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PubMed2006

Genetic diversity of pneumococcal surface protein A of Streptococcus pneumoniae meningitis in German children.

Pneumococcal surface protein A (PspA) is a possible candidate for the development of a pneumococcal vaccine that has the potential to offer a broad range of protection. PspA genes of pneumococcal meningitis isolates (n=40) isolated as part of an ongoing population-based nation-wide surveillance program on invasive pneumococcal disease in children in Germany were analyzed to expand our knowledge on the distribution of PspA families of this important vaccine candidate in Germany. The serotype distribution of the strains was as follows: serotype 4 (n=3), 6B (5), 9V (2), 14 (8), 18C (6), 19F (5), 23F (6), and 7F (5). The pspA genes of these strains could be assigned to 2 families containing 20 pneumococcal strains each. Family I could be subdivided into 2 clades with 17 strains in clade 1 and 3 strains in clade 2, and family II could be subdivided into 3 subgroups (clades 3-5) containing 16, 3, and 1 strain, respectively. Pneumococcal serotypes were distributed evenly over all clades and families. Interestingly, the distribution of the PspA gene families in Germany was seen to differ slightly that found in other countries.

Adolescent↗

PubMed1972

Kinetic studies on the two common inherited forms of human erythrocyte adenylate kinase.

1. The kinetic properties of two genetic variants of human erythrocyte adenylate kinase were studied at limiting concentrations of both ADP and MgADP(-) in the forward direction and at limiting concentrations of both AMP and MgATP(2-) in the reverse direction. 2. Primary reciprocal plots rule out the possibility of a Ping Pong mechanism for both forms of the enzyme. 3. Analysis of the kinetic data by an appropriate computer program gave the following K(m) values for the type 1 enzyme: AMP, 0.33mm+/-0.1; MgATP(2-), 0.95mm+/-0.13; ADP, 0.12mm+/-0.03; MgADP(-), 0.22mm+/-0.04. Values for the type 2 enzyme were: AMP, 0.27mm+/-0.03; MgATP(2-), 0.40mm+/-0.05; ADP, 0.08mm+/-0.07; MgADP(-), 0.20mm+/-0.04. 4. Product inhibition studies were done by studying the reverse reaction. With ADP as product inhibitor competitive inhibition patterns were obtained with AMP and/or MgATP(2-) as variable substrate. Similar results were obtained for product inhibition by MgADP(-) with AMP as variable substrate. The results are consistent with a Rapid Equilibrium Random mechanism. 5. Secondary plots of slope versus product concentration were linear. The data were fitted to the appropriate equation and analysed by computer to give values for the product inhibition constants. 6. Differences between the values of certain kinetic constants for the two forms of the enzyme were observed.

Adenosine Diphosphate↗

PubMed2005

Silent hemoglobin variants and determination of HbA(1c) with the high-resolution program of the HPLC HA-8160 hemoglobin analyzer.

OBJECTIVES: Evaluation of HbA1c determination with an automated ion-exchange high-performance liquid chromatography (HPLC) method in patients with clinically silent hemoglobin (Hb) variants. DESIGN AND METHODS: HbA1c values were determined with the Arkray HA-8160 ion-exchange HPLC using the high-resolution, 4.2-min beta-thalassemia screening mode in patients with silent hemoglobin (Hb) variants, namely, Hb Graz, Hb Sherwood Forest, Hb O Padova, and HbD. RESULTS: All of these hemoglobin variants caused additional peaks in the chromatograms, without HbA1c results in patients with Hb Graz and Hb Sherwood Forest, and demonstrated extra peaks with HbA1c results that were clinically too low for patients with Hb O Padova and in the patient with HbD. CONCLUSIONS: The development of this automated HPLC method modification with high-resolution beta-thalassemia screening mode aids identification of interference due to some clinically silent Hb variants in HbA(1c) determination.

Chromatography, High Pressure Liquid↗

PubMed1995

Major gene with sex-specific effects influences fat mass in Mexican Americans.

