conceptual framework to describe the tempo and mode of long-term protein evolution.

This Article was originally published without the correct Supplemental Table file (Table S1 was missing). In total, there are seven Supplemental Tables, and six were in the original submission. Furthermore, Fig. 1 was misplaced in the main text; it was embedded in the manuscript file even before the results section. Both issues have now been fixed in the HTML and PDF versions of this Article.

Objective The objective of this study was to describe and compare characteristics of women with obstetric fistula.Design Retrospective cross-sectional study.Setting Zambia's primary fistula repair centre, Monze Mission Hospital. Sample All women, August 2003 to December 2005.Method Review of case notes to obtain data on sociodemographic and obstetric characteristics, causative pregnancy, clinical details, and treatment. Comparison of characteristics with national data was undertaken.Results Of 259 women, 239 had socio-demographic and obstetric records and 254 had surgical records. Educational status and height of women were significantly below the national averages, while antenatal care uptake (97.5%) and proportion from the Northern Province were significantly above. Most women (77.9%) weighed £50 kg. Median age at marriage was 18 and at development of fistula was 22 years. 15.1% of women were divorced, 49.0% were primiparous, and 27.6% were parity four +. 67.5% of women had spent 2 days or longer in labour. Delays in receiving emergency obstetric care (EmOC) were experienced at home (67.5%) and at clinics (49.4%), usually due to transport difficulties. 89.1% delivered in a health facility, 50.2% of deliveries were by caesarean section, and 78.1% of babies were stillborn. 72.9% of repairs were successful, 17.3% resulted in residual stress incontinence, and 9.8% failed. Failure was significantly associated with previous repair.Conclusion More obstetric fistulae occur in areas where early marriage and pregnancy before pelvic maturity is attained is common and where obstetric care is inaccessible. In this study, age at marriage and fistula development was older than usually found, which may indicate that poor access to EmOC contributes more to this problem within Zambia.

In advanced age, some individuals maintain a stable cognitive trajectory while others experience a rapid decline. Such variation in cognitive trajectory is only partially explained by traditional neurodegenerative pathologies. Hence, to identify new processes underlying variation in cognitive trajectory, we perform an unbiased proteome-wide association study of cognitive trajectory in a discovery ( n = 104) and replication cohort ( n = 39) of initially cognitively unimpaired, longitudinally assessed older-adult brain donors. We find 579 proteins associated with cognitive trajectory after meta-analysis. Notably, we present evidence for increased neuronal mitochondrial activities in cognitive stability regardless of the burden of traditional neuropathologies. Furthermore, we provide additional evidence for increased synaptic abundance and decreased inflammation and apoptosis in cognitive stability. Importantly, we nominate proteins associated with cognitive trajectory, particularly the 38 proteins that act independently of neuropathologies and are also hub proteins of protein co-expression networks, as promising targets for future mechanistic studies of cognitive trajectory.

The molecular factors involved in the development of Post-Traumatic Stress Disorder (PTSD) remain poorly understood. Previous transcriptomic studies investigating the mechanisms of PTSD apply targeted approaches to identify individual genes under a cross-sectional framework lack a holistic view of the behaviours and properties of these genes at the system-level. Here we sought to apply an unsupervised gene-network based approach to a prospective experimental design using whole-transcriptome RNA-Seq gene expression from peripheral blood leukocytes of U.S. Marines (N=188), obtained both pre- and post-deployment to conflict zones. We identified discrete groups of co-regulated genes (i.e., co-expression modules) and tested them for association to PTSD. We identified one module at both pre- and post-deployment containing putative causal signatures for PTSD development displaying an over-expression of genes enriched for functions of innate-immune response and interferon signalling (Type-I and Type-II). Importantly, these results were replicated in a second non-overlapping independent dataset of U.S. Marines (N=96), further outlining the role of innate immune and interferon signalling genes within co-expression modules to explain at least part of the causal pathophysiology for PTSD development. A second module, consequential of trauma exposure, contained PTSD resiliency signatures and an over-expression of genes involved in hemostasis and wound responsiveness suggesting that chronic levels of stress impair proper wound healing during/after exposure to the battlefield while highlighting the role of the hemostatic system as a clinical indicator of chronic-based stress. These findings provide novel insights for early preventative measures and advanced PTSD detection, which may lead to interventions that delay or perhaps abrogate the development of PTSD.

All available non-identifying information was recorded for each specimen in Table S1. In total, 176 postmortem brain specimens (104 male, 72 female; postmortem interval of 21.7 ± 15.9 (mean ± SD) hours and pH, 6.41 ± 0.35) ranging in age from 6 post-conception weeks (PCW) to 20 postnatal years (PY) ( Figure 1 and Table S1) were included in this study. Fetal age was extrapolated based on the date of the mother's last menstruation, characteristics of the fetus noted upon ultrasonography scanning, foot length of the fetus, and visual inspection. The postmortem interval (PMI) was defined as hours between time of death and time when tissue samples were frozen. METHOD DETAILS Tissue dissectionTissue was dissected as described previously (Kang et al. 2011). Samples collected from 6 -9 PCW specimens contained the entire thickness of the cerebral wall. Samples collected from 12 -22 PCW specimens contained the cortical plate. Samples from 35 PCW -20 PY specimens were dissected such that the entire gray matter (layer 1-6) and part of the underlying subplate (4 -12 postnatal months) or white matter (1 -20 PY) were collected. RNA extraction and quality assessmentTotal RNA was extracted using mirVana kit (Ambion) with some modifications, as given in the following text, to the manufacturer's protocol, as described below. Each tissue sample was