Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “programmed genetic variation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 649 records · Page 36Linked to original sources

Early arterial lesions in infancy and childhood and ways of prevention.

Arterial lesions appear in the human vascular system early in life. In some predisposed arterial segments calcifications of the internal elastic sheets have regularly been demonstrated macroscopically in infancy and early childhood. Atherosclerotic lesions also begin in childhood, and the seeds of their later clinical manifestations are probably sown in infancy. Hyperlipemia, hypertension, and cigarette smoking represent the major risk factors of atherosclerosis and its premature development. Accordingly, the main task of pediatricians is early identification of the risk groups and their appropriate treatment, particularly of children with hyperlipoproteinemia type II and those with family history indicating a premature atherosclerotic event, hypertension, and diabetes mellitus. In most populations, however, elevated serum cholesterol levels are probably not caused by genetically determined metabolic disorders but mainly promoted by environmental factors, such as nutrition. Therefore, establishment of beneficial nutritional habits early in life may prevent the development or at least limit the extent of fatty streaks and their further transformation into fibrous plaques or more advanced atherosclerotic lesions. The education of the community, especially of parents, to the hazards of the cardiovascular risk factors must become an essential part of preventive programs directed to sound cardiovascular health. The wide individual variation of the extent of early lesions, e.g., of fatty streaking in childhood even in most homogeneous population subgroups, points to the existence of still undiscovered risk factors. Cooperative efforts between pediatric pathologists and pediatricians appear, therefore, a necessity for further progress in the evaluation of these factors and for establishing successful preventive programs.

Adult↗

Beta-thalassemia disease prevention: genetic medicine applied.

We report here an evaluation of a program for thalassemia-disease prevention, comprising education, population screening for heterozygotes, and reproductive counseling; the evaluation includes cost analysis. A preprogram survey in 1978 of 3,247 citizens in the high-risk communities (85% were high-school students) showed that 88% favored a program but that only 31% considered fetal diagnosis as an acceptable option. Screening in high school or before marriage was preferred by 56%. In a 25-month period (December 1979-December 1982), we screened 6,748 persons, including 5,117 senior high-school students, using MCV/HbA2 indices. The participation rate was 80% in the high-school group. The frequency for beta-thalassemia heterozygosity was 4.7% with 10-fold variation among ethnic groups at risk; the overall frequency for all variants found was 5.4%. We surveyed 60 carriers and 120 noncarriers after screening high-school students (response rate 77%): most carriers told parents (95%) and friends (67%) the test result; and 38% of the carriers' parents (vs. 18% of the noncarriers' parents) were also screened. Carriers would ascertain their spouses' genotype (91%) and approved uniformly (95%) the high-school screening experience and its goal. We performed 11 fetal diagnoses in a 25-month interval (greater than 75% participation in target population) either by fetoscopy and globin-chain analysis or by amniocentesis and genomic DNA analysis; two of three affected fetuses were aborted at parental request, there was one spontaneous abortion (after fetoscopy), and seven live births. The at-risk couples claimed pregnancy would not be contemplated without the fetal-diagnosis option. We analyzed economic costs of the program: cost per case prevented is approximately equal to $ 6,700, slightly less than cost-per-patient-treatment-year or about 4% of undiscounted treatment cost incurred in the first 25 years of life for an affected individual. These findings indicate: collective acceptance of the program, appropriate attitudes among carriers, general acceptance and efficacy of fetal diagnosis, and global cost-effectiveness.

Adolescent↗

Nucleotide substitution models and estimation of phylogeny.

The nucleotide substitution matrix inferred from avian data sets using cytochrome b differs considerably from the models commonly used in phylogenetic analyses. To analyze the possible effects of this particular pattern of change in phylogeny estimation we performed a computer simulation in which we started with a real sequence and used the inferred model of change to produce a tree of 10 species. Maximum parsimony (MP), maximum likelihood (ML), and various distance methods were then used to recover the topology and the branch lengths. We used two kinds of data with varying levels of variation. In addition, we tested with the removal of third positions and different weighting schemes. At low levels of variation, MP was outstanding in recovering the topology (90% correct), while unweighted pair-group method, arithmetic average (UPGMA), regardless of distances used, was poor (40%). At the higher level, most methods had a chance of around 40%-58% of finding the true tree. However, in most cases, the trees found were only slightly wrong, with only one or a few branches misplaced. On the other hand, the use of a "wrong" model had serious effects on the estimation of branch lengths (distances). Although precision was high, accuracy was poor with most methods, giving branch lengths that were biased downward. When seeded with the true distance matrix, Fitch and NJ always found the true tree, while UPGMA frequently failed to do so. The effect of removing third positions was dramatic at low levels of variation, because only one MP program was able to find a true tree at all, albeit rarely, while none of the others ever did so. At higher levels, the situation was better, but still much worse than with the whole data set.

Animals↗

Bioinformatic analysis of exon repetition, exon scrambling and trans-splicing in humans.

MOTIVATION: Using bioinformatic approaches we aimed to characterize poorly understood abnormalities in splicing known as exon scrambling, exon repetition and trans-splicing. RESULTS: We developed a software package that allows large-scale comparison of all human expressed sequence tags (EST) sequences to the entire set of human gene sequences. Among 5,992,495 EST sequences, 401 cases of exon repetition and 416 cases of exon scrambling were found. The vast majority of identified ESTs contain fragments rather than full-length repeated or scrambled exons. Their structures suggest that the scrambled or repeated exon fragments may have arisen in the process of cDNA cloning and not from splicing abnormalities. Nevertheless, we found 11 cases of full-length exon repetition showing that this phenomenon is real yet very rare. In searching for examples of trans-splicing, we looked only at reproducible events where at least two independent ESTs represent the same putative trans-splicing event. We found 15 ESTs representing five types of putative trans-splicing. However, all 15 cases were derived from human malignant tissues and could have resulted from genomic rearrangements. Our results provide support for a very rare but physiological occurrence of exon repetition, but suggest that apparent exon scrambling and trans-splicing result, respectively, from in vitro artifact and gene-level abnormalities. AVAILABILITY: Exon-Intron Database (EID) is available at http://www.meduohio.edu/bioinfo/eid. Programs are available at http://www.meduohio.edu/bioinfo/software.html. The Laboratory website is available at http://www.meduohio.edu/medicine/fedorov SUPPLEMENTARY INFORMATION: Supplementary file is available at http://www.meduohio.edu/bioinfo/software.html.

Algorithms↗

The innovation triad: an EvoDevo agenda.

This article introduces a special issue on evolutionary innovation and morphological novelty, two interrelated themes that have received a remarkable increase of attention over the past few years. We begin with a discussion of the question of whether innovation and novelty represent distinct evolutionary problems that require a distinct conceptualization. We argue that the mechanisms of innovation and their phenotypic results--novelty--can only be properly addressed if they are distinguished from the standard evolutionary themes of variation and adaptation, and we present arguments for making such a distinction. We propose that origination, the first formation of biological structures, is another distinct problem of morphological evolution, and that together with innovation and novelty it constitutes a conceptual complex we call the innovation triad. We define a problem agenda of the triad, which separates the analysis of the initiating conditions from the mechanistic realization of innovation, and we discuss the theoretical problems that arise from treating innovation as distinct from variation. Further, we categorize the empirical approaches that address themes of the innovation triad in recognizing four major strands of research: the morphology and systematics program, the gene regulation program, the epigenetic program, and the theoretical biology program. We provide examples of each program, giving priority to contributions in the present issue. In conclusion, we observe that the innovation triad is one of the defining topics of EvoDevo research and may represent its most pertinent contribution to evolutionary theory. We point out that an inclusion of developmental systems properties into evolutionary theory represents a shift of explanatory emphasis from the external factors of natural selection to the internal dynamics of developmental systems, complementing adaptation with emergence, and contingency with inherency.

Adaptation, Physiological↗

Methodologies for conservation assessments of the genetic biodiversity of aquatic macro-organisms.