Increased adiposity has repeatedly been identified as a major risk factor for a variety of chronic diseases. However, the question still remains whether the amount of adipose tissue itself is genetically mediated. To address this question, a segregation analysis, using maximum likelihood techniques as implemented in the computer program Pedigree Analysis Package (PAP), was performed on fat mass (kilograms of body fat) in a large sample of extended Mexican American families residing in San Antonio, TX. The only model not rejected was a Mendelian mixed model for fat mass, incorporating genotype x sex interaction. In males the major gene accounted for 37% of the total variance compared with 43% in females. In both sexes homozygous recessive individuals have a fat mass more than double that of individuals of the other two genotypes. It was possible to reject linkage of the anonymous major gene for fat mass with several candidate loci for obesity. However, tentative evidence of linkage was detected with markers on both chromosomes 2 and 11, thereby providing hypotheses for future testing.

Adolescent↗

PubMed2004

Genetic diversity and structure of urban populations of Pieris butterflies assessed using amplified fragment length polymorphism.

Conservation programs in urban ecosystems need to determine the genetic background in populations of urban dwellers. We examined the genetic diversity and structure of Pieris rapae and P. melete using AFLP markers, and compared them between species and between urban and rural environments. As a result: (i). in both species, there was no reduction in genetic diversity within urban populations by direct comparison of diversity measurements, although the analysis of molecular variance suggested significant reductions in the variance within seasonal subpopulations in urban populations; (ii). P. rapae retained greater genetic diversity within species and populations; (iii). populations of both species showed significant genetic differentiation, and P. melete was more strongly subdivided; (iv). in both species, geographically close populations did not cluster with one another in the upgma analysis; (v). there was no genetic isolation due to geographical distance in either species; (vi). the genetic composition of seasonal subpopulations differed in urban populations of both species, and the genetic distances among subpopulations were correlated with seasonal differences in P. rapae and with temporal differences in P. melete. These results indicate that the genetic diversity in urban populations of both species was reduced at times, but was maintained by dispersal from genetically differentiated populations. Differences in the ability and mode of dispersal in the two species may be reflected in the degree of population subdivision and patterns of seasonal change in the genetic composition.

Analysis of Variance↗

PubMed1984

Sex-related differences in depression. Familial evidence.

After a description of threshold models of familial transmission based on an underlying continuous liability distribution, family data from the NIMH-CRB Collaborative Psychobiology of Depression Program-Clinical are described. No sex differences are found for bipolar illness, whereas female relatives have an increased rate of primary unipolar illness when compared to male relatives. This effect persists when relatives are classified according to recurrence, current illness, onset within the last 10 years, and treatment. Moreover, a cohort effect is present in the data and indicates a sex ratio close to one in the young cohort (less than or equal to 25). We considered the transmission of illness from parent to offspring by using survival analysis to examine the proportion of ill brothers and sisters of probands according to the affection status of parents. A maternal effect is found, with the mother having a greater influence on the liability of offspring of either sex. This is at odds with the notion that males and females have identical liabilities, but females have a lower threshold reflecting acknowledgement of more symptoms, etc. However, the mean difference in liability between the sexes may be due to systematic biological/cultural differences, with parental transmission contributing to variation about their means.

Bipolar Disorder↗

PubMed2002

Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.

Rare germline mutations of macrophage scavenger receptor 1 (MSR1) gene were reported to be associated with prostate cancer risk in families with hereditary prostate cancer (HPC) and in patients with non-HPC (Xu et al. 2002). To further evaluate the role of MSR1 in prostate cancer susceptibility, at Johns Hopkins Hospital, we studied five common variants of MSR1 in 301 patients with non-HPC who underwent prostate cancer treatment and in 250 control subjects who participated in prostate cancer-screening programs and had normal digital rectal examination and PSA levels (<4 ng/ml). Significantly different allele frequencies between case subjects and control subjects were observed for each of the five variants (P value range.01-.04). Haplotype analyses provided consistent findings, with a significant difference in the haplotype frequencies from a global score test (P=.01). Because the haplotype that is associated with the increased risk for prostate cancer did not harbor any of the known rare mutations, it appears that the observed association of common variants and prostate cancer risk are independent of the effect of the known rare mutations. These results consistently suggest that MSR1 may play an important role in prostate carcinogenesis.

