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PubMed2003

Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever.

Dengue virus presents a growing threat to public health in the developing world. Four major serotypes of dengue virus have been characterized, and epidemiological evidence shows that dengue hemorrhagic fever (DHF), the more serious manifestation of the disease, occurs more frequently upon reinfection with a second serotype. We have studied dengue virus-specific T-cell responses in Thai children. During acute infection, few dengue-responsive CD8+ T cells were recovered; most of those present showed an activated phenotype and were undergoing programmed cell death. Many dengue-specific T cells were of low affinity for the infecting virus and showed higher affinity for other, probably previously encountered strains. Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T-cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.

Apoptosis↗

PubMed2006

Analysis of copy number variation in the normal human population within a region containing complex segmental duplications on 22q11 using high-resolution array-CGH.

A previously detected copy number polymorphism (Ep CNP) in patients affected with neuroectodermal tumors led us to investigate its frequency and length in the normal population. For this purpose, a program called Sequence Allocator was developed and applied for the construction of an array that consisted of unique and duplicated fragments, allowing the assessment of copy number variation within regions of segmental duplications. The average resolution of this array was 11 kb and we determined the size of the Ep CNP to be 290 kb. Analysis of normal controls identified 7.7 and 7.1% gains in peripheral blood and lymphoblastoid cell line (LCL) DNA, respectively, while deletions were found only in the LCL group (7.1%). This array platform allows the detection of DNA copy number variation within regions of pronounced genomic complexity, which constitutes an improvement over available technologies.

Cell Line↗

PubMed1995

Multistage selection for maximum economic return with an application to beef cattle breeding.

Methodology for selection index updating was developed to allow multistage selection. The program determines truncation points for each stage of selection that will maximize either profit or the ratio of aggregate economic gain to cost (R = delta H/C). Either maximum profit or R may be attained by reducing the cost of performance testing in later stages of a multistage program. In order to eliminate the need for multiple integration and assure convergence, a piecewise algorithm was developed. Examples of beef bull selection compared single-stage selection at 1 yr of age, two-stage selection at birth and 1 yr, two-stage selection at 205 d and 1 yr, and three-stage selection at birth, 205 d, and 1 yr. Selection based on three traits (birth weight, gain birth to 205 d, and gain 205 to 365 d) was compared with selection based on four traits (the above three plus ultrasound fat depth) and selection based on five traits (the above four plus feed:gain ratio). Five scenarios were used that allowed variation in proportion of candidates selected for breeding, number of progeny per selected bull, and proportion of profit returned to the nucleus herd. General conclusions based on the examples were 1) multistage selection reduced aggregate economic gain relative to that attained by single-stage selection, 2) inclusion of feed conversion in the index of traits resulted in reduced profit and aggregate economic gain, 3) measurement of feed conversion could be justified when selected bulls produced a large number of progeny, and 4) three-trait selection produced greater profit in all five scenarios than did four- or five-trait selection. Use of the selection updating program described here provides a new source of information that can be used in developing economically sound performance testing and selection programs.

Aging↗

PubMed2000

Transportation of maternal serum specimens for screening for chromosomal aneuploidies: effect of seasonal variations, distance, and freezing on the stability of the biological markers.

OBJECTIVES: We studied the stability of maternal serum markers for screening for Down syndrome [alpha-fetoprotein (AFP), unconjugated estriol (uE3), total human chorionic gonadotropin (hCG), and free beta-human chorionic gonadotropin] following transportation. DESIGN AND METHODS: For each gestational week between 14 and 18 weeks, we collected about 50 samples for each possible combination of three potential sources of variation during transportation: season (winter/summer), sample frozen/fresh (prior to analysis) and origin (local or referred in) for a total of 1845 specimens. Commercial assays were used (IMx, Abbott for AFP and total hCG; AutoDelfia and Wallac for free beta-hCG and AFP; and radioimmunoassay Ortho-Clinical Diagnostics, for uE3). RESULTS: Results of both total and free beta-hCG were significantly higher when samples were collected during summer and when they were sent to the laboratory from extramural blood drawing sites (multifactorial ANOVA, p < 0. 007). CONCLUSION: We conclude that both total and free beta-hCG can be adversely affected during transportation. The resulting higher concentrations of these markers may increase the false positive rate of prenatal screening programs for aneuploidies.