International organizations and biodiversity scientists recognize three levels of biodiversity: genetic, species, and ecosystem. However, most studies with the goal of assessing biodiversity collect data at only a single level--that of the species. Even when multiple levels of biodiversity are considered, usually only ecosystem diversity is also evaluated. Genetic diversity is virtually never considered. Yet, genetic diversity is essential for the maintenance of populations and species over ecological and evolutionary time periods. Moreover, because components of genetic diversity are independent of either species or ecosystem diversity, genetic diversity can provide a unique measure by which to assess the value of regions for conservation. Regions can be valuable for conservation of their genetic resources regardless of their levels of species or ecosystem uniqueness or diversity. In general, the same methods and statistical programs that are used to answer questions about population genetics and phylogenetics are applicable to conservation genetics. Thus, numerous genetic techniques, laboratory methods, and statistical programs are available for assessing regional levels of genetic diversity for conservation considerations. Here, we provide the rationale, techniques available, field and laboratory protocols, and statistical programs that can be used to estimate the magnitude and type of genetic diversity in regions. We also provide information on how to obtain commonly utilized statistical programs and the type of analyses that they include. The guide that we present here can be used to conduct investigations of the genetic diversity of regions under consideration for conservation of their natural resources.

Animals↗

Racial admixture and its impact on BMI and blood pressure in African and Mexican Americans.

Admixed populations such as African Americans and Hispanic Americans present both challenges and opportunities in genetic epidemiologic research. Because of variation in admixture levels among individuals, case-control association studies may be subject to stratification bias. On the other hand, admixed populations also present special opportunities both for examining the role of genetic and environmental factors for observed racial/ethnic differences, and for possibly mapping alleles that contribute to such differences. Here we examined the distribution and relationship of individual admixture (IA) estimates with BMI and three measures of blood pressure in two admixed populations in the NHLBI Family Blood Pressure Program (FBPP): African Americans and Mexican Americans. For the African Americans, we observed modest but significant differences in average African IA among four recruitment sites. We observed a slight excess of African IA among hypertensives compared to normotensives, and a positive (non-significant) regression of African IA on blood pressure in untreated participants. Within Mexican Americans, we found no difference in average IA between hypertensives and normotensives, but a positive (marginally significant) regression of African IA on diastolic blood pressure. We also observed a significant positive regression of Caucasian IA (and negative regression of Native American IA) on BMI. Our results are suggestive of genetic differences between Africans and non-Africans that influence blood pressure, but such effects are likely to be modest compared to environmental ones. Excess obesity among Native Americans compared to whites is not consistent with a simple genetic explanation.

Adult↗

The use of chemiluminescence and the ELISA spot assay to identify and enumerate rare immunoglobulin switch variants.

The use of chemiluminescence and the ELISA spot assay for identifying rare immunoglobulin switch variants is described. The technique utilizes nitrocellulose membranes and allows rapid screening of a large number of cells. The number of spots can be recorded either manually or automatically by using a commercially available colony counting program. This modification of the ELISA spot assay makes it less labor intensive and time consuming and can be adapted for the search for rare cells secreting small amounts of Ig or other macromolecules.

Animals↗

4CMenB vaccine coverage of invasive serogroup B meningococci collected in Belgium between 2016 and 2022.

Neisseria meningitidis infections can cause life-threatening meningitis and septicemia. In Europe, serogroup B (MenB) is the leading cause of invasive meningococcal disease (IMD), particularly in young children. Genomic surveillance of circulating MenB strains through whole genome sequencing (WGS) provides a powerful tool to assess the potential impact of vaccination strategies, including the 4CMenB vaccine, which is available for infants from 2 months of age. Here, we present a retrospective WGS-based analysis of clinical MenB IMD cases (n = 311) recovered in Belgium from 2016 to 2022 by the Belgian National Reference Center. High-quality WGS data were obtained for 281 of these strains, demonstrating high genetic diversity of the antigen targets included in the 4-component meningococcal serogroup B vaccine 4CMenB (fHbp, PorA, NHBA and NadA) and at the 4CMenB Antigen Sequence Types (BAST) level. Novel antigen combinations, not yet assigned a BAST ID, were detected in 23.5% of isolates. Vaccine coverage was predicted using the Genetic Meningococcal Antigen Typing System (gMATS) and the Meningococcal Deduced Vaccine Antigen Reactivity (MenDeVAR) index. Of the 281 strains, 79.5% (lower limit-upper limit: 68.0-91.5%) were predicted to be covered by the vaccine by gMATS, and 80.7% (lower limit-upper limit: 66.5-95.4%) by MenDeVAR. No evidence of variation in vaccine coverage was found throughout the study period nor between different age groups, demonstrating the broad applicability of 4CMenB. This study highlights the benefits of a pathogen surveillance program and the need for experimental characterization of continuously evolving antigenic subvariants of Neisseria meningitidis.

Humans↗

An inclusion analysis for studying HL-A specificities.

INCLAN (Inclusion analysis) is a computer program which provides a systematic search for the subtypic variants of a given serological specificity. This routine was found especially useful for the HL-A serology whose complexity often needs automatic displays. A detailed description of its structure is presented in this note.

Computers↗

Determination of the complete nucleotide sequence and haplotypes in the D-loop region of the mitochondrial genome in the oriental white stork, Ciconia boyciana.

The complete nucleotide sequence of the mitochondrial genome of the Oriental white stork, Ciconia boyciana, has been determined from captive storks by a novel method incorporating Long PCR and shotgun sequencing. 13 protein-coding genes, two ribosomal RNA genes and 22 transfer RNA genes were identified as in other vertebrate mitochondrial genomes. The position and direction of the NADH6 and tRNA-Glu genes were the same as previously reported for avian mitochondrial genomes. A 71 bp direct repeat and long CAAA repeat sequences were found at the 3' end of the D-loop region, together with SCB-1, SCB-2, SCB-3, and three TAS sequences. Direct sequencing of the PCR fragments in the D-loop region in 26 captive Oriental white storks originating from Japan, China, and Russia revealed nucleotide differences at 18 sites along 1,248 bp, and a total of nine haplotypes have been identified. It was found that one pair of individuals in the Japanese captive breeding program were of the same haplotype, suggesting that they were caught from the same nest. The pair has since been dissolved in consideration of the possibility of inbreeding depression.

Animals↗

Twenty-years of experiences in external quality assurance in Korea.

The Korean External Quality Assurance Scheme (KEQAS) was set up by a voluntary organization, the Korean Society of Quality Control in Clinical Pathology (KSQC) in 1976. The KSQC was reorganized as the Korean Association of Quality Assurance for Clinical Laboratories (KAQACL) in 1991. The KAQACL is a government authorized organization. With the growing popularity of the KEQAS, its coverage has expanded to include ten disciplines, and the number of participants has grown to 470 clinical laboratories by the end of 1998. The ten programs are: clinical chemistry, clinical microbiology, diagnostic hematology, diagnostic immunology. blood bank, urinalysis, immunoassay, TDM (therapeutic drug monitoring), inborn errors of metabolism and diagnostic genetics. KAQACL membership accreditation is based on the QAP return rate, of which the minimum criterion for acceptability is 50%. Membership in KAQACL is highly regarded by the Inspection and Accreditation Program of the Korean Hospital Association and is an essential requirement for outreach services of commercial laboratories. While monitoring the quality of laboratory performances during the last two decades, the KEQAS has provided information on reliability of laboratory performances regarding methods, manufacturers and laboratory groups. The inter-laboratory coefficient variations (CVs) and the variance index score (VIS) have gradually decreased over the years, particularly during the 1990s. The participants who achieved good performances (less than 100 VIS) in clinical chemistry tests have gradually increased in number up to 83.2% of all participants.

Accreditation↗

Chemical mutagenesis testing in Drosophila: I. Comparison of positive and negative control data for sex-linked recessive lethal mutations and reciprocal translocations in three laboratories.

As part of the validation phase of the Drosophila melanogaster segment of the National Toxicology Program, a comparison has been made of positive and negative controls for sex-linked recessive lethal mutations and reciprocal translocations from three laboratories. This comparison involves approximately 700,000 spontaneous recessive lethal mutation tests, 70,000 spontaneous translocation tests, and screens for genetic damage induced by N-nitrosodimethylamine and beta-propiolactone. Spontaneous frequencies for lethal mutations and translocations were homogeneous in the laboratories regardless of solvent or broods sampled. Inhomogeneity was observed in induced frequencies among laboratories, but the variation was no greater than that found within a laboratory.

Animals↗

Determination of melting temperature for variant detection using dHPLC: a comparison between an empirical approach and DNA melting prediction software.