Case-Control Studies↗

PubMed1984

The Collaborative Lipid Research Clinics Program Family Study: detection of major genes influencing lipid levels by examination of heterogeneity of familial variances.

Age, sex-adjusted, and transformed lipid and lipoprotein data on over 1,200 white North American sibships in the Collaborative Lipid Research Clinics Family Study were analyzed for possible major genes causing high or low levels of these traits. The sibships were stratified on the basis of parents' trait values, and within-sibship variance in the high (or low) families was compared to that in the normal families via an F-test. The null hypothesis of multifactorial transmission was strongly rejected for low LDL, low total cholesterol, and high HDL families. An analysis of spouse-pair variance gave similar results. This may reflect the presence of dominant genes for hyperalpha- and hypobetalipoproteinemia. There was weaker evidence for single genes causing hyperbetalipoproteinemia. There was no evidence for major genes influencing triglyceride levels. Methodological issues with significant bearing on these results and those of other studies are discussed.

Biometry↗

PubMed2005

Biomarker metabolites capturing the metabolite variance present in a rice plant developmental period.

BACKGROUND: This study analyzes metabolomic data from a rice tillering (branching) developmental profile to define a set of biomarker metabolites that reliably captures the metabolite variance of this plant developmental event, and which has potential as a basis for rapid comparative screening of metabolite profiles in relation to change in development, environment, or genotype. Changes in metabolism, and in metabolite profile, occur as a part of, and in response to, developmental events. These changes are influenced by the developmental program, as well as external factors impinging on it. Many samples are needed, however, to characterize quantitative aspects of developmental variation. A biomarker metabolite set could benefit screening of quantitative plant developmental variation by providing some of the advantages of both comprehensive metabolomic studies and focused studies of particular metabolites or pathways. RESULTS: An appropriate set of biomarker metabolites to represent the plant developmental period including the initiation and early growth of rice tillering (branching) was obtained by: (1) determining principal components of the comprehensive metabolomic profile, then (2) identifying clusters of metabolites representing variation in loading on the first three principal components, and finally (3) selecting individual metabolites from these clusters that were known to be common among diverse organisms. The resultant set of 21 biomarker metabolites was reliable (P = 0.001) in capturing 83% of the metabolite variation in development. Furthermore, a subset of the biomarker metabolites was successful (P = 0.05) in correctly predicting metabolite change in response to environment as determined in another rice metabolomics study. CONCLUSION: The ability to define a set of biomarker metabolites that reliably captures the metabolite variance of a plant developmental event was established. The biomarker metabolites are all commonly present in diverse organisms, so studies of their quantitative relationships can provide comparative information concerning metabolite profiles in relation to change in plant development, environment, or genotype.

Amino Acids↗

PubMed1986

Heredity and changes in hormones and metabolic rates with short-term training.

The purpose of this experiment was to assess the effects of a 22-day training program on resting metabolic rate (RMR), thermic effect of a meal (TEM), and associated hormonal changes. Six pairs of male monozygotic twins were submitted to a 22-day ergocycle exercise program designed to induce a deficit in energy balance of 4.2 MJ per day. RMR and TEM after a 4.2-MJ meal challenge were measured before and after training. Results indicated that RMR and TEM did not change significantly, although a large variation in response between twin pairs was observed. Moreover, training reduced (P less than 0.05) basal and postprandial insulin response, plasma thyroid hormones triiodothyronine (T3), thyroxine (T4), and FT4 (P less than 0.05). Absolute changes in RMR and TEM exhibited significant within-pair resemblance in response, with intraclass correlations reaching r = 0.81 (P less than 0.05) and r = 0.72 (P less than 0.05), respectively. Changes in T4 and FT4 also exhibited moderate within-pair resemblance (0.42 less than or equal to r less than or equal to 0.71). These results suggest that short-term exercise training does not modify RMR and TEM but can significantly decrease plasma levels of insulin and thyroid hormones. Moreover, the similarity of response within twin pairs suggests that heredity plays a role in determining RMR, TEM, and thyroid hormone adaptation to exercise training generating a negative energy balance.