Biomarkers↗

PubMed2004

Haplotype block partitioning and tag SNP selection using genotype data and their applications to association studies.

Recent studies have revealed that linkage disequilibrium (LD) patterns vary across the human genome with some regions of high LD interspersed by regions of low LD. A small fraction of SNPs (tag SNPs) is sufficient to capture most of the haplotype structure of the human genome. In this paper, we develop a method to partition haplotypes into blocks and to identify tag SNPs based on genotype data by combining a dynamic programming algorithm for haplotype block partitioning and tag SNP selection based on haplotype data with a variation of the expectation maximization (EM) algorithm for haplotype inference. We assess the effects of using either haplotype or genotype data in haplotype block identification and tag SNP selection as a function of several factors, including sample size, density or number of SNPs studied, allele frequencies, fraction of missing data, and genotyping error rate, using extensive simulations. We find that a modest number of haplotype or genotype samples will result in consistent block partitions and tag SNP selection. The power of association studies based on tag SNPs using genotype data is similar to that using haplotype data.

Algorithms↗

PubMed2004

Statistical evaluation of local alignment features predicting allergenicity using supervised classification algorithms.

BACKGROUND: Recently, two promising alignment-based features predicting food allergenicity using the k nearest neighbor (kNN) classifier were reported. These features are the alignment score and alignment length of the best local alignment obtained in a database of known allergen sequences. METHODS: In the work reported here a much more comprehensive statistical evaluation of the potential of these features was performed, this time for the prediction of allergenicity in general. The evaluation consisted of the following four key components. (1) A new high quality database consisting of 318 carefully selected, non-redundant allergens and 1,007 sequences carefully selected to be non-allergens. (2) Three different supervised algorithms: the kNN classifier, the Bayesian linear Gaussian classifier, and the Bayesian quadratic Gaussian classifier. (3) A large set of local alignment procedures defined using the FASTA3 alignment program by means of a wide range of different parameter settings. (4) Novel performance curves, alternative to conventional receiver-operating characteristic curves, to display not only average behaviors but also statistical variations due to small data sets. RESULTS: The linear Gaussian classifier proved most useful among the tested supervised machine learning algorithms, closely followed by the quadratic Gaussian equivalent and kNN. The overall best classification results were obtained with a novel feature vector consisting of the combined alignment scores derived from local alignment procedures using different substitution matrices. CONCLUSIONS: The models reported here should be useful as a part of an integrated assessment scheme for potential protein allergenicity and for future comparisons with alternative bioinformatic approaches.

Algorithms↗

PubMed2002

DNA fngerprinting of Mycobacterium tuberculosis: lessons learned and implications for the future.

DNA fingerprinting of Mycobacterium tuberculosis--a relatively new laboratory technique--offers promise as a powerful aid in the prevention and control of tuberculosis (TB). Established in 1996 by the Centers for Disease Control and Prevention (CDC), the National Tuberculosis Genotyping and Surveillance Network was a 5-year prospective, population-based study of DNA fingerprinting conducted from 1996 to 2000. The data from this study suggest multiple molecular epidemiologic and program management uses for DNA fingerprinting in TB public health practice. From these data, we also gain a clearer understanding of the overall diversity of M. tuberculosis strains as well as the presence of endemic strains in the United States. We summarize the key findings and the impact that DNA fingerprinting may have on future approaches to TB control. Although challenges and limitations to the use of DNA fingerprinting exist, the widespread implementation of the technique into routine TB prevention and control practices appears scientifically justified.

Centers for Disease Control and Prevention, U.S.↗

PubMed2026

QTLs associated with phenolic acid accumulation and antioxidant activity in tropical maize.

