Arboretum: Reconstruction and analysis of the evolutionary history of condition-specific transcriptional modules

Comparative functional genomics studies the evolution of biological processes by analyzing functional data, such as gene expression profiles, across species. A major challenge is to compare profiles collected in a complex phylogeny. Here, we present Arboretum, a novel scalable computational algorithm that integrates expression data from multiple species with species and gene phylogenies to infer modules of coexpressed genes in extant species and their evolutionary histories. We also develop new, generally applicable measures of conservation and divergence in gene regulatory modules to assess the impact of changes in gene content and expression on module evolution. We used Arboretum to study the evolution of the transcriptional response to heat shock in eight species of Ascomycota fungi and to reconstruct modules of the ancestral environmental stress response (ESR). We found substantial conservation in the stress response across species and in the reconstructed components of the ancestral ESR modules. The greatest divergence was in the most induced stress, primarily through module expansion. The divergence of the heat stress response exceeds that observed in the response to glucose depletion in the same species. Arboretum and its associated analyses provide a comprehensive framework to systematically study regulatory evolution of condition-specific responses.Howard Hughes Medical InstituteBroad Institute of MIT and HarvardNational Institutes of Health (U.S.) (Pioneer Award)National Institutes of Health (U.S.) (R01 2R01CA119176-01)Burroughs Wellcome Fund (Career Award at the Scientific Interface)Alfred P. Sloan Foundatio

Sex ratio of the offspring of New Zealand phenoxy herbicide producers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

OBJECTIVES: Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has inconsistently been associated with a decreased sex ratio of the offspring (number of male births divided by total births). We conducted a study among men and women who were employed in a New Zealand phenoxy herbicide production plant between 1969 and 1984, to study their offspring sex ratio in relation to their back-calculated TCDD serum concentrations determined in 2007/2008. METHODS: A total of 127 men and 21 women reported that 355 children were conceived after starting employment at the plant. The association between their lipid-standardised TCDD serum concentrations back-calculated to the time of their offspring's birth and the probability of a male birth was estimated through logistic regression, adjusting for the age of the exposed parent at birth, current body mass index and smoking. RESULTS: The overall sex ratio was 0.55 (197 boys, 158 girls). For fathers with serum TCDD concentrations ≥20 pg/g lipid at time of birth, the sex ratio was 0.47 (OR 0.49; 95% CI 0.30 to 0.79). The probability of a male birth decreased with higher paternal serum TCDD at time of birth (<4; 4-20; 20-100; ≥100 pg/g lipid), with ORs of 1.00 (reference); 1.00 (95% CI 0.50 to 2.02); 0.52 (95% CI 0.29 to 0.92); 0.45 (95% CI 0.23 to 0.89), p trend 0.007. For exposed mothers, the sex ratio was not reduced. CONCLUSIONS: This study indicates that paternal serum TCDD concentrations in excess of an estimated 20 pg/g lipid at time of conception are associated with a reduced sex ratio

Serum concentrations of chlorinated dibenzo-p-dioxins, furans and PCBs, among former phenoxy herbicide production workers and firefighters in New Zealand.

PURPOSE: To quantify serum concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like compounds in former phenoxy herbicide production plant workers and firefighters, 20 years after 2,4,5-T production ceased. METHODS: Of 1025 workers employed any time during 1969-1984, 430 were randomly selected and invited to take part in a morbidity survey and provide a blood sample; 244 (57%) participated. Firefighters stationed in close proximity of the plant and/or engaged in call-outs to the plant between 1962 and 1987 also participated (39 of 70 invited). Reported here are the serum concentrations of TCDD and other chlorinated dibenzo-dioxins, dibenzofurans, and polychlorinated biphenyls (PCBs). Determinants of the serum concentrations were assessed using linear regression. RESULTS: The 60 men who had worked in the phenoxy/TCP production area had a mean TCDD serum concentration of 19.1 pg/g lipid, three times the mean concentration of the 141 men and 43 women employed in other parts of the plant (6.3 and 6.0 pg/g respectively), and more than 10 times the mean for the firefighters (1.6 pg/g). Duration of employment in phenoxy herbicide synthesis, maintenance work, and work as a boilerman, chemist, and packer were associated with increased serum concentrations of TCDD and 1,2,3,4,7-pentachlorodibenzo-p-dioxin (PeCDD). Employment as a boilerman was also associated with elevated serum concentrations of PCBs. CONCLUSIONS: Occupations in the plant associated with phenoxy herbicide synthesis had elevated levels of TCDD and PeCDD. Most other people working within the plant, and the local firefighters, had serum concentrations of dioxin-like compounds comparable to those of the general population

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.

We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis

European birth cohorts for environmental health research

Many pregnancy and birth cohort studies investigate the health effects of early-life environmental contaminant exposure. An overview of existing studies and their data is needed to improve collaboration, harmonization, and future project planning

Large-Scale Pathway-Based Analysis of Bladder Cancer Genome-Wide Association Data from Five Studies of European Background

Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ∼90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I2 statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways (‘Aromatic amine metabolism’ [PGSEA = 0.0100, PARTP = 0.0020], ‘NAD biosynthesis’ [PGSEA = 0.0018, PARTP = 0.0086], ‘NAD salvage’ [PARTP = 0.0068], ‘Clathrin derived vesicle budding’ [PARTP = 0.0018], ‘Lysosome vesicle biogenesis’ [PGSEA = 0.0023, PARTP<0.00012], ’Retrograde neurotrophin signaling’ [PGSEA = 0.00840], and ‘Mitotic metaphase/anaphase transition’ [PGSEA = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis