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PubMed2006

Measuring marker information content by the ambiguity of block boundaries observed in dense SNP data.

Recent studies have noted that the boundary of common haplotype blocks in hapmap constructions involve a certain degree of ambiguity, and so do the resulting "tagSNPs". Here, we report how to address this issue at the level of individual SNP markers. We introduce a measure called the marker ambiguity score (MAS), and evaluate its utility by simulation studies based on a real dataset of 2949 SNPs spanning a region of 56.1M bp. We show that the MAS method can be used to assess the level of boundary ambiguity caused by varying ethnic background, sample sizes for hapmap construction, and disease aggregation. We find a striking difference in overall patterns of block boundary distributions in two ethnic groups (blacks and whites), and subtle changes in block structures that agree with the evolutionary history of the two populations. Our analyses suggest that a sample size of 200 or more subjects is probably needed for "stable" hapmap constructions. In addition, we demonstrate that there are subtle changes in block boundaries in hapmaps constructed in disease populations versus normal controls. This approach can quantify the information content of individual markers in the context of highly dense SNP data, which may have important implications in designing efficient genome-wide association mapping projects.

Computer Simulation↗
PubMed2006

A changing climate for grassland research.

Here, we review the current genetic approaches for grass improvement and their potential for the enhanced breeding of new varieties appropriate for a sustainable agriculture in a changing global climate. These generally out-breeding, perennial, self-incompatible species present unique challenges and opportunities for genetic analysis. We emphasise their distinctiveness from model species and from the in-breeding, annual cereals. We describe the modern genetic approaches appropriate for their analysis, including association mapping. Sustainability traits discussed here include stress resistance (drought, cold and pathogeneses) and favourable agronomic characters (nutrient use efficiency, carbohydrate content, fatty acid content, winter survival, flowering time and biomass yield). Global warming will predictably affect temperature-sensitive traits such as vernalisation, and these traits are under investigation. Grass biomass utilisation for carbon-neutral energy generation may contribute to reduced atmospheric carbon emissions. Because the wider potential outcomes of climate change are unpredictable, breeders must be reactive to events and have a range of well-characterised germplasm available for new applications.

Agriculture↗
PubMed2006

Forest-tree population genomics and adaptive evolution.

Forest trees have gained much attention in recent years as nonclassical model eukaryotes for population, evolutionary and ecological genomic studies. Because of low domestication, large open-pollinated native populations, and high levels of both genetic and phenotypic variation, they are ideal organisms to unveil the molecular basis of population adaptive divergence in nature. Population genomics, in its broad-sense definition, is an emerging discipline that combines genome-wide sampling with traditional population genetic approaches to understanding evolution. Here we briefly review traditional methods of studying adaptive genetic variation in forest trees, and describe a new, integrated population genomics approach. First, alleles (haplotypes) at candidate genes for adaptive traits and their effects on phenotypes need to be characterized via sequencing and association mapping. At this stage, functional genomics can assist in understanding gene action and regulation by providing detailed transcriptional profiles. Second, frequencies of alleles in native populations for causative single-nucleotide polymorphisms are estimated to identify patterns of adaptive variation across heterogeneous environments. Population genomics, through deciphering allelic effects on phenotypes and identifying patterns of adaptive variation at the landscape level, will in the future constitute a useful tool, if cost-effective, to design conservation strategies for forest trees.

Adaptation, Physiological↗
PubMed2004

A comparison of sequence-based polymorphism and haplotype content in transcribed and anonymous regions of the barley genome.

Direct estimates of sequence diversity provides an abundant source of DNA polymorphisms based on single nucleotide polymorphisms (SNPs). The frequency and distribution of nucleotide diversity within 23 genes associated with grain germination in barley were determined in a sample of accessions representing European cultivars, landraces, and wild barley accessions from throughout the fertile crescent. The overall nucleotide diversity ranged from 0.0021 to 0.0189 with a single nucleotide change being detected every 78 bp and insertion-deletion events being observed every 680 bp. Within the cultivated (H. vulgare) genepool, a small number of haplotypes were detected, the total number of haplotypes observed in H. spontaneum was almost double that detected in H. vulgare (46 and 26, respectively). Distinct haplotypes were observed in the H. spontaneum and landrace genepools, which are highly divergent from H. vulgare. A comparison of SNP-based haplotype data with EST-derived SSRs and genomic SSRs revealed a similar trend of decreasing variability in the cultivated genepool. However, the number of unique alleles identified in the cultivated sample was much greater with genomic SSRs (18%) compared with only 2.1% for SNPs and 3.8% for EST-derived SSRs. The potential utility of SNPs and EST-derived SSRs for association mapping in barley is discussed.

