A parallel genetic algorithm to discover patterns in genetic markers that indicate predisposition to multifactorial disease.

This paper describes a novel algorithm to analyze genetic linkage data using pattern recognition techniques and genetic algorithms (GA). The method allows a search for regions of the chromosome that may contain genetic variations that jointly predispose individuals for a particular disease. The method uses correlation analysis, filtering theory and genetic algorithms to achieve this goal.

Total synthesis of cis-sylvaticin.

An asymmetric total synthesis of (+)-cis-sylvaticin is described. Key steps include the use of permanganate-mediated oxidative cyclization of 1,5-dienes to synthesize the two major fragments 2 and 3 and a catalytically efficient tethered RCM to unite these THF-containing fragments. In addition, t-BuP 4 base was found to reliably promote rapid alkylation of the butenolide precursor fragment 4.

Extracting disease risk profiles from expression data for linkage analysis: application to prostate cancer.

The genetic factors underlying many complex traits are not well understood. The Genetic Analysis Workshop 15 Problem 1 data present the opportunity to explore whether gene expression data from microarrays can be utilized to define useful phenotypes for linkage analysis in complex diseases. We utilize expression profiles for multiple genes that have been associated with a disease to develop a composite 'risk profile' that can be used to map other loci involved in the same disease process.

Analysis of high-density single-nucleotide polymorphism data: three novel methods that control for linkage disequilibrium between markers in a linkage analysis.

We performed a multipoint linkage analysis for rheumatoid arthritis (RA) using high-density single-nucleotide polymorphism (SNP) data for chromosome 6 and chromosome 21 using Genetic Analysis Workshop 15 (GAW15) data. These regions were previously shown to have high LOD scores, not accounting for linkage disequilibrium (LD). We propose three novel methods to control for LD in a linkage analysis: allow for LD between markers using graphical modeling, eliminate high-LD markers by principal-component analysis (PCA) using haplotype data, and eliminate high-LD markers by PCA using genotype data.

Meta-genetic association of rheumatoid arthritis and PTPN22 using PedGenie 2.1.

PedGenie beta version 2.1 is a unique, flexible, and easily implemented analysis software tool that is enhanced significantly by incorporation of meta-statistics to allow valid combined analysis of multiple studies, including mixtures of family-based and independent resources, in the detection of genetic association with common disease. Genetic Analysis Workshop 15 Problem 2 data, provided by the North American Rheumatoid Arthritis Consortium, were used to demonstrate PedGenie 2.

Further mapping of 10q26 supports strong association of HTRA1 polymorphisms with age-related macular degeneration.

Age-related macular degeneration (AMD) is a complex disorder with genetic and environmental influences. The genetic influences affecting AMD are not well understood and few genes have been consistently implicated and replicated for this disease. A polymorphism (rs11200638) in a transcription factor binding site of the HTRA1 gene has been described, in previous reports, as being most significantly associated with AMD.

Shared genomic segment analysis. Mapping disease predisposition genes in extended pedigrees using SNP genotype assays.

We examine the utility of high density genotype assays for predisposition gene localization using extended pedigrees. Results for the distribution of the number and length of genomic segments shared identical by descent among relatives previously derived in the context of genomic mismatch scanning are reviewed in the context of dense single nucleotide polymorphism maps. We use long runs of loci at which cases share a common allele identically by state to localize hypothesized predisposition genes.

PedGenie: meta genetic association testing in mixed family and case-control designs.

Background: PedGenie software, introduced in 2006, includes genetic association testing of cases and controls that may be independent or related (nuclear families or extended pedigrees) or mixtures thereof using Monte Carlo significance testing. Our aim is to demonstrate that PedGenie, a unique and flexible analysis tool freely available in Genie 2.4 software, is significantly enhanced by incorporating meta statistics for detecting genetic association with disease using data across multiple study groups.

Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease.

Background: Single nucleotide polymorphisms (SNPs) in matrix metalloproteinase (MMP) genes may be associated with myocardial infarction (MI) and coronary artery disease (CAD), but studies of multiple MMP genes and their tissue inhibitors (TIMPs) are scarce. Furthermore, differentiation of predictive ability by end point (MI vs CAD) has not been addressed. This study evaluated the association with MI of SNPs in genes encoding MMPs 1, 2, 3, and 9 and TIMPs 1, 2, and 3.

Statistical recombinant mapping in extended high-risk Utah pedigrees narrows the 8q24 prostate cancer locus to 2.0 Mb.

Background: Chromosome 8q24 is a region of compelling interest for prostate cancer (PRCA). Linkage, association, and admixture analysis initially indicated the region. Subsequently, several variants at 8q24 have been found to independently associate with PRCA.

Genome-wide scans meta-analysis for pulse pressure.

