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PubMed2002

Principles, organization, and operation of a DNA bank for clinical trials: a Department of Veterans Affairs cooperative study.

The mapping and sequencing of the human genome promises rapid growth in understanding the genetically influenced mechanisms that underlie human disease. To realize this promise fully, it is necessary to relate genetic information to clinical phenotypes. Genetic tissue banking in clinical studies provides opportunities to analyze the genetic contribution to variation in response to treatments. The challenges to progress are likely to come from the complex organizational, social, political, and ethical issues that must be resolved in order to put clinical and DNA bank information together. Concerns about subjects' rights, informed consent, privacy, and ownership of genetic material require attention in the development of DNA banks. In this paper we describe one approach to the solution of these problems that was adopted by one clinical trials group, the Department of Veterans Affairs Cooperative Studies Program.

Clinical Trials as Topic↗
PubMed2002

Microsatellite variation in the reintroduced Pennsylvania elk herd.

Relocation programs have restored elk (Cervus elaphus) to portions of its vast historical range. We examine the consequences of these relocation programs by assessing variation at 10 microsatellite loci in three elk herds, a source herd (Yellowstone National Park), a large herd reintroduced from Yellowstone (Custer State Park) and a bottlenecked herd reintroduced from both Yellowstone and Custer (the Pennsylvania herd). Observed single locus heterozygosities ranged from 0.000 to 0.739. Multi-locus heterozygosities ranged from 0.222 to 0.589. Although significant differences were detected among all three herds, the Yellowstone National Park and Custer State Park herds possessed similar levels of variation and heterozygosity, and the genetic distance between these two herds was small. The Pennsylvania herd, on the other hand, experienced a 61.5% decrease in heterozygosity relative to its source herds, possessed no unique and few rare alleles, and the genetic distances between the Pennsylvania herd and its sources were large. Simulations were performed to identify bottleneck scenarios in agreement with levels of variation in the Pennsylvania herd. Our data confirm that the rate of population growth post-relocation may have important genetic consequences and indicate that theoretical predictions regarding the maintenance of genetic variation during relocation events must be viewed with caution when small numbers of a polygynous species are released.

Animals↗
PubMed1983

Analysis of the covariance structure of digital ridge counts in the offspring of monozygotic twins.

Improved methods for analysis of covariance structures now permit the rigorous testing of multivariate genetic hypotheses. Using Jöreskog's Lisrel IV computer program we have conducted a confirmatory factor analysis of dermal ridge counts on the individual fingers of 509 offspring of 107 monozygotic twin pairs. Prior to the initiation of the model-fitting procedure, the sex-adjusted ridge counts for the offspring of male and female twins were partitioned by a multivariate nested analysis of variance yielding five 10 X 10 variance-covariance matrices containing a total of 275 distinctly observed parameters with which to estimate latent sources of genetic and environmental variation and test hypotheses about the factor structure of those latent causes. To provide an adequate explanation for the observed patterns of covariation, it was necessary to include additive genetic, random environmental, epistatic and maternal effects in the model and a structure for the additive genetic effects which included a general factor and allowed for hand asymmetry and finger symmetry. The results illustrate the value of these methods for the analysis of interrelated metric traits.

Analysis of Variance↗
PubMed2006

Assessing a quick monitoring method using rocky intertidal communities as a bioindicator: a multivariate approach in Algeciras Bay.

A multivariate approach was used to test the value of intertidal communities as a bioindicator of environmental conditions at Algeciras Bay, southern Spain. The study area is located in the Strait of Gibraltar and it is subjected to a variety of anthropic impacts. Eight localities (5 inside and 3 outside the bay) were selected, and four transects were undertaken in each locality to characterise the fauna and flora. The spatial distribution of the intertidal species reflected the physico-chemical conditions of Algeciras Bay. The stations located outside the bay, characterised by high hydrodynamism and dissolved oxygen and low sedimentation and turbidity, had a higher diversity and species richness than the inner stations. According to the BIO-ENV procedure and CCA, water turbidity was the factor which best correlated with the intertidal assemblages. SIMPER showed that the molluscs Chtamalus stellatus, Mytilus cf edulis, Littorina neritoides and Balanus perforatus, and the algae Gelidium pusillum, Corallina elongata, Asparagopsis armata, Colpomenia sinuosa and Fucus spiralis were the species that most contributed to the dissimilarity between internal and external sites. The present study, based on the spatial distribution of intertidal taxa, yielded similar results to those previously obtained in the area with costly physico-chemical analysis based on complex matrices of subtidal epifaunal communities. Consequently, the intertidal sampling method proposed in this study is presented here as a quick, effective alternative strategy, and can be useful in environmental monitoring programs, since these communities are easily accessible and amenable to sample, and the sessile nature of the majority of the species makes future, long-term monitoring relatively simple.