Base Sequence↗
PubMed1983

Selective activation of the adrenal medulla during acute bilateral carotid occlusion and its modulation by alpha-adrenergic receptors in the rat.

The sympathoadrenal activity was studied during baroreflex stimulation in chloralose anesthetized rats. Circulating norepinephrine (NE) and epinephrine (E) levels were used as indices of sympathetic fiber and adrenal medulla activities, respectively, under basal conditions and during a 1-min bilateral carotid occlusion (CO). In vagotomized rats, the CO induced a significant increase in mean arterial pressure (MAP) associated with an increase in circulating E levels, while this procedure did not alter blood pressure or circulating NE or E levels in intact animals. Following vagotomy, the baroreflex stimulation activated specifically the adrenal medulla, without alteration of the sympathetic fiber activity since the NE levels were not modified by the occlusion. Moreover, in support of that hypothesis, chemical sympathectomy did not decrease the pressure response to CO while bilateral adrenalectomy almost completely abolished this response. The elevation of circulating E induced by the CO was greatly potentiated by pretreatment with Yohimbine, a selective alpha 2-antagonist, and was completely abolished by administration of Clonidine, an alpha 2-agonist, while phenoxybenzamine, which is mainly an alpha 1-antagonist, did not potentiate significantly the E response to CO. These results therefore suggest that the baroreflex activation of the adrenal medulla induced by CO may be modulated in vivo via alpha 2-adrenergic receptors that could be localized on chromaffin cells.

Adrenal Medulla↗
PubMed1996

Concept hierarchy memory model: a neural architecture for conceptual knowledge representation, learning, and commonsense reasoning.

This article introduces a neural network based cognitive architecture termed Concept Hierarchy Memory Model (CHMM) for conceptual knowledge representation and commonsense reasoning. CHMM is composed of two subnetworks: a Concept Formation Network (CFN), that acquires concepts based on their sensory representations; and a Concept Hierarchy Network (CHN), that encodes hierarchical relationships between concepts. Based on Adaptive Resonance Associative Map (ARAM), a supervised Adaptive Resonance Theory (ART) model, CHMM provides a systematic treatment for concept formation and organization of a concept hierarchy. Specifically, a concept can be learned by sampling activities across multiple sensory fields. By chunking relations between concepts as cognitive codes, a concept hierarchy can be learned/modified through experience. Also, fuzzy relations between concepts can now be represented in terms of the weights on the links connecting them. Using a unified inferencing mechanism based on code firing, CHMM performs an important class of commonsense reasoning, including concept recognition and property inheritance.

Algorithms↗
PubMed1997

Comparison of effective and ineffective target sites that demonstrate concealed entrainment in patients with coronary artery disease undergoing radiofrequency ablation of ventricular tachycardia.

BACKGROUND: Concealed entrainment has been useful in guiding catheter ablation of monomorphic ventricular tachycardia in patients with coronary artery disease. However, not all sites with concealed entrainment result in successful ablation of the targeted ventricular tachycardia. The purpose of this prospective study was to identify factors at sites that demonstrate concealed entrainment that differentiate effective from ineffective target sites. METHODS AND RESULTS: In 14 consecutive patients with hemodynamically stable monomorphic ventricular tachycardia and coronary artery disease, radiofrequency ablation of 26 ventricular tachycardias was performed. Ablation was attempted at 46 sites that demonstrated concealed entrainment. Twenty-five of the targeted ventricular tachycardias (96%) were successfully ablated. The positive predictive value of concealed entrainment for successful ablation was 54%; it increased to 72% in the presence of a stimulus-QRS interval/ventricular tachycardia cycle length ratio of < or = 70%, to 82% in the presence of a match of the stimulus-QRS and electrogram-QRS interval, and to 89% in the presence of isolated mid diastolic potentials that could not be dissociated from ventricular tachycardia during entrainment. CONCLUSIONS: The positive predictive value of concealed entrainment for identification of successful ablation sites in patients with sustained ventricular tachycardia and coronary artery disease can be significantly enhanced by the presence of associated mapping criteria, particularly an isolated mid diastolic potential that cannot be dissociated from the tachycardia.