Genome scans for identifying susceptibility loci for pulse pressure have produced inconclusive results. A heterogeneity-based genome search meta-analysis was applied to available genome-scan data on pulse pressure. A genome search meta-analysis divides the whole genome into 120 bins and identifies bins that rank high on average in terms of linkage statistics across genome scans unweighted or weighted by study size.

Multiple less common genetic variants explain the association of the cholesteryl ester transfer protein gene with coronary artery disease.

Objectives: The objective of this study was to identify associations of the cholesteryl ester transfer protein (CETP) gene with coronary artery disease (CAD) with tagging (t) single nucleotide polymorphisms (SNPs) chosen to optimally account for intra-genic variation.

Background: The CETP gene plays a critical role in lipoprotein metabolism, but the common and well-studied TaqIB variant is inconsistently predictive of CAD.

Methods: From a deoxyribonucleic acid bank of 10,020 individuals, nondiabetic nonsmoking patients (n = 4,811) with angiographically defined, clinically significant CAD (> or =70% stenosis) or normal coronaries were genotyped for 11 CETP tSNPs.

Wilms tumor suppressor WTX negatively regulates WNT/beta-catenin signaling.

Aberrant WNT signal transduction is involved in many diseases. In colorectal cancer and melanoma, mutational disruption of proteins involved in the degradation of beta-catenin, the key effector of the WNT signaling pathway, results in stabilization of beta-catenin and, in turn, activation of transcription. We have used tandem-affinity protein purification and mass spectrometry to define the protein interaction network of the beta-catenin destruction complex.

Compelling evidence for a prostate cancer gene at 22q12.3 by the International Consortium for Prostate Cancer Genetics.

Previously, an analysis of 14 extended, high-risk Utah pedigrees localized in the chromosome 22q linkage region to 3.2 Mb at 22q12.3-13.

Small-molecule synergist of the Wnt/beta-catenin signaling pathway.

The Wnt/beta-catenin signaling pathway regulates cell fate and behavior during embryogenesis, adult tissue homeostasis, and regeneration. When inappropriately activated, the pathway has been linked to colorectal cancer and melanoma, and when attenuated it may contribute to Alzheimer's disease and osteoporosis. Small molecules that modulate Wnt signaling will likely provide new insights into the regulation of this key developmental pathway and ultimately provide pharmacological agents to control Wnt signaling in vivo.

Stereocontrolled synthesis of (-)-galanthamine.

An enantioselective synthesis of (-)-galanthamine has been realized in 11 linear steps starting from isovanillin. A Mitsunobu aryl ether forming reaction was used to assemble the galanthamine backbone, which was stitched together using enyne ring-closing metathesis, Heck, and N-alkylation reactions affording the tetracyclic ring system. Control of relative and absolute stereochemistry was derived from an easily accessible enantiomerically enriched propargylic alcohol 13.

Current status of functional MRI on small animals: application to physiology, pathophysiology, and cognition.

This review aims to make the reader aware of the potential of functional MRI (fMRI) in brain activation studies in small animal models. As small animals generally require anaesthesia for immobilization during MRI protocols, this is believed to be a serious limitation to the type of question that can be addressed with fMRI. We intend to introduce a fresh view with an in-depth overview of the surprising number of fMRI applications in a wide range of important research domains in neuroscience.

Genome-wide linkage analysis for aggressive prostate cancer in Utah high-risk pedigrees.

Background: It has been proposed that studying alternative phenotypes, such as tumor aggressiveness, may be a solution for overcoming the apparent heterogeneity that has hindered the identification of prostate cancer (PC) genes. We present the results of a genome-scan for predisposition to aggressive PC using the Utah high-risk pedigree resource.

Methods: We identified 259 subjects with aggressive PC in 57 extended and nuclear families.

Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome.

Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25-30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 (CYLN2) and general transcription factors (GTF2I and GTF2IRD1) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients.

A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the developed world and has a strong genetic predisposition. A locus at human chromosome 10q26 affects the risk of AMD, but the precise gene(s) have not been identified. We genotyped 581 AMD cases and 309 normal controls in a Caucasian cohort in Utah.

Localization of a prostate cancer predisposition gene to an 880-kb region on chromosome 22q12.3 in Utah high-risk pedigrees.

Chromosome 22q has become recently a region of interest for prostate cancer. We identified previously a logarithm of odds (LOD) of 2.42 at chromosome 22q12.

Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics.

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component.

Identification of excess clustering of coronary heart diseases among extended pedigrees in a genealogical population database.

Background: First-degree family history of early coronary artery disease (CAD) and myocardial infarction (MI) is prognostic among disease-free individuals but may be unreliable. This study evaluated deaths caused by CAD, MI, hypertensive heart disease (HtnHD), and congestive heart failure (CHF) among close and distant relatives.

Methods: The Utah Population Database contains >2.