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PubMed2004

Base-By-Base: single nucleotide-level analysis of whole viral genome alignments.

BACKGROUND: With ever increasing numbers of closely related virus genomes being sequenced, it has become desirable to be able to compare two genomes at a level more detailed than gene content because two strains of an organism may share the same set of predicted genes but still differ in their pathogenicity profiles. For example, detailed comparison of multiple isolates of the smallpox virus genome (each approximately 200 kb, with 200 genes) is not feasible without new bioinformatics tools. RESULTS: A software package, Base-By-Base, has been developed that provides visualization tools to enable researchers to 1) rapidly identify and correct alignment errors in large, multiple genome alignments; and 2) generate tabular and graphical output of differences between the genomes at the nucleotide level. Base-By-Base uses detailed annotation information about the aligned genomes and can list each predicted gene with nucleotide differences, display whether variations occur within promoter regions or coding regions and whether these changes result in amino acid substitutions. Base-By-Base can connect to our mySQL database (Virus Orthologous Clusters; VOCs) to retrieve detailed annotation information about the aligned genomes or use information from text files. CONCLUSION: Base-By-Base enables users to quickly and easily compare large viral genomes; it highlights small differences that may be responsible for important phenotypic differences such as virulence. It is available via the Internet using Java Web Start and runs on Macintosh, PC and Linux operating systems with the Java 1.4 virtual machine.

Base Composition↗
PubMed1998

Mutations in the glucokinase gene of the fetus result in reduced birth weight.

Low birth weight and fetal thinness have been associated with non-insulin dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and adulthood. It has been proposed that this association results from fetal programming in response to the intrauterine environment. An alternative explanation is that the same genetic influences alter both intrauterine growth and adult glucose tolerance. Fetal insulin secretion in response to maternal glycaemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. We hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene, could reduce fetal growth and birth weight in addition to causing hyperglycaemia after birth. In 58 offspring, where one parent has a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P=0.002). In 19 of 21 sibpairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P=0.0002). Maternal hyperglycaemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P=0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. We propose that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycaemia, by the maternal genotype. This observation suggests that variation in fetal growth could be used in the assessment of the role of genes which modify either insulin secretion or insulin action.

Adult↗
PubMed2006

Diversity of wild and cultivated pearl millet accessions (Pennisetum glaucum [L.] R. Br.) in Niger assessed by microsatellite markers.

Genetic diversity of crop species in sub-Sahelian Africa is still poorly documented. Among such crops, pearl millet is one of the most important staple species. In Niger, pearl millet covers more than 65% of the total cultivated area. Analyzing pearl millet genetic diversity, its origin and its dynamics is important for in situ and ex situ germplasm conservation and to increase knowledge useful for breeding programs. We developed new genetic markers and a high-throughput technique for the genetic analysis of pearl millet. Using 25 microsatellite markers, we analyzed genetic diversity in 46 wild and 421 cultivated accessions of pearl millet in Niger. We showed a significantly lower number of alleles and lower gene diversity in cultivated pearl millet accessions than in wild accessions. This result contrasts with a previous study using iso-enzyme markers showing similar genetic diversity between cultivated and wild pearl millet populations. We found a strong differentiation between the cultivated and wild groups in Niger. Analyses of introgressions between cultivated and wild accessions showed modest but statistically supported evidence of introgressions. Wild accessions in the central region of Niger showed introgressions of cultivated alleles. Accessions of cultivated pearl millet showed introgressions of wild alleles in the western, central, and eastern parts of Niger.

Alleles↗
PubMed1997

Influence of partitioning data by sex on genetic variance and covariance components for weaning weight in beef cattle.

Heterogeneity of (co)variance components (VC) by sex is currently accounted for in national genetic evaluations for Simmental cattle. Parameters used in the national evaluation program are estimated from data split into male, female, and steer populations. Analyzing only male data does not account for selection of females, and vice versa. To determine the impact of selection, a Monte Carlo simulation was used, and estimates of VC for weaning weight were obtained when data were partitioned by sex. Weaning weight data were simulated using homogeneous VC for males and females for random and selected populations. Restricted maximum likelihood estimates were obtained for direct and maternal genetic and permanent and temporary environmental variances and genetic covariance between direct and maternal effects by analyzing complete or split data. Estimates differed (P < .01) from input values in data from selected populations split by sex, yielding a spurious heterogeneity of VC for sex. The heterogeneity was reduced in models using genetic groups but not completely removed. Splitting data by sex also influenced VC estimates in data simulated with heterogeneous VC for males and females.