Adult↗
PubMedDate not supplied

Long-term converting enzyme inhibition and sympathetic nerve function in hypertensive humans.

Orthostatic hypotension is uncommon during oral converting enzyme inhibition, even when combined with salt depletion. To assess the mechanisms responsible for the cardiovascular homeostasis in this condition, we studied the blood pressure (BP), heart rate (HR), total plasma catecholamines (CA), and plasma renin activity (PRA) responses after 20 minutes of 60 degrees head-up tilt in four groups of hypertensive patients. Group 1 included seven untreated patients; Group 2, eight patients on converting enzyme inhibitor (captopril) therapy; Group 3, six patients on diuretic therapy and Group 4, 15 patients on combined captopril and diuretic therapy. Long-term converting enzyme inhibition alone or in combination with diuretics resulted in reduction of mean arterial pressure (MAP) associated with a marked increase in PRA and fall in plasma aldosterone concentration (PAC). Pronounced increases in HR and plasma CA on tilt were observed in all groups. In Groups 1, 2, and 3, BP was maintained during tilt; in Group 4, three patients fainted between 5 and 15 minutes while the other 12 had a normal response to tilt. Plasma catecholamines increased more significantly after 15 and 20 minutes of tilt, more in Groups 3 and 4 than in Group 1, while no differences in HR response were observed among groups. Results suggest that sympathetic compensatory mechanisms are adequate in the majority of patients to maintain BP during converting enzyme inhibition even when combined with salt depletion. In a few who exhibited orthostatic hypotension, a vasovagal attack seemed to be responsible for bradycardia and fall in BP.

Adult↗
PubMed2005

CoaSim: a flexible environment for simulating genetic data under coalescent models.

BACKGROUND: Coalescent simulations are playing a large role in interpreting large scale intra-specific sequence or polymorphism surveys and for planning and evaluating association studies. Coalescent simulations of data sets under different models can be compared to the actual data to test the importance of different evolutionary factors and thus get insight into these. RESULTS: We have created the CoaSim application as a flexible environment for Monte Carlo simulation of various types of genetic data under equilibrium and non-equilibrium coalescent processes for a variety of applications. Interaction with the tool is through the Guile version of the Scheme scripting language. Scheme scripts for many standard and advanced applications are provided and these can easily be modified by the user for a much wider range of applications. A graphical user interface with less functionality and flexibility is also included. It is primarily intended as an exploratory and educational tool CONCLUSION: CoaSim is a powerful tool because of its flexibility and ease of use. This is illustrated through very varied uses of the application, e.g. evaluation of association mapping methods, parametric bootstrapping, and design and choice of markers for specific questions.

Case-Control Studies↗
PubMed2006

PSMIX: an R package for population structure inference via maximum likelihood method.

BACKGROUND: Inference of population stratification and individual admixture from genetic markers is an integrative part of a study in diverse situations, such as association mapping and evolutionary studies. Bayesian methods have been proposed for population stratification and admixture inference using multilocus genotypes and widely used in practice. However, these Bayesian methods demand intensive computation resources and may run into convergence problem in Markov Chain Monte Carlo based posterior samplings. RESULTS: We have developed PSMIX, an R package based on maximum likelihood method using expectation-maximization algorithm, for inference of population stratification and individual admixture. CONCLUSION: Compared with software based on Bayesian methods (e.g., STRUCTURE), PSMIX has similar accuracy, but more efficient computations.PSMIX and its supplemental documents are freely available at http://bioinformatics.med.yale.edu/PSMIX.

Algorithms↗
PubMed2005

Factors reducing the expected deflection in initial orientation in clock-shifted homing pigeons.

To orient from familiar sites, homing pigeons can rely on both an olfactory map and visual familiar landmarks. The latter can in principle be used in two different ways: either within a topographical map exploited for piloting or in a so-called mosaic map associated with a compass bearing. One way to investigate the matter is to put the compass and the topographical information in conflict by releasing clock-shifted pigeons from familiar locations. Although the compass orientation is in general dominant over a piloting strategy, a stronger or weaker tendency to correct towards the home direction by clock-shifted pigeons released from very familiar sites has often been observed. To investigate which factors are involved in the reduction of the deviation due to clock-shift, we performed a series of releases with intact and anosmic pigeons from familiar sites in unshifted and clock-shifted conditions and a series of releases from the same sites with naive clock-shifted birds. Our data suggest that the following factors have a role in reducing deviation due to the clock-shift: familiarity with the release site, the lack of olfactory information and some unknown site-dependent features.