Animals↗
PubMed2005

Molecular characterization and relatedness of Haematobia irritans (horn fly) populations, by RAPD-PCR.

Haematobia irritans is a hematophagous parasite of cattle that causes significant economic losses in many parts of the world, including Brazil. In the present work, one American and four Brazilian populations of this species were studied by Random Amplified Polymorpht DNA (RAPD) to assess basically genetic variability within and between populations. Ten different decamer random primers were employed in the genomic DNA amplification, yielding 117 fragments in the five H. irritans populations. In Drosophila prosaltans, used as an outgroup, 81 fragments were produced. Forty-three of these fragments were shared by both species. Among the H. irritans samples, that from Rio Branco (Acre State, Brazil) produced the smallest numbers of fragments and polymorphic bands. This high genetic homogenity may be ascribed to its geographic origin (in the Northwest of Brazil), which causes high isolation and low gene flow, unlike the other Brazilian populations, from the South Central region, in which cattle trade is very intensive. Marker fragments (exclusive bands) detected in every sample enabled the population origin to be characterized, but they are also potentially useful for further approaches such as the putative origin of Brazilian populations from North America. Similarity indices [Nei & Li, 1979, Proc. Natl. Acad. Sci. USA 76: 5269-5273] and phylogenetic trees, rooted by using the outgroup and produced by the Phylogenetic Analysis using Parsimony (PAUP 4.0-Swofford, 2001) program showed the closest relationships between flies from Sao Jose do Rio Preto and Turúba (both from São Paulo State, Brazil) while flies from the geographically distant Rio Branco showed the greatest differentiation relative to the others.

Animals↗
PubMed2004

Lack of cytotoxic property in a variant of Epstein-Barr virus latent membrane protein-1 isolated from nasopharyngeal carcinoma.

Latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus (EBV) is a membrane protein that activates multiple signaling pathways and transcription factors, including NF-kappaB. Our recent report demonstrated that expression of LMP1 induced programmed cell death in an NF-kappaB-dependent manner. In this study, we demonstrate that a variant CAO-LMP1 derived from EBV-infected nasopharyngeal carcinoma (NPC) does not induce cell death unlike the prototype B95.8-LMP1, although both types of LMP1 show NF-kappaB activation to a similar extent. Studies with chimeric or mutated proteins identified two amino acids in the transmembrane domain, which are commonly substituted in NPC-derived LMP1 variants, being critical for cell death induction by B95.8-LMP1. Furthermore, we show that the B95.8 transmembrane domain co-operates with NF-kappaB to trigger cell death program. Thus, our results reveal a particular feature of the transmembrane domain of tumor-derived CAO-LMP1 and suggest its possible contribution to the pathogenesis of NPC.

Amino Acid Sequence↗
PubMed2006

A whole genome long-range haplotype (WGLRH) test for detecting imprints of positive selection in human populations.

MOTIVATION: The identification of signatures of positive selection can provide important insights into recent evolutionary history in human populations. Current methods mostly rely on allele frequency determination or focus on one or a small number of candidate chromosomal regions per study. With the availability of large-scale genotype data, efficient approaches for an unbiased whole genome scan are becoming necessary. METHODS: We have developed a new method, the whole genome long-range haplotype test (WGLRH), which uses genome-wide distributions to test for recent positive selection. Adapted from the long-range haplotype (LRH) test, the WGLRH test uses patterns of linkage disequilibrium (LD) to identify regions with extremely low historic recombination. Common haplotypes with significantly longer than expected ranges of LD given their frequencies are identified as putative signatures of recent positive selection. In addition, we have also determined the ancestral alleles of SNPs by genotyping chimpanzee and gorilla DNA, and have identified SNPs where the non-ancestral alleles have risen to extremely high frequencies in human populations, termed 'flipped SNPs'. Combining the haplotype test and the flipped SNPs determination, the WGLRH test serves as an unbiased genome-wide screen for regions under putative selection, and is potentially applicable to the study of other human populations. RESULTS: Using WGLRH and high-density oligonucleotide arrays interrogating 116 204 SNPs, we rapidly identified putative regions of positive selection in three populations (Asian, Caucasian, African-American), and extended these observations to a fourth population, Yoruba, with data obtained from the International HapMap consortium. We mapped significant regions to annotated genes. While some regions overlap with genes previously suggested to be under positive selection, many of the genes have not been previously implicated in natural selection and offer intriguing possibilities for further study. AVAILABILITY: the programs for the WGLRH algorithm are freely available and can be downloaded at http://www.affymetrix.com/support/supplement/WGLRH_program.zip.

Algorithms↗
PubMed2025

Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.

BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246 K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86 K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.

Humans↗
PubMed2004

GenomeMixer: a complex genetic cross simulator.