Detection of DNA sequence variants by the use of denaturing high-performance liquid chromatography (dHPLC) is a relatively new method (Underhill et al., 1997) and has distinct advantages over other methods such as single-strand conformation polymorphism (SSCP), direct sequencing, and DNA chip hybridization. The dHPLC-based single-nucleotide polymorphism (SNP) screening relies on different DNA thermodynamic properties between perfectly matched base pairs in homoduplex molecules and single base-pair mismatches in heteroduplex DNAs. Separation of the two forms of duplex DNAs by dHPLC is based on ionic forces between the negatively charged DNA and the hydrophobic stationary phase, which consists of C(18) chains on PSDVB (polystyrene-divinylbenzene) beads coated with a positively charged ion-pairing agent (TEAA, triethylammonium acetate). Removal of the DNA from the TEAA-coated beads is dependent upon a mobile organic phase, in the form of a linear acetonitrile gradient. The major factor that influences the success of dHPLC to detect sequence variation is the thermal stability of the duplex DNA, which is determined by the melting temperature (TM(50)), where 50% of the DNA strand is single stranded and 50% is double stranded. The TM(50) predicts the best probability of detecting a single base-pair change based on the altered thermodynamics it imparts to the DNA duplex. Generally, there are two ways to determine this melting temperature, either empirically or with the aid of predictive DNA melting analysis software. Such programs include the DNAMelt program located on the Stanford University DNA Sequencing and Technology Center website, MeltCalc (Schutz and von Ahsen 1999), and WAVEMAKER, the proprietary melting analysis software provided with the Transgenomic WAVE dHPLC system. The goal of the current study was to determine whether currently available predictive DNA melting programs could be used to increase efficiency and throughput of SNP detection. A wide range of amplicons, differing in both size and GC composition, were selected for analysis to simulate the broad spectrum of PCR products that may be encountered during a large-scale dHPLC screening project.

Chromatography, High Pressure Liquid↗

Development of rheumatoid arthritis is not associated with two polymorphisms in the Crohn's disease gene CARD15.

INTRODUCTION: It has been proposed that genetic susceptibility loci for rheumatoid arthritis (RA) may be shared with other autoimmune/inflammatory diseases. Recently, common variation in the CARD15 (NOD2) gene on chromosome 16q12 has been associated with Crohn's disease (CD) in several independent populations. CARD15 is an excellent functional and positional candidate gene for RA. METHODS: Genomic DNA was obtained from 392 RA cases and 471 ethnically matched healthy controls. All samples were genotyped for two polymorphisms in CARD15, 1007fs and R702W, using 5' nuclease reporter assays. Allele frequencies were compared between cases and controls using the chi(2) test. Estimated haplotype frequencies across the two mutations were determined using the EH program. RESULTS: The allele frequency of the 1007fs variant in RA cases was 1.8% compared with 1.6% in normal controls (not significant). The frequency of the R702W variant was 4.0% in both cases and controls. Haplotypes carrying either of the two mutations accounted for 5.6% of possible haplotypes. A haplotype carrying both mutations was rare, with estimated frequency <0.01%. This study provided high power to detect an association of similar magnitude to that in Crohn's disease. These data therefore exclude the possibility that the contribution of these mutations to RA is comparable to that seen in CD. CONCLUSION: Within defined statistical parameters, we excluded a role for the CARD15 1007fs and R702W variants in RA susceptibility. These data do not preclude a role for other polymorphisms in the CARD15 gene in RA susceptibility. Results from other autoimmune and inflammatory diseases will reveal whether the CARD15 gene is in fact a common autoimmune susceptibility locus.

Arthritis, Rheumatoid↗

Use of the sensitive/less-sensitive (detuned) EIA strategy for targeting genetic analysis of HIV-1 to recently infected blood donors.