Adolescent↗

PubMed2026

Integrating molecular subtypes, genomics and functional dependencies to identify context-specific therapeutic vulnerabilities in small cell lung cancer.

Small cell lung cancer is one of the most aggressive malignancies, characterized by rapid tumor growth, early metastatic spread and extremely poor survival. Although most patients initially respond to platinum-based chemotherapy, relapse is almost inevitable and treatment options at recurrence remain limited. The recent introduction of immune checkpoint inhibitors has provided only modest clinical benefit, largely due to the fact that these tumors are immunologically cold. These limitations highlight the urgent need to better understand the molecular features of small cell lung cancer in order to identify more effective therapeutic strategies. In this review, we summarize current knowledge of the molecular landscape of small cell lung cancer, with particular emphasis on transcriptome-based classifications that have identified four major molecular subtypes defined by distinct transcriptional regulators and gene expression programs. We discuss how these classifications have improved the biological understanding of the disease and stimulated efforts to develop subtype-specific therapeutic strategies. At the same time, we highlight important limitations of this framework, including the remarkable transcriptional plasticity of tumor cells, which allows dynamic transitions between subtypes and may contribute to therapeutic resistance. To address these challenges, we examine additional molecular features that may represent more stable vulnerabilities, including recurrent genomic alterations, such as the widespread loss of tumor suppressor genes or oncogene amplifications through extrachromosomal DNA. We also discuss emerging approaches aimed at identifying novel context-specific cancer dependencies, including genome-scale functional screens in vitro and in vivo and genetic restraint analyses. Finally, we consider the growing potential of liquid biopsy strategies, which exploit the high level of circulating tumor DNA in patients with this disease to detect clinically relevant genomic alterations and monitor tumor evolution. Overall, this review highlights both the opportunities and challenges associated with molecular stratification in small cell lung cancer. The integration of transcriptional classifications with genomic and functional approaches may help identify more robust therapeutic vulnerabilities and guide the development of more effective treatments for this highly aggressive disease.

Cancer vulnerabilities↗

PubMed2004

EST clustering error evaluation and correction.

MOTIVATION: The gene expression intensity information conveyed by (EST) Expressed Sequence Tag data can be used to infer important cDNA library properties, such as gene number and expression patterns. However, EST clustering errors, which often lead to greatly inflated estimates of obtained unique genes, have become a major obstacle in the analyses. The EST clustering error structure, the relationship between clustering error and clustering criteria, and possible error correction methods need to be systematically investigated. RESULTS: We identify and quantify two types of EST clustering error, namely, Type I and II in EST clustering using CAP3 assembling program. A Type I error occurs when ESTs from the same gene do not form a cluster whereas a Type II error occurs when ESTs from distinct genes are falsely clustered together. While the Type II error rate is <1.5% for both 5' and 3' EST clustering, the Type I error in the 5' EST case is approximately 10 times higher than the 3' EST case (30% versus 3%). An over-stringent identity rule, e.g., P >/= 95%, may even inflate the Type I error in both cases. We demonstrate that approximately 80% of the Type I error is due to insufficient overlap among sibling ESTs (ISO error) in 5' EST clustering. A novel statistical approach is proposed to correct ISO error to provide more accurate estimates of the true gene cluster profile.

Algorithms↗

PubMed2003

Bounds on the minimum number of recombination events in a sample history.

Recombination is an important evolutionary factor in many organisms, including humans, and understanding its effects is an important task facing geneticists. Detecting past recombination events is thus important; this article introduces statistics that give a lower bound on the number of recombination events in the history of a sample, on the basis of the patterns of variation in the sample DNA. Such lower bounds are appropriate, since many recombination events in the history are typically undetectable, so the true number of historical recombinations is unobtainable. The statistics can be calculated quickly by computer and improve upon the earlier bound of Hudson and Kaplan 1985. A method is developed to combine bounds on local regions in the data to produce more powerful improved bounds. The method is flexible to different models of recombination occurrence. The approach gives recombination event bounds between all pairs of sites, to help identify regions with more detectable recombinations, and these bounds can be viewed graphically. Under coalescent simulations, there is a substantial improvement over the earlier method (of up to a factor of 2) in the expected number of recombination events detected by one of the new minima, across a wide range of parameter values. The method is applied to data from a region within the lipoprotein lipase gene and the amount of detected recombination is substantially increased. Further, there is strong clustering of detected recombination events in an area near the center of the region. A program implementing these statistics, which was used for this article, is available from http://www.stats.ox.ac.uk/mathgen/programs.html.

