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Sawhney V.,St. Bartholomew's Hospital | Sawhney V.,Queen Mary, University of London | Brouilette S.,Partek, Inc. | Abrams D.,Childrens Hospital | And 6 more authors.
Current Genomics | Year: 2012

Cardiovascular disease (CVD) is a heterogeneous, complex trait that has a major impact on human morbidity and mortality. Common genetic variation may predispose to common forms of CVD in the community, and rare genetic conditions provide unique pathogenetic insights into these diseases. With the advent of the Human Genome Project and the genomic era, new tools and methodologies have revolutionised the field of genetic research in cardiovascular medicine. In this review, we describe the rationale for the current emphasis on large-scale genomic studies, elaborate on genome wide association studies and summarise the impact of genomics on clinical cardiovascular medicine and how this may eventually lead to new therapeutics and personalised medicine. © 2012 Bentham Science Publishers.

Stevens E.L.,Program in Human Genetics | Heckenberg G.,Partek, Inc. | Roberson E.D.O.,Program in Human Genetics | Roberson E.D.O.,Washington University in St. Louis | And 4 more authors.
PLoS Genetics | Year: 2011

It is an assumption of large, population-based datasets that samples are annotated accurately whether they correspond to known relationships or unrelated individuals. These annotations are key for a broad range of genetics applications. While many methods are available to assess relatedness that involve estimates of identity-by-descent (IBD) and/or identity-by-state (IBS) allele-sharing proportions, we developed a novel approach that estimates IBD0, 1, and 2 based on observed IBS within windows. When combined with genome-wide IBS information, it provides an intuitive and practical graphical approach with the capacity to analyze datasets with thousands of samples without prior information about relatedness between individuals or haplotypes. We applied the method to a commonly used Human Variation Panel consisting of 400 nominally unrelated individuals. Surprisingly, we identified identical, parent-child, and full-sibling relationships and reconstructed pedigrees. In two instances non-sibling pairs of individuals in these pedigrees had unexpected IBD2 levels, as well as multiple regions of homozygosity, implying inbreeding. This combined method allowed us to distinguish related individuals from those having atypical heterozygosity rates and determine which individuals were outliers with respect to their designated population. Additionally, it becomes increasingly difficult to identify distant relatedness using genome-wide IBS methods alone. However, our IBD method further identified distant relatedness between individuals within populations, supported by the presence of megabase-scale regions lacking IBS0 across individual chromosomes. We benchmarked our approach against the hidden Markov model of a leading software package (PLINK), showing improved calling of distantly related individuals, and we validated it using a known pedigree from a clinical study. The application of this approach could improve genome-wide association, linkage, heterozygosity, and other population genomics studies that rely on SNP genotype data. © 2011 Stevens et al.

Stevens E.L.,Program in Human Genetics | Heckenberg G.,Partek, Inc. | Baugher J.D.,Program in Biochemistry | Roberson E.D.O.,Program in Human Genetics | And 4 more authors.
European Journal of Human Genetics | Year: 2012

A set of Centre dtude du Polymorphisme Humain (CEPH) cell lines serves as a large reference collection that has been widely used as a benchmark for allele frequencies in the analysis of genetic variants, to create linkage maps of the human genome, to study the genetics of gene expression, to provide samples to the HapMap and 1000 Genomes projects, and for a variety of other applications. An explicit feature of the CEPH collection is that these multigenerational families represent reference panels of known relatedness, consisting mostly of three-generation pedigrees with large sibships, two parents, and grandparents. We applied identity-by-state (IBS) and identity-by-descent (IBD) methods to high-density genotype data from 186 CEPH individuals in 13 families. We identified unexpected relatedness between nominally unrelated grandparents both within and between pedigrees. For one pair, the estimated Cotterman coefficient of relatedness k1 exceeded 0.2, consistent with one-eighth sharing (eg, first-cousins). Unexpectedly, significant IBD2 values were discovered in both second-degree and parent-child relationships. These were accompanied by regions of homozygosity in the offspring, which corresponded to blocks lacking IBS0 in purportedly unrelated parents, consistent with inbreeding. Our findings support and extend a 1999 report, based on the use of short tandem-repeat polymorphisms, that several CEPH families had regions of homozygosity consistent with autozygosity. We benchmarked our IBD approach (called kcoeff) against both RELPAIR and PREST software packages. Our findings may affect the interpretation of previous studies and the design of future studies that rely on the CEPH resource. © 2012 Macmillan Publishers Limited All rights reserved.