Aging↗
PubMed1999

Craniofacial variability in parents of children with cleft lip and cleft palate.

The purpose of this study was to determine whether there are variations in the craniofacial morphology between parents of children with non-syndromic cleft lip and palate and normal controls with no history of cleft in the families in a Saudi sample. Frontal skull radiographs were obtained from a study group consisting of 40 couples, who have a child with cleft deformity and control group of 32 males and 35 females, who have no history of clefts in the family. A total of 18 landmarks were digitized for each individual by a custom made computer program. T-test, logistic regression analysis were applied to the data. Significant findings were obtained for both males and females of the affected children. The males displayed wider nasal cavity and a narrower maxillary width with asymmetry of the face. Females showed smaller facial dimension as a whole, and asymmetry of the face.

Adult↗
PubMed2001

Influence of intercodon and base frequencies on codon usage in filarial parasites.

Base frequency, codon usage, and intercodon identity were analyzed in five filarial parasite species representing five Onchocercidae genera. Wucheria bancrofti, Brugia malayi, Onchocerca volvulus, Acanthocheilonema viteae, and Dirofilaria immitis gene sequences were downloaded from NCBI, and analysis was performed using locally designed computer programs and other freely available applications. A clear sequence bias was observed among the nematode species examined. At the nucleotide level, AT basepairs were present in gene sequences at higher frequencies than GC. In addition, codons ending in A or T were used proportionately more than those with G or C in the third-codon position. In addition, the amino acids used most often corresponded to codons ending in AT basepairs. Intercodon base proportion was biased in that A was found most often at N4, second only to T in certain specific cases. Since all of these sequence biases were observed in a relatively consistent fashion among all of the organisms studied, we conclude that sequence bias is a genetic characteristic, which is associated with multiple filarial genera.

Animals↗
PubMed1989

Heterogeneity evidence and linkage studies on Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth neuropathy type 1 (CMT1) is an autosomal dominant disorder originally localized to chromosome 1 by linkage to the Duffy blood group. Studies have since shown that the disorder may be heterogeneous, as not all families show this linkage. We tested genetic heterogeneity by the HOMOG computer program in 15 CMT1 pedigrees informative for Duffy. We detected no evidence for heterogeneity in this sample, but when we combined results with previously published lod scores, heterogeneity was statistically significant. Twelve of the 15 families studied did not show linkage to Duffy. We found six of these families to be informative for a chromosome 19 marker, apolipoprotein CII (ApoC2). Despite a previous report showing probable linkage of a non-Duffy-linked CMT1 pedigree to two chromosome 19 markers, we did not detect significant linkage of ApoC2 to CMT1 in these families.

Apolipoprotein C-II↗
PubMed1997

Minisatellite DNA markers reveal hybridisation between the endangered black robin and tomtit.

We have used multilocus minisatellite DNA profiling to assess genetic variation in the endangered and highly inbred black robins and the closely related tomtits. These species are restricted to wild populations on the Chatham Islands, off the east coast of New Zealand. DNA profiles revealed a remarkable degree of genetic similarity among black robins, as well as among the tomtits sampled, although the typical profiles of these two species were clearly distinct. The parentage of two putative hybrid chicks and one putative hybrid adult was established for a 'black robin' adult male and an adult tomtit female which were found nesting together. The 'black robin' male, despite being morphologically a typical black robin, was found to possess a number of minisatellite-containing restriction fragments not recorded from the black robin population (n = 103). These fragments were however detected in tomtits. Consequently, this bird appeared to be an F1 hybrid and his three offspring were F2 hybrids. Mitochondrial DNA sequencing of members of this family showed that the 'black robin' male had cytochrome b and 16S of black robin, rather than tomtit, haplotypes. This indicates that the black robin adult male hybrid was the result of a black robin female mating with a tomtit male. These findings are particularly important since tomtits had been used as cross-foster parents for black robins, as part of an earlier conservation recovery program. The existence of any hybrids thus detected would have important implications for cross-fostering programs generally, since may such programs are now being implemented in conservation programs worldwide.