Algorithms↗

PubMed2025

Development and validation of a high-density 'Amahysnp' genotyping array in grain amaranth (Amaranthus hypochondriacus).

BACKGROUND: Grain amaranth has recently gained global attention as a promising crop alternative to traditional cereals due to its nutritional value and adaptability to various growing conditions. Although gene banks conserve extensive collections of amaranth germplasm, the genomic and phenotypic characterization of these resources is limited, which hinders their full utilization in breeding programs. A major challenge is the lack of high-throughput genotyping assays essential for comprehensive genomic characterization and trait mapping. High-density SNP arrays have become standard tools for genome-wide analysis across multiple loci, enabling molecular breeding across a range of crop species. RESULTS: In this study, we developed a 64 K high-throughput SNP genotyping array named "AmahySNP", using Affymetrix® Axiom® technology. The array contains 64,069 high-density SNPs distributed across both genic (55.17%) and non-genic (44.83%) regions of the Amaranthus hypochondriacus genome. The genic region includes 8,879 genes, which consist of 4,830 single-copy genes and 4,049 multi-copy genes distributed across 16 scaffolds. These genes cover various functional regions, including exons (10.5%), introns (40.1%), 5'UTRs (1.6%), and 3'UTRs (2.9%), respectively. The AmahySNP array was effectively utilized for population structure analysis, genetic diversity studies, core development, and genome wide association studies (GWAS) in amaranth germplasm. A representative core set of 112 accessions was identified, which includes two released varieties (Annapurna and Suvarna) and 100 diverse accessions from 12 different regions, representing 12% of the total 917 accessions evaluated. Phylogenetic analysis revealed three major genetic clusters, independent of their geographical origins. GWAS conducted using 22,763 polymorphic SNPs from 540 genotypes identified 13 novel loci associated days to flowering (DTF) trait, seven of which were located within annotated genes. CONCLUSIONS: The AmahySNP 64 K SNP chip a valuable genomic tool for amaranth research and breeding with a strong potential to accelerate its genetic improvement. It enables high-throughput genotyping for a wide range of applications, including GWAS and other genomic studies, and will significantly advance the exploration of natural genetic variations. Ultimately, this resource will empower amaranth breeders to develop improved amaranth cultivars with enhanced crop yield, resilience, and nutritional quality, contributing to global food security and sustainable agriculture.

Amaranthus↗

PubMedDate not supplied

[Analysis of the structure of DNA cistrons coding proteins with known sequences].

Proceeding from the amino acid sequence of a number of proteins, with the help of a special computer program we have determined the frequency of pyrimidine isopliths of different length, the degree of clustering and the degree of asymmetry of complementary chains of the corresponding DNA cistrons, as well as the range of variation of these parametres which depends on the code degeneracy. The degree of asymmetry of the chains of DNA cistrons (H/L), calculated for 255 proteins of a known composition, may vary from 0.7 to 1.8. For 90% of these proteins the mean Py/Pu ratio in the coding chain of DNA is above 1. The conclusion has been made that the majority of amino acids contained in the proteins is coded for by purine triplets. It was found that the distribution of pyrimidine isopliths between DNA cistrons coding for different proteins is other than random and has a "DNA-like" character. The degree of clustering of pyrimidines (beta) in cistrons of different proteins may vary from 6.0 to 14.3. The cistrons of some proteins were found to contain long lyrimidine fragments with about 24 residues. A positive correlation (r2 = 0.74) was found to exist between the degree of clustering of pyrimidines and the degree of asymmetry of the chains corresponding to different proteins of DNA cistrons.

Amino Acid Sequence↗

PubMed1994

Predicted stem-loop structures and variation in nucleotide sequence of 3' noncoding regions among animal calicivirus genomes.