Fousteri G.,La Jolla Institute for Allergy and Immunology | Jasinski J.,University of Colorado at Denver | Jasinski J.,Partek, Inc. | Dave A.,La Jolla Institute for Allergy and Immunology | And 10 more authors.
Diabetes | Year: 2012

In diabetic patients and susceptible mice, insulin is a targeted autoantigen. Insulin B chain 9-23 (B:9-23) autoreactive CD4 T cells are key for initiating autoimmune diabetes in NOD mice; however, little is known regarding their origin and function. To this end, B:9-23-specific, BDC12-4.1 T-cell receptor (TCR) transgenic (Tg) mice were studied, of which, despite expressing a single TCR on the recombination activating gene-deficient background, only a fraction develops diabetes in an asynchronous manner. BDC12-4.1 CD4 T cells convert into effector (Teff) and Foxp3 +-expressing adaptive regulatory T cells (aTregs) soon after leaving the thymus as a result of antigen recognition and homeostatic proliferation. The generation of aTreg causes the heterogeneous diabetes onset, since crossing onto the scurfy (Foxp3) mutation, BDC12-4.1 TCR Tg mice develop accelerated and fully penetrant diabetes. Similarly, adoptive transfer and bone marrow transplantation experiments showed differential diabetes kinetics based on Foxp3 + aTreg's presence in the BDC12-4.1 donors. A single-specificity, insulin-reactive TCR escapes thymic deletion and simultaneously converts into aTreg and Teff, establishing an equilibrium that determines diabetes penetrance. These results are of particular importance for understanding disease pathogenesis. They suggest that once central tolerance is bypassed, autoreactive cells arriving in the periphery do not by default follow solely a pathogenic fate upon activation. © 2012 by the American Diabetes Association.

Liu W.,University of Missouri | Liu W.,Sony Electronics Inc. | Dong L.,Partek, Inc. | Zeng W.,University of Missouri
IEEE Transactions on Circuits and Systems for Video Technology | Year: 2010

During the past ten years, Wyner-Ziv video coding (WZVC) has gained a lot of research interests because of its unique characteristics of simple encoding, complex decoding. However, the performance gap between WZVC and conventional video coding has never been closed to the point promised by the information theory. In this paper, we illustrate the chicken-and-egg dilemma encountered in WZVC: high-efficiency WZVC requires good estimation of side information (SI); however, good SI estimation is not possible for the decoder without access to the decoded current frame. To resolve such a dilemma, we present and advocate a framework that explores an important concept of decoder-side progressive-learning. More specifically, a decoder-side multi-resolution motion refinement (MRMR) scheme is proposed, where the decoder is able to learn from the already-decoded lower-resolution data to refine the motion estimation (ME), which in turn greatly improves the SI quality as well as the coding efficiency for the higher resolution data. Theoretical analysis shows that at high rates, decoder-side MRMR outperforms motion extrapolation by as much as 5 dB, while falling behind conventional encoder-side inter-frame ME by only about 1.5 dB. In addition, since decoder-side ME does not suffer from the bit-rate overhead in transmitting the motion information, further performance gain can be achieved for decoder-side MRMR by incorporating fractional-pel motion search, block matching with smaller block sizes, and multiple hypothesis prediction. We also present a practical WZVC implementation with MRMR, which shows comparable coding performance as H.264 at very high bit-rates. © 2006 IEEE.

Kim Y.H.,University of Houston | Liang H.,University of Houston | Liu X.,University of Houston | Lee J.-S.,University of Houston | And 14 more authors.
Cancer Research | Year: 2012

Gastric cancer is the most common cancer in Asia and most developing countries. Despite the use of multimodality therapeutics, it remains the second leading cause of cancer death in the world. To identify the molecular underpinnings of gastric cancer in the Asian population, we applied an RNA-sequencing approach to gastric tumor and noncancerous specimens, generating 680 million informative short reads to quantitatively characterize the entire transcriptome of gastric cancer (including mRNAs and miRNAs). A multilayer analysis was then developed to identify multiple types of transcriptional aberrations associated with different stages of gastric cancer, including differentially expressed mRNAs, recurrent somatic mutations, and key differentially expressed miRNAs. Through this approach, we identified the central metabolic regulator AMP-activated protein kinase (AMPK)α as a potential functional target in Asian gastric cancer. Furthermore, we experimentally showed the translational relevance of this gene as a potential therapeutic target for early-stage gastric cancer in Asian patients. Together, our findings not only provide a valuable information resource for identifying and elucidating the molecular mechanisms of Asian gastric cancer, but also represent a general integrative framework to develop more effective therapeutic targets. ©2012 AACR.