Amino Acid Sequence↗
PubMed2002

A collection of 33 novel human mtDNA homoplasmic variants.

Mitochondria are involved in cellular energy production via oxidative phosphorylation and this function may be damaged by any mutation in mitochondrial DNA (mtDNA). To identify novel mtDNA mutations, we have developed a program to systematically screen the entire mitochondrial genome in a large number of individuals with clinical and/or morphological features of mitochondrial dysfunction, but still no genetic diagnosis. The sequence-data were obtained with an automated rapid system, which gave us a series of information: in the eleven mitochondrial genomes analyzed we observed the presence of 33 differences from the revised Cambridge Reference Sequence (Andrews et al., 1999), but they were all homoplasmic in the patients' tissues analyzed (skeletal muscle and blood), suggesting that they are unlikely to be primarily pathogenic though they may be co-responsible in the determination of the disease. This work can therefore help complete the already ample mtDNA polymorphism existent database.

Adult↗
PubMed2005

Optimization of inclusive fitness.

The first fully explicit argument is given that broadly supports a widespread belief among whole-organism biologists that natural selection tends to lead to organisms acting as if maximizing their inclusive fitness. The use of optimization programs permits a clear statement of what this belief should be understood to mean, in contradistinction to the common mathematical presumption that it should be formalized as some kind of Lyapunov or even potential function. The argument reveals new details and uncovers latent assumptions. A very general genetic architecture is allowed, and there is arbitrary uncertainty. However, frequency dependence of fitnesses is not permitted. The logic of inclusive fitness immediately draws together various kinds of intra-genomic conflict, and the concept of 'p-family' is introduced. Inclusive fitness is thus incorporated into the formal Darwinism project, which aims to link the mathematics of motion (difference and differential equations) used to describe gene frequency trajectories with the mathematics of optimization used to describe purpose and design. Important questions remain to be answered in the fundamental theory of inclusive fitness.

Adaptation, Biological↗
PubMed2005

Which strategy is better for linkage analysis: single-nucleotide polymorphisms or microsatellites? Evaluation by identity-by-state-identity-by-descent transformation affected sib-pair method on GAW14 data.

The central issue for Genetic Analysis Workshop 14 (GAW14) is the question, which is the better strategy for linkage analysis, the use of single-nucleotide polymorphisms (SNPs) or microsatellite markers? To answer this question we analyzed the simulated data using Duffy's SIB-PAIR program, which can incorporate parental genotypes, and our identity-by-state - identity-by-descent (IBS-IBD) transformation method of affected sib-pair linkage analysis which uses the matrix transformation between IBS and IBD. The advantages of our method are as follows: the assumption of Hardy-Weinberg equilibrium is not necessary; the parental genotype information maybe all unknown; both IBS and its related IBD transformation can be used in the linkage analysis; the determinant of the IBS-IBD transformation matrix provides a quantitative measure of the quality of the marker in linkage analysis. With the originally distributed simulated data, we found that 1) for microsatellite markers there are virtually no differences in types I and II error rates when parental genotypes were or were not used; 2) on average, a microsatellite marker has more power than a SNP marker does in linkage detection; 3) if parental genotype information is used, SNP markers show lower type I error rates than microsatellite markers; and 4) if parental genotypes are not available, SNP markers show considerable variation in type I error rates for different methods.

Chromosome Mapping↗
PubMed1994

Traversing the biological complexity in the hierarchy between genome and CAD endpoints in the population at large.

An emerging challenge facing those who are concerned about the efficacy of public health programs is to understand how information from the DNA revolution might be used to improve our ability to predict the initiation, progression and severity of a common disease having a complex multifactorial etiology. In the course of research to evaluate the role of information about DNA, combinations of genome types and environmental exposures that predispose to disease will be identified. Such information is expected to be useful in efforts to identify individuals and families at higher risk of disease and to predict their responses to a proposed therapy. This paper begins with a discussion of the features of a realistic biological model for the study of a common multifactorial disease. We present evidence for the complexity in the relationship between genome type variation and variation in risk of coronary artery disease (CAD) and review the preliminary results of our studies to determine whether information about genome type variation can improve our ability to predict the distribution of CAD among individuals in the population at large. Such studies make it apparent that new analytical strategies are necessary to deal with the plethora of genome type information available for the evaluation of risk of a common disease like CAD. This shift in the research paradigm will build upon new strategies to understand the organization of natural systems that are coming from outside the mainstream of genetic research.