UNLABELLED: GenomeMixer is a cross-platform application that simulates meiotic recombination events for large and complex multigenerational genetic crosses among sexually reproducing diploid species and outputs simulated progeny to several standard mapping programs. AVAILABILITY: Documentation, C++ source, and binaries for Mac OS X and x86 Linux are freely available at http://www.nervenet.org/genome_mixer/. GenomeMixer can be compiled on any system with support for the Trolltech Qt toolkit, including Windows.

Chromosome Mapping↗
PubMed2004

Multiple-interval mapping for quantitative trait loci controlling endosperm traits.

Endosperm traits are trisomic inheritant and are of great economic importance because they are usually directly related to grain quality. Mapping for quantitative trait loci (QTL) underlying endosperm traits can provide an efficient way to genetically improve grain quality. As the traditional QTL mapping methods (diploid methods) are usually designed for traits under diploid control, they are not the ideal approaches to map endosperm traits because they ignore the triploid nature of endosperm. In this article, a statistical method considering the triploid nature of endosperm (triploid method) is developed on the basis of multiple-interval mapping (MIM) to map for the underlying QTL. The proposed triploid MIM method is derived to broadly use the marker information either from only the maternal plants or from both the maternal plants and their embryos in the backcross and F2 populations for mapping endosperm traits. Due to the use of multiple intervals simultaneously to take multiple QTL into account, the triploid MIM method can provide better detection power and estimation precision, and as shown in this article it is capable of analyzing and searching for epistatic QTL directly as compared to the traditional diploid methods and current triploid methods using only one (or two) interval(s). Several important issues in endosperm trait mapping, such as the relation and differences between the diploid and triploid methods, variance components of genetic variation, and the problems if effects are present and ignored, are also addressed. Simulations are performed to further explore these issues, to investigate the relative efficiency of different experimental designs, and to evaluate the performance of the proposed and current methods in mapping endosperm traits. The MIM-based triploid method can provide a powerful tool to estimate the genetic architecture of endosperm traits and to assist the marker-assisted selection for the improvement of grain quality in crop science. The triploid MIM FORTRAN program for mapping endosperm traits is available on the worldwide web (http://www.stat.sinica.edu.tw/chkao/).

Chromosome Mapping↗
PubMed1993

Research-oriented genetic management of nonhuman primate colonies.

Genetic management is an important component of the general management of nonhuman primate colonies. However, standard genetic management techniques were developed primarily to address the goals of population conservation, particularly in zoo situations. The special needs of colonies that produce animals for biomedical research have not previously been fully addressed and the great potential of genetic management in the research environment remains to be realized. A research-oriented genetic management approach balances long-term breeding goals and current and future experimental needs, yielding a comprehensive overall colony management program. Pedigree information, genetic markers (e.g., serum proteins, red blood cell enzymes, restriction fragment length polymorphisms, and single-locus microsatellites), and quantitative traits (e.g., routinely gathered clinical chemical values, weights, and blood pressures) can be used alone or in combination to estimate genetic variability in the colony and to characterize animals for experimentally relevant traits. The statistical power of experiments using nonhuman primates can be improved when animals are selected on the basis of their genetic values or genotypes for experimentally relevant traits because the quantified genetic variation among subjects can then be minimized. The incorporation of experimental needs into the overall genetic management plans for captive breeding colonies helps ensure the long-term viability of colonies for meeting the demands of both breeding and research.

Animals↗
PubMed2003

User-friendly algorithms for estimating completeness and diversity in randomized protein-encoding libraries.

Directed evolution of proteins depends on the production of molecular diversity by random mutagenesis. While a number of methods have been developed for introducing this diversity, the best ways to sample it are not always clear. Here we used simple statistics to analyse completeness and diversity in randomized libraries generated by oligonucleotide-directed mutagenesis, error-prone polymerase chain reaction (epPCR) and in vitro recombination of highly homologous sequences. For oligonucleotide-directed mutagenesis, we derive equations to estimate how complete a given library is expected to be and also to predict the size of library required to give a fixed probability of being 100% complete. We describe the statistical bases for computer programs which estimate the number of distinct variants represented in epPCR and shuffled libraries, dubbed PEDEL and DRIVeR, respectively. These programs allow the user to calculate (rather than guess) the diversity represented in a given library and also provide empirical guidelines for maximizing this diversity. PEDEL and DRIVeR are available at www.bio.cam.ac.uk/ approximately blackburn/stats.html.

Algorithms↗
PubMed2002

Purebred-crossbred performance and genetic evaluation of postweaning growth and carcass traits in Bos indicus x Bos taurus crosses in Australia.