Maize represents a significant source of phytochemicals, with phenolic acids standing out as one of the most extensively studied functional compound families. These bioactive molecules have gained attention for their potent antioxidant properties and potential contributions to human health improvement. To evaluate the segregation of phenolic compounds in maize and its genetic basis, this study was conducted to identify quantitative trait loci (QTLs) associated with major phenolic compounds and their antioxidant capacity. The mapping population comprised 100 recombinant inbred lines (RILs) derived from the cross between P84 and Kilima. Twelve traits were analyzed: free and cell wall-bound antioxidant capacity, total phenolic content, and contents of p-coumaric acid, ferulic acid, three isomers of di-ferulic acid, and three isomers of tri-ferulic acid. The RILs exhibited substantial diversity in phenolic compound profiles. In total, 19 QTLs were identified for nine traits, with the number of associated regions ranging from 1 to 5 and explaining between 2.95% and 37.48% of the phenotypic variation. This research provides substantial evidence for the co-localization of major QTLs for principal phenolic acids in maize with genomic regions harboring genes putatively related to their biosynthesis and biotic resistance. This is the first study to report QTLs associated with triferulic acids in maize. The identified regions co-localizing with biotic stress resistance genes represent targets for marker-assisted selection toward the improvement of phenolic acid accumulation in maize breeding programs.

QTLs↗

PubMed1986

A major gene for primary hypoalphalipoproteinemia.

Sixteen kindreds were ascertained through probands clinically determined to have primary hypoalphalipoproteinemia, characterized by bottom decile high-density lipoprotein cholesterol (HDL-c), but otherwise normolipidemic. Age- and sex-adjusted, standardized HDL-c levels on 64 individuals in 14 nuclear families in which the proband was a parent were analyzed using the unified mixed model of segregation analysis as implemented in the computer program POINTER. The analysis proceeded by using the likelihood of offspring conditional on the parental phenotypes (conditional likelihood), which appears to overcome the limitation of possible heterogeneity in the selection criteria and provides an appropriate correction for the ascertainment. In these families, the multifactorial contribution to the phenotype appears to be small and significant only in the offspring generation. Although it was not possible to resolve the dominance pattern at the major locus since none of a recessive, additive, or dominant hypothesis could be firmly rejected, these families provided clear evidence for a major gene. Genetic heterogeneity is still a possibility, even within "primary" hypoalphalipoproteinemia.

Cholesterol, HDL↗

PubMedDate not supplied

Molecular genetic and morphological analyses of the African wild dog (Lycaon pictus).

African wild dog populations have declined precipitously during the last 100 years in eastern Africa. The possible causes of this decline include a reduction in prey abundance and habitat; disease; and loss of genetic variability accompanied by inbreeding depression. We examined the levels of genetic variability and distinctiveness among populations of African wild dogs using mitochondrial DNA (mtDNA) restriction site and sequence analyses and multivariate analysis of cranial and dental measurements. Our results indicate that the genetic variability of eastern African wild dog populations is comparable to that of southern Africa and similar to levels of variability found in other large canids. Southern and eastern populations of wild dogs show about 1% divergence in mtDNA sequence and form two monophyletic assemblages containing three mtDNA genotypes each. No genotypes are shared between the two regions. With one exception, all wild dogs examined from zoos had southern African genotypes. Morphological analysis supports the distinction of eastern and southern African wild dog populations, and we suggest they should be considered separate subspecies. An eastern African wild dog breeding program should be initiated to ensure preservation of the eastern African form and to slow the loss of genetic variability that, while not yet apparent, will inevitably occur if wild populations continue to decline. Finally, we examined the phylogenetic relationships of wild dogs to other wolf-like canids through analysis of 736 base pairs (bp) of cytochrome b sequence and showed wild dogs to belong to a phylogenetically distinct lineage of the wolf-like canids.

Africa, Eastern↗

PubMed2004

Evaluating the performance of likelihood methods for detecting population structure and migration.