Coronary Disease↗
PubMed2006

An empirical verification of population assignment methods by marking and parentage data: hatchery and wild steelhead (Oncorhynchus mykiss) in Forks Creek, Washington, USA.

Assignment tests are increasingly applied in ecology and conservation, although empirical comparisons of methods are still rare or are restricted to few of the available approaches. Furthermore, the performance of assignment tests in cases with low population differentiation, violations of Hardy-Weinberg equilibrium and unbalanced sampling designs has not been verified. The release of adult hatchery steelhead to spawn in Forks Creek in 1996 and 1997 provided an opportunity to compare the power of different assignment methods to distinguish their offspring from those of sympatric wild steelhead. We compared standard assignment methods requiring baseline samples (frequency, distance and Bayesian) and clustering approaches with and without baseline information, using six freely available computer programs. Assignments were verified by parentage data obtained for a subset of returning offspring. All methods provided similar assignment success, despite low differentiation between wild and hatchery fish (F(ST) = 0.02). Bayesian approaches with baseline data performed best, whereas the results of clustering methods were variable and depended on the samples included in the analysis and the availability of baseline information. Removal of a locus with null alleles and equalizing sample sizes had little effect on assignments. Our results demonstrate the robustness of most assignment tests to low differentiation and violations of assumptions, as well as their utility for ecological studies that require correct classification of different groups.

Alleles↗
PubMed1994

Presence of multiple genetic subtypes of human immunodeficiency virus type 1 proviruses in Uganda.

DNA sequences encoding the C2-V3 regions or the C2-V5 regions of the surface glycoprotein gp120 of the human immunodeficiency virus type 1 (HIV-1) were amplified by the polymerase chain reaction (PCR) from peripheral blood mononuclear cells obtained in 1990/1992 from 20 infected Ugandans. The PCR-amplified DNA was cloned into a phagemid vector and between 1 and 12 clones from each provirus were sequenced. The Ugandan proviruses were aligned into four subtypes (A, B, C, and D) by phylogenetic analysis of consensus nucleotide sequences for the C2-V3 regions. Analysis of the deduced amino acid sequences of the C2-V3 regions by a maximum parsimony program gave a similar phylogenetic relationship. The data indicated that phylogenetic analysis of nucleotide and/or amino acid sequences from the C2-V3 regions is a reliable method of subtype determination. The consensus amino acid sequence of the subtype A and D proviruses were almost identical to those of the Albert et al. group B and group A proviruses, respectively. The deduced amino acid sequences of the C2-V5 regions of six of these proviruses showed considerable diversity both between patients and within patients. The region varied in length between 234 and 243 amino acids and included deletions and repetitions, particularly in the V4 region.

Adult↗
PubMed2006

Induction of competence regulons as a general response to stress in gram-positive bacteria.

Bacterial transformation, a programmed mechanism for genetic exchange originally discovered in Streptococcus pneumoniae, is widespread in bacteria. It is based on the uptake and integration of exogenous DNA into the recipient genome. This review examines whether induction of competence for genetic transformation is a general response to stress in gram-positive bacteria. It compares data obtained with bacteria chosen for their different lifestyles, the soil-dweller Bacillus subtilis and the major human pathogen S. pneumoniae. The review focuses on the relationship between competence and other global responses in B. subtilis, as well as on recent evidence for competence induction in response to DNA damage or antibiotics and for the ability of S. pneumoniae to use competence as a substitute for SOS. This comparison reveals that the two species use different fitness-enhancing strategies in response to stress conditions. Whereas B. subtilis combines competence and SOS induction, S. pneumoniae relies only on competence to generate genetic diversity through transformation.

Bacillus subtilis↗
PubMed2000

Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program. National Heart, Lung and Blood Institute.