Caliciviruses are nonenveloped with a polyadenylated genome of approximately 7.6 kb and a single capsid protein. The "RNA Fold" computer program was used to analyze 3'-terminal noncoding sequences of five feline calicivirus (FCV), rabbit hemorrhagic disease virus (RHDV), and two San Miguel sea lion virus (SMSV) isolates. The FCV 3'-terminal sequences are 40-46 nucleotides in length and 72-91% similar. The FCV sequences were predicted to contain two possible duplex structures and one stem-loop structure with free energies of -2.1 to -18.2 kcal/mole. The RHDV genomic 3'-terminal RNA sequences are 54 nucleotides in length and share 49% sequence similarity to homologous regions of the FCV genome. The RHDV sequence was predicted to form two duplex structures in the 3'-terminal noncoding region with a single stem-loop structure, resembling that of FCV. In contrast, the SMSV 1 and 4 genomic 3'-terminal noncoding sequences were 185 and 182 nucleotides in length, respectively. Ten possible duplex structures were predicted with an average structural free energy of -35 kcal/mole. Sequence similarity between the two SMSV isolates was 75%. Furthermore, extensive cloverleaflike structures are predicted in the 3' noncoding region of the SMSV genome, in contrast to the predicted single stem-loop structures of FCV or RHDV.

Base Sequence↗

PubMedDate not supplied

TP53 polymorphisms and haplotypes in South Amerindians and neo-Brazilians.

To evaluate the genetic diversity of Brazilian populations and contribute to the knowledge of their evolutionary history this study investigated three TP53 polymorphisms (BstUI and MspI RFLPs in exon 4 and intron 6, respectively, and a 16 bp duplication in intron 3). The populations studied were: 114 Amerindians from five Brazilian Indian tribes (Gavião, Surui, Zoró, Wai-Wai and Xavante), 95 Euro-Brazilians and 70 Afro-Brazilians. The polymorphisms were all analysed using PCR amplifications. Gene frequencies and haplotype prevalences were calculated using the ARLEQUIN software. The genetic affinities of these groups with other world populations were estimated by the D(A) distance and neighbour joining method, using the NJBAFD computer program. Neo-Brazilians (immigrants from Europe and Africa) generally presented more variability than Amerindians, Afro-Brazilians being the most variable population. Among Amerindians, Gavião is the only group polymorphic for the three markers. Wai-Wai showed variability in BstUI and MspI RFLPs, while the other tribes were monomorphic for the 16 bp A1 and MspI A2 alleles. A rare haplotype (1-2-1) was verified among the Wai-Wai. This haplotype was previously described in a Chinese sample only, but with low frequency. Therefore, either this combination was lost in the other tribes by genetic drift, recombination, or other factor, or it occurs in the Wai-Wai and Chinese by independent events. The Gavião also presented a haplotype (2-1-1) not observed in the other Amerindians; but since it is present in Euro- and Afro-Brazilians. its occurrence there is probably due to interethnic admixture. The relationships of several world populations obtained using TP53 indicates that this marker is very efficient in clustering populations of the same ethnic group.

Brazil↗

PubMed1996

A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection.

Stimulation of the Fas (APO-1, CD95) receptor, which is present on a variety of cells, usually triggers a process of programmed cell death. Systemic injection of anti-Fas antibody into mice leads to fulminant liver destruction resulting from massive hepatocyte apoptosis, and to rapid death. Hepatocytes bear Fas but do not express Bcl-2, a protein that plays, in a number of conditions, a protective role against apoptosis. We have generated mice whose liver expresses Bcl-2 as the result of bcl-2 transgene placed under the control of the hepatocyte-specific alpha1-anti-trypsin gene promoter, but is otherwise not distinguishable from that of normal mice. These mice display a marked to almost total resistance to liver damage induced by anti-Fas antibody injection. This protective effect of Bcl-2 occurs in the absence of significant variations, in the stimulated livers, in the level of expression of other proteins also involved in resistance or sensitivity to apoptosis, namely Bcl-x, Bax, Bad, Bak, and p53. Mice with protected livers, however, die almost as rapidly as normal mice, which indicates that acute lethality results from stimulation of Fas receptors present on other target organs or cells.

Animals↗