A plethora of statistical models have recently been developed to estimate components of population genetic history. Very few of these methods, however, have been adequately evaluated for their performance in accurately estimating population genetic parameters of interest. In this paper, we continue a research program of evaluation of population genetic methods through computer simulation. Specifically, we examine the software MIGRATEE-N 1.6.8 and test the accuracy of this software to estimate genetic diversity (Theta), migration rates, and confidence intervals. We simulated nucleotide sequence data under a neutral coalescent model with lengths of 500 bp and 1000 bp, and with three different per site Theta values of (0.00025, 0.0025, 0.025) crossed with four different migration rates (0.0000025, 0.025, 0.25, 2.5) to construct 1000 evolutionary trees per-combination per-sequence-length. We found that while MIGRATEE-N 1.6.8 performs reasonably well in estimating genetic diversity (Theta), it does poorly at estimating migration rates and the confidence intervals associated with them. We recommend researchers use this software with caution under conditions similar to those used in this evaluation.

Computer Simulation↗

PubMed1990

Telomere interactions may condition the programming of antigen expression in Trypanosoma brucei.

The AnTat 1.1 antigen type typically occurs late in a chronic infection by the EATRO 1125 stock of Trypanosoma brucei. The AnTat 1.1 gene, which is located 24 kb from a chromosome end, seems exclusively expressed by acting as a donor in gene conversion events targeted to the telomeric expression site. We report that this gene is sufficiently provided with the homology blocks required for recombination with the expression site, and is not interrupted by stop codons up to the 3' block of homology. A possible reason for its low probability of activation is an inverse orientation with respect to the proximal chromosome end, since, if correctly positioned, it is readily expressed at an early stage of infection, following gene conversion. This suggests that interactions between chromosome ends may precede and favour the rearrangements leading to antigenic variation.

Animals↗

PubMed2007

A study of how socioeconomic status moderates the relationship between SNPs encompassing BDNF and ADHD symptom counts in ADHD families.

Recent animal research suggests that brain-derived neurotrophic factor (BDNF), may mediate response to different environmental stimuli. In this paper, we evaluated the possible role of BDNF as a moderator of attention deficit hyperactivity disorder (ADHD) in the context of different socioeconomic classes. We genotyped ten single nucleotide polymorphisms (SNPs) in and around BDNF in 229 families and evaluate whether there are SNP-by-socioeconomic status (SES) interactions for attention deficit hyperactivity. We developed three quantitative phenotypes for ADHD from nine inattentive and nine hyperactive-impulsive symptoms that were used in SNP-by-SES interaction analyses using a new methodology implemented in the computer program PBAT. Findings were adjusted for multiple comparisons using the false discovery rate. We found multiple significant SNP-by-SES interactions using the inattentive symptom count. This study suggests that different SES classes may modify the effect of the functional variant(s) in and around BDNF to have an impact on the number of ADHD symptom counts that are observed. The two exons within BDNF represent potential functional variants that may be causing the observed associations.

Attention Deficit Disorder with Hyperactivity↗

PubMed2007

Optimisation of contribution of candidate parents to maximise genetic gain and restricting inbreeding using semidefinite programming.

An approach for optimising genetic contributions of candidates to control inbreeding in the offspring generation using semidefinite programming (SDP) was proposed. Formulations were done for maximising genetic gain while restricting inbreeding to a preset value and for minimising inbreeding without regard of gain. Adaptations to account for candidates with fixed contributions were also shown. Using small but traceable numerical examples, the SDP method was compared with an alternative based upon Lagrangian multipliers (RSRO). The SDP method always found the optimum solution that maximises genetic gain at any level of restriction imposed on inbreeding, unlike RSRO which failed to do so in several situations. For these situations, the expected gains from the solution obtained with RSRO were between 1.5-9% lower than those expected from the optimum solution found with SDP with assigned contributions varying widely. In conclusion SDP is a reliable and flexible method for solving contribution problems.

Animals↗

PubMed2001

Breeding for nutritional characteristics in cereals.

