34 research outputs found
Pathema: a clade-specific bioinformatics resource center for pathogen research
Pathema (http://pathema.jcvi.org) is one of the eight Bioinformatics Resource Centers (BRCs) funded by the National Institute of Allergy and Infectious Disease (NIAID) designed to serve as a core resource for the bio-defense and infectious disease research community. Pathema strives to support basic research and accelerate scientific progress for understanding, detecting, diagnosing and treating an established set of six target NIAID Category A–C pathogens: Category A priority pathogens; Bacillus anthracis and Clostridium botulinum, and Category B priority pathogens; Burkholderia mallei, Burkholderia pseudomallei, Clostridium perfringens and Entamoeba histolytica. Each target pathogen is represented in one of four distinct clade-specific Pathema web resources and underlying databases developed to target the specific data and analysis needs of each scientific community. All publicly available complete genome projects of phylogenetically related organisms are also represented, providing a comprehensive collection of organisms for comparative analyses. Pathema facilitates the scientific exploration of genomic and related data through its integration with web-based analysis tools, customized to obtain, display, and compute results relevant to ongoing pathogen research. Pathema serves the bio-defense and infectious disease research community by disseminating data resulting from pathogen genome sequencing projects and providing access to the results of inter-genomic comparisons for these organisms
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
Recommended from our members
Structural and Thermodynamic Features of Polycyclic Aromatic Hydrocarbon - DNA Adducts in the NRAS(Q61) Sequence Context
The relative genotoxicity of different polycyclic aromatic hydrocarbons (PAHs) is widely thoughtto be a function of the structural and thermodynamic features of their corresponding PAH-DNA
adducts. As a result, accurate parameters for molecular mechanics force fields are crucial to the
study of such systems via molecular dynamics (MD). While transferability of parameters among
structurally similar molecular systems is frequently a goal when parameterizing novel residues for
the CHARMM force field, we will show that planar bay region and non-planar fjord region PAH-
DNA adduct systems require distinct dihedral terms to accurately model the torsional potential
energy surface of the adduct covalent bond that links a PAH-diol-epoxide and adenine, despite
identical atomic connectivity. We then examine the use of the Truncated Singular Value Decom-
position and Tikhonov Regularization in standard form to address ill-posed least squares problems
Ax = b that frequently arise in molecular mechanics force field parameter optimization. Utilizing
the Discrete Picard Condition and/or a well-defined gap in the singular value spectrum when A
has a well-determined numerical rank, we are able to systematically determine truncation and in
turn regularization parameters that are correspondingly used to produce truncated and regularized
solutions to the ill-posed least squares problem at hand. These solutions in turn result in optimized
force field dihedral terms that accurately parameterize the torsional energy landscape. As the solu-
tions produced by this approach are unique, it has the advantage of avoiding the multiple iterations
and guess and check work often required to optimize molecular mechanics force field parameters.
With optimized parameters for bay and fjord region PAH-DNA adduct systems developed, we con-
duct alchemical free energy perturbation calculations over closed thermodynamic cycles in order
to gauge the relative genotoxicities of several IARC Group 2A/B and 3 PAHs in the NRAS(Q61)
DNA sequence context. These calculations reveal that the fjord region PAHs examined in this
work as well as other IARC Group 2A/B and 3 PAHs exhibit greater relative binding affinity as
compared to the IARC Group 1 known human carcinogen B[a]P. These PAHs are also less likely to
form productive PAH-DNA protein binding complexes required in the recognition step of global
genomic - nucleotide excision repair, indicating that they are more likely to persist and induce
mutations in subsequent DNA replication cycles. Further examination reveals that the intercalated
conformation and structural differences among PAH-DNA adducts have an impact on stabilizing
van der Waals interactions and hydrogen bonding between nucleobase pairs in NRAS(Q61) that
are generally associated with trends in relative binding free energies
Recommended from our members
Regularization of least squares problems in CHARMM parameter optimization by truncated singular value decompositions.
We examine the use of the truncated singular value decomposition and Tikhonov regularization in standard form to address ill-posed least squares problems Ax = b that frequently arise in molecular mechanics force field parameter optimization. We illustrate these approaches by applying them to dihedral parameter optimization of genotoxic polycyclic aromatic hydrocarbon-DNA adducts that are of interest in the study of chemical carcinogenesis. Utilizing the discrete Picard condition and/or a well-defined gap in the singular value spectrum when A has a well-determined numerical rank, we are able to systematically determine truncation and in turn regularization parameters that are correspondingly used to produce truncated and regularized solutions to the ill-posed least squares problem at hand. These solutions in turn result in optimized force field dihedral terms that accurately parameterize the torsional energy landscape. As the solutions produced by this approach are unique, it has the advantage of avoiding the multiple iterations and guess and check work often required to optimize molecular mechanics force field parameters