OBJECTIVE: To corroborate the validity of the recently developed sensitive/less sensitive (S/LS) dual enzyme immunoassay (EIA) strategy for the detection of recently infected individuals and to genetically analyze recently transmitted strains of HIV-1 in a US blood donor population. DESIGN: The S/LS EIA strategy was used to identify 33 recently infected subjects among 281 enrolled HIV-1 seropositive blood donors (from a total of 410 HIV-1 infected subjects identified from 5 230 463 blood donations screened by participating US blood centers in 1995-1996). METHODS: We analysed three host response and viral characteristics were associated with recent HIV-1 infection: rapidly increasing EIA optical density (OD) values, genetically homogeneous env gene quasispecies, and putative non-syncytium inducing env V3 loop sequences. The drug resistance genotypes of the recently transmitted strains were determined by DNA sequencing. RESULTS: Increasing EIA OD values, clonal HIV-1 quasispecies and V3 loop sequences with inferred NSI phenotypes were generally detected in LS EIA non-reactive samples. Thirty-two subtype B and one CRF02_AG recombinant HIV-1 were detected. Genetic evidence for drug resistance to zidovudine (K70R) and non-nucleoside analog reverse transcriptase inhibitors (V108I) was detected in one strain each, and three other strains showed the presence of accessory protease inhibitor resistance mutations. CONCLUSIONS: Immunologic and virologic results further substantiate the validity of the S/LS EIA strategy for the detection of recent infections and illustrate its use for targeting molecular and epidemiological investigations to incident cases identified from large cross-sectional screening programs, rather than the more costly and logistically difficult longitudinal studies.

AIDS Serodiagnosis↗

Changes in health-related behaviours following BRCA 1/2 genetic testing: the case of hormone replacement therapy.

OBJECTIVE: To determine hormone replacement therapy (HRT)use among women at high risk for breast cancer and ovarian cancer, before genetic testing for the cancer susceptibility genes BRCA1 and BRCA2, and 1 year following disclosure of the test results. METHODS: Participants were 209 French-Canadian women (from 67 high-risk families) who were tested for BRCA1/2 mutations as part of the multidisciplinary research program INHERIT BRCAs (INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility). Use of HRT was recorded at the first genetic counselling session and through a self-administered questionnaire 1 year after result disclosure. RESULTS: At the genetic counselling session, approximately 15% of women (31/209) reported using HRT, a proportion that is significantly lower than the 25% observed among similarly aged women from the general Quebec population (P < .001). Further analyses, based on the generalized estimating equations models, were carried out to evaluate variations in HRT use from the first genetic counselling session up to 1 year post-disclosure of BRCA1/2 test results. These analyses indicated a trend toward decreased HRT use among BRCA1/2 mutation carriers (P = .08). CONCLUSIONS: Women at high risk for breast cancer and ovarian cancer tend to avoid HRT when BRCA1/2 mutations are either suspected or confirmed. Further studies are needed to assess the actual risk of HRT use among women at high risk of breast cancer, and to develop clinical guidelines regarding its use in this population of women.

Adult↗

Molecular architecture of the neuromuscular junction.

The neuromuscular junction (NMJ) is a complex structure that serves to efficiently communicate the electrical impulse from the motor neuron to the skeletal muscle to signal contraction. Over the last 200 years, technological advances in microscopy allowed visualization of the existence of a gap between the motor neuron and skeletal muscle that necessitated the existence of a messenger, which proved to be acetylcholine. Ultrastructural analysis identified vesicles in the presynaptic nerve terminal, which provided a beautiful structural correlate for the quantal nature of neuromuscular transmission, and the imaging of synaptic folds on the muscle surface demonstrated that specializations of the underlying protein scaffold were required. Molecular analysis in the last 20 years has confirmed the preferential expression of synaptic proteins, which is guided by a precise developmental program and maintained by signals from nerve. Although often overlooked, the Schwann cell that caps the NMJ and the basal lamina is proving to be critical in maintenance of the junction. Genetic and autoimmune disorders are known that compromise neuromuscular transmission and provide further insights into the complexities of NMJ function as well as the subtle differences that exist among NMJ that may underlie the differential susceptibility of muscle groups to neuromuscular transmission diseases. In this review we summarize the synaptic physiology, architecture, and variations in synaptic structure among muscle types. The important roles of specific signaling pathways involved in NMJ development and acetylcholine receptor (AChR) clustering are reviewed. Finally, genetic and autoimmune disorders and their effects on NMJ architecture and neuromuscular transmission are examined.

Animals↗