Extensive genetic variation within large species such as the major cereals can be confidently expected for any new trait of interest. This has now been extensively demonstrated for the nutrient content of cereal grains that is of interest under deficient conditions both to human nutritionists and to cereal agronomists. As cereals are eaten in large quantity by practically everyone, they are the ideal vehicles for changing the balance of nutrient intake of the whole human population. Doing so appears to be necessary as the World Health Organization has identified deficient micronutrient intake in well over half of all people globally, notably women and children. Of major concern are iron, zinc, selenium iodine, calcium and vitamin A-related carotenoids. Our results show that for any staple so far studied, the intake of iron, calcium and zinc from cereals can be doubled, and the content/intake of essential carotenoids can be increased by much greater factors. To prove to rigid scientific standards that greater intake results in greater absorption and measurable health benefits is quite difficult, but it is currently being pursued in various ways. This proof of bioavailability is all that impedes implementation in breeding programs.

Agriculture↗

PubMed2002

Microsatellite diversities and gene flow in the tsetse fly, Glossina morsitans s.l.

Tsetse flies occupy discontinuous habitats and gene flow among them needs to be investigated in anticipation of area-wide control programs. Genetic diversities were estimated at six microsatellite loci in seven Glossina morsitans submorsitans Newstead (Diptera: Glossinidae) populations and five microsatellite loci in six G. m. morsitans Westwood populations. Nei's unbiased diversities were 0.808 and 76 alleles in G. m. submorsitans and 0.727 and 55 alleles in G. m. morsitans. Diversities were less in three laboratory cultures. Matings were random within populations. Populations were highly differentiated genetically. Populations were strongly subdivided, as indicated by fixation indices (F(ST)) of 0.18 in G. m. morsitans and 0.17 in G. m. submorsitans. 35% of the genetic variance in G. m. submorsitans was attributed to differences between populations from The Gambia and Ethiopia. All available genetic evidence suggests that genetic drift is much greater than gene flow among G. morsitans s.l. populations.

Alleles↗

PubMed2004

Stabilizing selection on genomic divergence in a wild fish population.

Conservation programs use breeding protocols to increase genomic divergence (by mating genetically dissimilar individuals) in an attempt to circumvent population declines resulting from inbreeding depression. However, disruption of either beneficial gene complexes or local genetic adaptations can lead to outbreeding depression, and thus, there should be a reduction in fitness of individuals at either end of the genomic divergence continuum. Although such simultaneous inbreeding and outbreeding depression has been observed in plant populations, it rarely has been demonstrated in animal populations. Here, I use both genetic and phenotypic measures to show that there is stabilizing selection on genomic divergence in a wild population of bluegill sunfish (Lepomis macrochirus). I also show that breeding individuals that exercise mate choice produce offspring that are closer to the optimal level of genomic divergence than random mating alone would predict.

Animals↗

PubMed2006

Reduced splicing efficiency induced by synonymous substitutions may generate a substrate for natural selection of new splicing isoforms: the case of CFTR exon 12.

Alternative splicing has been associated with increased evolutionary changes and with recent exon creation or loss. The addition of a new exon can be explained by its inclusion in only a fraction of the transcripts leaving the original form intact and giving to the new form the possibility to evolve independently but the exon loss phenomenon is less clear. To explore the mechanism that could be involved in CFTR exon 12 lower splicing efficiency in primates, we have analyzed the effect of multiple synonymous variations. Random patterns of synonymous variations were created in CFTR exon12 and the majority of them induced exon inclusion, suggesting a suboptimal splicing efficiency of the human gene. In addition, the effect of each single synonymous substitution on splicing is strongly dependent on the exonic context and does not correlate with available in silico exon splicing prediction programs. We propose that casual synonymous substitutions may lead to a reduced splicing efficiency that can result in a variable proportion of exon loss. If this phenomenon happens in in-frame exons and to an extent tolerated by the cells it can have an important evolutionary effect since it may generate a substrate for natural selection of new splicing isoforms.

Alternative Splicing↗