Pathway-based outlier method reveals heterogeneous genomic structure of autism in blood transcriptome

Background: Decades of research strongly suggest that the genetic etiology of autism spectrum disorders (ASDs) is heterogeneous. However, most published studies focus on group differences between cases and controls. In contrast, we hypothesized that the heterogeneity of the disorder could be characterized by identifying pathways for which individuals are outliers rather than pathways representative of shared group differences of the ASD diagnosis. Methods: Two previously published blood gene expression data sets – the Translational Genetics Research Institute (TGen) dataset (70 cases and 60 unrelated controls) and the Simons Simplex Consortium (Simons) dataset (221 probands and 191 unaffected family members) – were analyzed. All individuals of each dataset were projected to biological pathways, and each sample’s Mahalanobis distance from a pooled centroid was calculated to compare the number of case and control outliers for each pathway. Results: Analysis of a set of blood gene expression profiles from 70 ASD and 60 unrelated controls revealed three pathways whose outliers were significantly overrepresented in the ASD cases: neuron development including axonogenesis and neurite development (29% of ASD, 3% of control), nitric oxide signaling (29%, 3%), and skeletal development (27%, 3%). Overall, 50% of cases and 8% of controls were outliers in one of these three pathways, which could not be identified using group comparison or gene-level outlier methods. In an independently collected data set consisting of 221 ASD and 191 unaffected family members, outliers in the neurogenesis pathway were heavily biased towards cases (20.8% of ASD, 12.0% of control). Interestingly, neurogenesis outliers were more common among unaffected family members (Simons) than unrelated controls (TGen), but the statistical significance of this effect was marginal (Chi squared P < 0.09). Conclusions: Unlike group difference approaches, our analysis identified the samples within the case and control groups that manifested each expression signal, and showed that outlier groups were distinct for each implicated pathway. Moreover, our results suggest that by seeking heterogeneity, pathway-based outlier analysis can reveal expression signals that are not apparent when considering only shared group differences

Community Outreach through Genomics Education Partnership

The J Craig Venter Institute (JCVI) has recently partnered with undergraduate university faculty to expand the scope of education and outreach program as part of the NIAID&#x2019;s BRC initiative, by joining forces with faculty members participating in the Genomics Education Partnership (GEP). The goal of the GEP is to provide opportunities for undergraduate students to participate in genomics research and gain hands on experience. Faculty members trained on annotation methodologies and tools during the Prokaryotic Annotation Workshop conducted at JCVI, impart their knowledge in the classroom as part of the semester course. As a pilot project, we are currently collaborating with 3 groups lead by a faculty member, spread across 3 universities in the community curation of bacterial genomes. Each participating undergraduate group collectively annotates a specific bacterial genome that was sequenced at JCVI and run through the automatic annotation pipeline. Remote access to genome sequence data, pre-computed gene predictions, search results, automatic annotation and bioinformatics analysis is provided through our web-based manual annotation tool, MANATEE. The students log into JCVI genome databases with user specific ids and password and learn to annotate single genes, entire metabolic pathways leading to analysis of a question that may be unique to the genome being analyzed.&#xa0;Users of the genome data receive dedicated support and guidance from our in house annotation experts on the usage of JCVI&#x2019;s tools and annotation methodologies. Through this exercise, the undergraduate students are introduced to concepts of genomics and bioinformatics and gain deeper understanding of the concepts of cellular metabolism and disease pathology, which may lead them to making scientific research their career path. Some groups are focusing on genome specific pathways and plan to conduct wet lab experiments to understand unique genome features. We are highly encouraged that this model of web based, remote access, community annotation has been successful and propose to leverage the community of annotators to update annotations of pathogen genomes in Pathema-BRC

Chromatin structure and evolution in the human genome

<p>Abstract</p> <p>Background</p> <p>Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time.</p> <p>Results</p> <p>In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important.</p> <p>Conclusion</p> <p>We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.</p

Relationships between deprivation and duration of children's emergency admissions for breathing difficulty, feverish illness and diarrhoea in North West England: an analysis of hospital episode statistics

Background In the United Kingdom there has been a long term pattern of increases in children's emergency admissions and a substantial increase in short stay unplanned admissions. The emergency admission rate (EAR) per thousand population for breathing difficulty, feverish illness and diarrhoea varies substantially between children living in different Primary Care Trusts (PCTs). However, there has been no examination of whether disadvantage is associated with short stay unplanned admissions at PCT-level. The aim of this study was to determine whether differences between emergency hospital admission rates for breathing difficulty, feverish illness and diarrhoea are associated with population-level measures of multiple deprivation and child well-being, and whether there is variation by length of stay and age. Methods Analysis of hospital episode statistics and secondary analysis of Index of Multiple Deprivation (IMD) 2007 and Local Index of Child Well-being (CWI) 2009 in ten adjacent PCTs in North West England. The outcome measure for each PCT was the emergency admission rate to hospital for breathing difficulty, feverish illness and diarrhoea. Results 23,496 children aged 0-14 were discharged following emergency admission for breathing difficulty, feverish illness and/or diarrhoea during 2006/07. The emergency admission rate ranged from 27.9 to 62.7 per thousand. There were no statistically significant relationships between shorter (0 to 3 day) hospitalisations and the IMD or domains of the CWI. The rate for hospitalisations of 4 or more days was associated with the IMD (Kendall's taub = 0.64) and domains of the CWI: Environment (taub = 0.60); Crime (taub = 0.56); Material (taub = 0.51); Education (taub = 0.51); and Children in Need (taub = 0.51). This pattern was also evident in children aged under 1 year, who had the highest emergency admission rates. There were wide variations between the proportions of children discharged on the day of admission at different hospitals. Conclusions Differences between rates of the more common shorter (0 to 3 day) hospitalisations were not explained by deprivation or well-being measured at PCT-level. Indices of multiple deprivation and child well-being were only associated with rates of children's emergency admission for breathing difficulty, feverish illness and diarrhoea for hospitalisations of 4 or more days

Statin use and association with colorectal cancer survival and risk:Case control study with prescription data linkage

Background: In Scotland colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer death. Epidemiological studies have reported conflicting associations between statins and CRC risk and there is one published report of the association between statins and CRC survival.Methods: Analysis was carried out on 309 cases and 294 controls from the Scottish Study of Colorectal Cancer (SOCCS). Cox's hazard and logistic regression models were applied to investigate the association between statin use and CRC risk and survival.Results: In an adjusted logistic regression model, statins were found to show a statistically significant association for three of the four statin variables and were found to not show a statistically significant association with either all-cause or CRC-specific mortality (OR 0.49; 95%CI 0.49-1.36; p-value = 0.17 and OR 0.33; 95%CI 0.08-1.35; P-value = 0.12, respectively).Conclusion: We did find a statistically significant association between statin intake and CRC risk but not statin intake and CRC-specific mortality. However, the study was insufficiently powered and larger scale studies may be advisable.</p