Brouilette S.,Queen Mary, University of London | Brouilette S.,Partek, Inc. | Kuersten S.,Illumina | Mein C.,Queen Mary, University of London | And 14 more authors.
Developmental Dynamics | Year: 2012

Background: Deep sequencing of single cell-derived cDNAs offers novel insights into oncogenesis and embryogenesis. However, traditional library preparation for RNA-seq analysis requires multiple steps with consequent sample loss and stochastic variation at each step significantly affecting output. Thus, a simpler and better protocol is desirable. The recently developed hyperactive Tn5-mediated library preparation, which brings high quality libraries, is likely one of the solutions. Results and Conclusions: Here, we tested the applicability of hyperactive Tn5-mediated library preparation to deep sequencing of single cell cDNA, optimized the protocol, and compared it with the conventional method based on sonication. This new technique does not require any expensive or special equipment, which secures wider availability. A library was constructed from only 100 ng of cDNA, which enables the saving of precious specimens. Only a few steps of robust enzymatic reaction resulted in saved time, enabling more specimens to be prepared at once, and with a more reproducible size distribution among the different specimens. The obtained RNA-seq results were comparable to the conventional method. Thus, this Tn5-mediated preparation is applicable for anyone who aims to carry out deep sequencing for single cell cDNAs. Developmental Dynamics 241:1584-1590, 2012. © 2012 Wiley Periodicals, Inc.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.88M | Year: 2013

DESCRIPTION provided by applicant The broad long term objective of the proposed research is to develop and market a commercial software product that can be used to facilitate the analysis of genetic changes in order to elucidate chromosomal abnormalities that underlie diseases such as autism spectrum disorder bipolar disorder and schizophrenia Recent technological advances allow samples of DNA from patients to be analyzed on single nucleotide polymorphism SNP arrays generating up to millions of data points from each sample In parallel next generation sequencing NGS of whole genomes or whole exomes allows the determination of sequence data from individuals with mental health or other diseases as well as sequence data from affected and unaffected family members These data must be analyzed to identify chromosomal abnormalities e g DNA mutations hemizygous or homozygous deletions or translocations that confer risk for these diseases Software such as Partek R Genomics Suiteandquot GS offers a robust set of tools to perform data analysis and visualization A goal of this proposal is to enhance the Partek GS and Partek Flowandquot commercial products by introducing innovative practically useful software modules that define genetic relatedness in studies based on SNP and or NGS data Specific Aim is to develop and incorporate methods for the determination of genetic relatedness based on SNP data including data sets of pedigrees and large populations These methods allow the relationship between all pairs of individuals in a data set to be determined with high accuracy even for large studies with thousands of samples Specific Aim is to develop and incorporate methods for the determination of genetic relatedness based on NGS data including whole genome sequences of individuals These methods will provide a significant new dimension to the analysis of genome sequence data facilitating the identification of variants that are relevant to disease For Specific Aim we will apply these novel methods to two data sets whole exome sequence data from individuals with autism data from over trios obtained from dbGaP and SNP and whole genome or whole exome sequences from quintets of father mother child child child in which at least one child is diagnosed with autism These studies will demonstrate the utility of the novel software methods and demonstrate how they can facilitate the discovery of genetic variants that underlie autism and other mental health disorders PUBLIC HEALTH RELEVANCE Newly available technologies allow the measurement of millions of variations in DNA sequence between samples from individuals with diseases such as autism and schizophrenia relative to unaffected individuals controls The proposed research is designed to create software analysis tools that will facilitate the discovery of chromosomal abnormalities in diseases This may lead to improved diagnosis and treatments for these disorders serving a large public health need

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