Animals↗
PubMed2025

Diversification, loss, and virulence gains of the major effector AvrStb6 during continental spread of the wheat pathogen Zymoseptoria tritici.

Interactions between plant pathogens and their hosts are highly dynamic and mainly driven by pathogen effectors and plant receptors. Host-pathogen co-evolution can cause rapid diversification or loss of pathogen genes encoding host-exposed proteins. The molecular mechanisms that underpin such sequence dynamics remains poorly investigated at the scale of entire pathogen species. Here, we focus on AvrStb6, a major effector of the global wheat pathogen Zymoseptoria tritici, evolving in response to the cognate receptor Stb6, a resistance widely deployed in wheat. We comprehensively captured effector gene evolution by analyzing a global thousand-genome panel using reference-free sequence analyses. We found that AvrStb6 has diversified into 59 protein isoforms with a strong association to the pathogen spreading to new continents. Across Europe, we found the strongest differentiation of the effector consistent with high rates of Stb6 deployment. The AvrStb6 locus showed also a remarkable diversification in transposable element content with specific expansion patterns across the globe. We detected AvrStb6 gene losses and evidence for transposable element-mediated disruptions. We used virulence datasets of genome-wide association mapping studies to predict virulence changes across the global panel. Genomic predictions suggested marked increases in virulence on Stb6 cultivars concomitant with the spread of the pathogen to Europe and the subsequent spread to further continents. Finally, we genotyped French bread wheat cultivars for Stb6 and monitored resistant cultivar deployment concomitant with AvrStb6 evolution. Taken together, our data provides a comprehensive view of how a rapidly diversifying effector locus can undergo large-scale sequence changes concomitant with gains in virulence on resistant cultivars. The analyses highlight also the need for large-scale pathogen sequencing panels to assess the durability of resistance genes and improve the sustainability of deployment strategies.

Ascomycota↗
PubMed2005

Combining the meiosis Gibbs sampler with the random walk approach for linkage and association studies with a general complex pedigree and multimarker loci.

A linkage analysis for finding inheritance states and haplotype configurations is an essential process for linkage and association mapping. The linkage analysis is routinely based upon observed pedigree information and marker genotypes for individuals in the pedigree. It is not feasible for exact methods to use all such information for a large complex pedigree especially when there are many missing genotypic data. Proposed Markov chain Monte Carlo approaches such as a single-site Gibbs sampler or the meiosis Gibbs sampler are able to handle a complex pedigree with sparse genotypic data; however, they often have reducibility problems, causing biased estimates. We present a combined method, applying the random walk approach to the reducible sites in the meiosis sampler. Therefore, one can efficiently obtain reliable estimates such as identity-by-descent coefficients between individuals based on inheritance states or haplotype configurations, and a wider range of data can be used for mapping of quantitative trait loci within a reasonable time.

Computer Simulation↗
PubMed2005

Nucleotide diversity and linkage disequilibrium in cold-hardiness- and wood quality-related candidate genes in Douglas fir.

Nuclear sequence variation and linkage disequilibrium (LD) were studied in 15 cold-hardiness- and 3 wood quality-related candidate genes in Douglas fir [Pseudotsuga menziesii (Mirb.) Franco]. This set of genes was selected on the basis of its function in other plants and collocation with cold-hardiness-related quantitative trait loci (QTL). The single-nucleotide polymorphism (SNP) discovery panel represented 24 different trees from six regions in Washington and Oregon plus parents of a segregating population used in the QTL study. The frequency of SNPs was one SNP per 46 bp across coding and noncoding regions on average. Haplotype and nucleotide diversities were also moderately high with H(d) = 0.827 +/- 0.043 and pi = 0.00655 +/- 0.00082 on average, respectively. The nonsynonymous (replacement) nucleotide substitutions were almost five times less frequent than synonymous ones and substitutions in noncoding regions. LD decayed relatively slowly but steadily within genes. Haploblock analysis was used to define haplotype tag SNPs (htSNPs). These data will help to select SNPs for association mapping, which is already in progress.

Adaptation, Physiological↗
PubMed2006

Assessment of linkage disequilibrium in potato genome with single nucleotide polymorphism markers.