Growth and carcass data on 7,154 cattle from a purebred project and 1,241 cattle from a crossbred project, comprising 916 first-crosses and 325 purebred Brahman controls, were analyzed to estimate genetic parameters, including the genetic correlations between purebred and crossbred performance (rpc). The data also allowed the estimation of sire breed means for various growth and carcass traits. Crossbred calves were produced using 9 Angus, 8 Hereford, 7 Shorthorn, 14 Belmont Red, and 8 Santa Gertrudis sires bred to Brahman dams. These same sires produced 1,568 progeny in a separate purebreeding project. Cattle in both projects were managed under two finishing regimens (pasture and feedlot) to representative market live weights of 400 (domestic), 520 (Korean), and 600 kg (Japanese). The traits studied included live weight at around 400 d of age (400W), hot carcass weight (CWT), retail beef yield percentage (RBY), intramuscular fat percentage (IMF), rump fat depth (P8), and preslaughter ultrasound scanned eye muscle area (SEMA). Estimated breeding values (EBV) of sires from their BREEDPLAN genetic evaluations were used to assess their value in predicting crossbred performance. Regressions of actual crossbred calf performance on sire EBV for each of the traits differed little from their expectation of 0.5. Angus sires produced crossbred carcasses with the highest P8 and lowest RBY but highest IMF. In contrast, crossbred progeny from Belmont Red sires had the lightest 400W and CWT, lowest P8, and highest RBY. Estimates of rpc were 0.48, 0.48, 0.83, 0.95, 1.00, and 0.78 for 400W, CWT, RBY, IMF, P8, and SEMA, respectively. Commercial breeders selecting sires for crossbreeding programs with Brahman females, based on EBV computed from purebred data, might encounter some reranking of sire's performance for weight-related traits, with little expected change in carcass traits.

Adipose Tissue↗
PubMed1997

Genes and politics.

Explore the source record for details and available documents.

Biological Evolution↗
PubMed2005

Varicella vaccination of children in the United States: assessment after the first decade 1995-2005.

Live attenuated varicella vaccine (strain Oka) was approved for administration to healthy children in the United States in 1995. Over the past 10 years, varicella vaccine has been given to millions of children, usually at ages between 12 and 18 months. In states such as California, Michigan, and Texas, there has been a marked decline in the number of reported cases of varicella. Furthermore, there has been a 75% decrease in varicella-related hospitalizations across the United States, as well as a similar decrease in the number of deaths caused by complications of chickenpox. The main unanticipated result has been a growing number of outbreaks of varicella among immunized children ("breakthrough varicella"). The most cited risk factors for breakthrough varicella include the following: (1) 3-5-year interval since immunization and (2) immunization at the youngest ages, especially 12 months. Explanations for breakthrough varicella include a lessened immune response among the youngest recipients of the vaccine. Another possibility is genetic variation among circulating VZV strains. VZV strains can be separated into two geographic clades called European/North American and Asian, based on single nucleotide polymorphisms. Two mutant North American strains have been isolated from patients in the last 10 years. Several genomic differences between Oka vaccine strain and other strains have also been identified, including one site at the DNA origin of replication. Since breakthrough disease among vaccine recipients appears to be more common in the United States than in Japan, further comparisons between the varicella vaccination programs in Japan and the United States are warranted. In addition, data from varicella vaccination programs in Europe should provide further insight into the effectiveness of varicella vaccination in different geographic and ethnic populations.

Age Factors↗
PubMed2000

Risk estimation and value-of-information analysis for three proposed genetic screening programs for chronic beryllium disease prevention.

Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. We describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and we apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DP beta 1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity (approximately 94%) but low specificity (approximately 70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort, the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD evaluations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.

Berylliosis↗
PubMed1993

Tay-Sachs disease screening and diagnosis: evolving technologies.

Tay-Sachs disease (TSD) is an autosomal recessive, progressive, and fatal neurodegenerative disorder. Within the last 25 years, the discovery of the enzymatic basis of the disease, the deficiency of the enzyme hexosaminidase A, has made possible both enzymatic diagnosis of TSD and heterozygote identification. TSD is the first genetic condition for which a community-based heterozygote screening program was attempted with the intention of reducing the incidence of a genetic disease. In this article we review the clinical, biochemical, and molecular features of TSD as well as the development of laboratory technology that has been deployed in community genetic screening programs. We describe the assay procedures used and some of the limitations in their accuracy. We consider the impact of DNA-based technology on the process of identification of individuals carrying mutant genes associated with TSD and we discuss the social context within which genetic screening occurs.

Alleles↗
PubMedDate not supplied

A non-statistical approach to protein mutational variability.

The non-statistical, non-Markovian model of protein mutational variability is described. There are presented the essential features of the algorithm of genetic semihomology and some examples of its application. The results of genetic semihomology approach are compared with the results obtained by using statistical algorithms and matrices which are assumed in widely used programs such as ClustalW, FASTA, MultAlin and BLAST. The aim of the new algorithm elaboration is to improve the accuracy of the results of protein sequence comparison, avoid the wrong assumptions and misinterpretation of the results, and increase the amount of information available from such study.

Amino Acid Sequence↗