OBJECTIVE: To evaluate the association between the angiotensinogen-6 polymorphism (AGT-6) and blood pressure levels. DESIGN: Data were analysed from the first 4,322 subjects of the NHLBI Family Blood Pressure Program (FBPP), consisting of four networks (GenNet, GENOA, HyperGEN and SAPPHIRe), each conducting a multicentre observational family study to identify and characterize the genetic determinants of hypertension and blood pressure. The four studies use different designs (concordant sibpairs, discordant pairs, sibships, extended pedigrees), target different ethnic groups (Caucasian, African-American, Japanese, Chinese), and have different inclusion/exclusion criteria. However, the protocols and definitions were standardized across networks before data collection to allow maximum poolability. METHODS: Each network/racial group was analysed separately, using generalized linear models that accounted for the non-independence of family members and/or the confounding of anti-hypertensive medications as needed. The results were also pooled using a pre-planned meta-analysis technique. RESULTS: AGT-6 was not significantly associated with blood pressure in any network/racial group. In the meta-analysis, the pooled effect of AGT-6 was small [hazard ratio = 1.10, 95% confidence interval (CI) = 0.99-1.22, P= 0.0647 for systolic; hazard ratio = 1.04, 95% CI = 0.89-1.21, P= 0.6383 for diastolic]. A post-hoc analysis restricting to subjects meeting JNC VI criteria for Stage I hypertension (blood pressure > 140/90 mmHg or medicated) showed a stronger statistically significant relationship for systolic blood pressure (hazard ratio = 1.44, 95% CI = 1.04-2.00, P= 0.0283). CONCLUSIONS: AGT-6 has minimal to no effect on the inter-individual variation of blood pressure levels, and is at best a 'minor gene' for blood pressure in the population as a whole.

Adolescent↗
PubMed2003

Genetic diversity of Eurycoma longifolia inferred from single nucleotide polymorphisms.

Eurycoma longifolia Jack. is a treelet that grows in the forests of Southeast Asia and is widely used throughout the region because of its reported medicinal properties. Widespread harvesting of wild-grown trees has led to rapid thinning of natural populations, causing a potential decrease in genetic diversity among E. longifolia. Suitable genetic markers would be very useful for propagation and breeding programs to support conservation of this species, although no such markers currently exist. To meet this need, we have applied a genome complexity reduction strategy to identify a series of single nucleotide polymorphisms (SNPs) within the genomes of several E. longifolia accessions. We have found that the occurrence of these SNPs reflects the geographic origins of individual plants and can distinguish different natural populations. This work demonstrates the rapid development of molecular genetic markers in species for which little or no genomic sequence information is available. The SNP markers that we have developed in this study will also be useful for identifying genetic fingerprints that correlate with other properties of E. longifolia, such as high regenerability or the appearance of bioactive metabolites.

Conservation of Natural Resources↗
PubMed2004

Mapping QTL associated with resistance to Fusarium head blight in the Nanda2419 x Wangshuibai population. I. Type II resistance.

Scab disease caused by Fusarium spp. has been a major concern for both wheat producers and consumers. Deployment of scab-resistant varieties is the major strategy to curb this disease. To identify the scab resistance genes in wheat cv. Wangshuibai, we produced a F(6:7) recombinant inbred line (RIL) population by crossing Wangshuibai with the scab-susceptible cultivar Nanda2419. The RILs were evaluated for scab resistance in the field by single floret inoculation in two replicates in 2002 and one replicate in 2003. The number of diseased spikelets (NDS) and the length of diseased rachides (LDR) were investigated to reflect the Type II resistance. Among 654 simple sequence repeat (SSR) markers surveyed, 326 were found to be polymorphic between the parents. A partial molecular map was constructed with these markers that covered over 2,210 cM of the wheat genome. Six chromosome regions showed association with both NDS and LDR in a one-way anova analysis, even though the variation explained by them varied between the two traits. Eight intervals were detected for their association with Type II resistance through interval mapping, five of which were not identified in single-point analysis. The quantitative trait loci (QTL) with large effects were the ones in the interval of Xgwm533-3-Xgwm533-1 on chromosome 3B and in the interval of Xwmc539-Xbarc024 on chromosome 6B, whose alleles favoring resistance originate from Wangshuibai. In addition, a QTL whose resistance allele originated from Nanda2419 was consistently detected in the interval of Xs1021m-Xgwm47-1 on chromosome 2B. These results suggest that Wangshuibai is the major source for Type II resistance in this population. The markers associated with these QTL would facilitate the use of scab-resistant genes of Wangshuibai in scab resistance breeding programs of wheat.

Chromosome Mapping↗