Estimation of Parent Specific DNA Copy Number in Tumors using High-Density Genotyping Arrays

Chromosomal gains and losses comprise an important type of genetic change in tumors, and can now be assayed using microarray hybridization-based experiments. Most current statistical models for DNA copy number estimate total copy number, which do not distinguish between the underlying quantities of the two inherited chromosomes. This latter information, sometimes called parent specific copy number, is important for identifying allele-specific amplifications and deletions, for quantifying normal cell contamination, and for giving a more complete molecular portrait of the tumor. We propose a stochastic segmentation model for parent-specific DNA copy number in tumor samples, and give an estimation procedure that is computationally efficient and can be applied to data from the current high density genotyping platforms. The proposed method does not require matched normal samples, and can estimate the unknown genotypes simultaneously with the parent specific copy number. The new method is used to analyze 223 glioblastoma samples from the Cancer Genome Atlas (TCGA) project, giving a more comprehensive summary of the copy number events in these samples. Detailed case studies on these samples reveal the additional insights that can be gained from an allele-specific copy number analysis, such as the quantification of fractional gains and losses, the identification of copy neutral loss of heterozygosity, and the characterization of regions of simultaneous changes of both inherited chromosomes

Parsimonious Higher-Order Hidden Markov Models for Improved Array-CGH Analysis with Applications to Arabidopsis thaliana

Array-based comparative genomic hybridization (Array-CGH) is an important technology in molecular biology for the detection of DNA copy number polymorphisms between closely related genomes. Hidden Markov Models (HMMs) are popular tools for the analysis of Array-CGH data, but current methods are only based on first-order HMMs having constrained abilities to model spatial dependencies between measurements of closely adjacent chromosomal regions. Here, we develop parsimonious higher-order HMMs enabling the interpolation between a mixture model ignoring spatial dependencies and a higher-order HMM exhaustively modeling spatial dependencies. We apply parsimonious higher-order HMMs to the analysis of Array-CGH data of the accessions C24 and Col-0 of the model plant Arabidopsis thaliana. We compare these models against first-order HMMs and other existing methods using a reference of known deletions and sequence deviations. We find that parsimonious higher-order HMMs clearly improve the identification of these polymorphisms. Moreover, we perform a functional analysis of identified polymorphisms revealing novel details of genomic differences between C24 and Col-0. Additional model evaluations are done on widely considered Array-CGH data of human cell lines indicating that parsimonious HMMs are also well-suited for the analysis of non-plant specific data. All these results indicate that parsimonious higher-order HMMs are useful for Array-CGH analyses. An implementation of parsimonious higher-order HMMs is available as part of the open source Java library Jstacs (www.jstacs.de/index.php/PHHMM)

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

Appraisal of Dental Arch Dimension in Gujarati Males and Females

Aim : This study is carried out on Gujarati population to collect the relevant data & evaluate the arch dimensions. Materials and Method: Full mouth dental casts were obtained from 60 subjects (30 males and 30 females) aged 18-25 years belonging to Gujarati population inhabiting in Gujarat. Eighteen buccal cusp tips and mid-incisal edge points were marked on each maxillary and mandibular cast. All the digital images were transferred to AutoCAD and the co-ordinates of buccal cusp tips of all teeth were determined. Arch widths and depths were computer generated as straight-line distance between the dental landmarks. Results: Comparison of arch dimensions between males and females showed that, the transverse measurements i.e. inter-canine width and inter-second molar width were significantly larger in male subjects as compared to those of females in both the arches. Also in the maxillary and mandibular arch the canine depth and second molar depth was significantly larger in males as compared to that of females. In the maxillary and mandibular arch, the inter-canine width and inter-second molar width were highly significant, and second molar depth was significant, while canine depth was significant in maxilla but not in mandible. Conclusion: The arch dimensions showed that the males had significantly larger inter-canine width, inter-molar width, canine depth and molar depth in maxillary and mandibular arches as compared to those of females