The extent of linkage disequilibrium (LD) is an important factor in designing association mapping experiments. Unlike other plant species that have been analyzed so far for the extent of LD, cultivated potato (Solanum tuberosum L.), an outcrossing species, is a highly heterozygous autotetraploid. The favored genotypes of modern cultivars are maintained by vegetative propagation through tubers. As a first step in the LD analysis, we surveyed both coding and noncoding regions of 66 DNA fragments from 47 accessions for single nucleotide polymorphism (SNP). In the process, we combined information from the potato SNP database with experimental SNP detection. The total length of all analyzed fragments was >25 kb, and the number of screened sequence bases reached almost 1.4 million. Average nucleotide polymorphism (=11.5x10(-3)) and diversity (pi=14.6x10(-3)) was high compared to the other plant species. The overall Tajima's D value (0.5) was not significant, but indicates a deficit of low-frequency alleles relative to expectation. To eliminate the possibility that an elevated D value occurs due to population subdivision, we assessed the population structure with probabilistic statistics. The analysis did not reveal any significant subdivision, indicating a relatively homogenous population structure. However, the analysis of individual fragments revealed the presence of subgroups in the fragment closely linked to the R1 resistance gene. Data pooled from all fragments show relatively fast decay of LD in the short range (r2=0.208 at 1 kb) but slow decay afterward (r2=0.137 at approximately 70 kb). The estimate from our data indicates that LD in potato declines below 0.10 at a distance of approximately 10 cM. We speculate that two conflicting factors play a vital role in shaping LD in potato: the outcrossing mating type and the very limited number of meiotic generations.

Alleles↗
PubMed2006

Multilocus patterns of nucleotide diversity, linkage disequilibrium and demographic history of Norway spruce [Picea abies (L.) Karst].

DNA polymorphism at 22 loci was studied in an average of 47 Norway spruce [Picea abies (L.) Karst.] haplotypes sampled in seven populations representative of the natural range. The overall nucleotide variation was limited, being lower than that observed in most plant species so far studied. Linkage disequilibrium was also restricted and did not extend beyond a few hundred base pairs. All populations, with the exception of the Romanian population, could be divided into two main domains, a Baltico-Nordic and an Alpine one. Mean Tajima's D and Fay and Wu's H across loci were both negative, indicating the presence of an excess of both rare and high-frequency-derived variants compared to the expected frequency spectrum in a standard neutral model. Multilocus neutrality tests based on D and H led to the rejection of the standard neutral model and exponential growth in the whole population as well as in the two main domains. On the other hand, in all three cases the data are compatible with a severe bottleneck occurring some hundreds of thousands of years ago. Hence, demographic departures from equilibrium expectations and population structure will have to be accounted for when detecting selection at candidate genes and in association mapping studies, respectively.

Chromosomes, Plant↗
PubMed2004

Comparative population genetics of the panicoid grasses: sequence polymorphism, linkage disequilibrium and selection in a diverse sample of sorghum bicolor.

Levels of genetic variation and linkage disequilibrium (LD) are critical factors in association mapping methods as well as in identification of loci that have been targets of selection. Maize, an outcrosser, has a high level of sequence variation and a limited extent of LD. Sorghum, a closely related but largely self-pollinating panicoid grass, is expected to have higher levels of LD. As a first step in estimation of population genetic parameters in sorghum, we surveyed 27 diverse S. bicolor accessions for sequence variation at a total of 29,186 bp in 95 short regions derived from genetically mapped RFLPs located throughout the genome. Consistent with its higher level of inbreeding, the extent of LD is at least severalfold greater in sorghum than in maize. Total sequence variation in sorghum is about fourfold lower than that in maize, while synonymous variation is fivefold lower, suggesting a smaller effective population size in sorghum. Because we surveyed a species-wide sample, the mating system, which primarily affects population-level diversity, may not be primarily responsible for this difference. Comparisons of polymorphism and divergence suggest that both directional and diversifying selection have played important roles in shaping variation in the sorghum genome.

Genes, Plant↗
PubMed2007

Quantitative genetics of secondary hip joint osteoarthritis in a Labrador Retriever-Greyhound pedigree.

OBJECTIVE: To evaluate the quantitative inheritance of secondary hip joint osteoarthritis in a canine pedigree. ANIMALS: 137 Labrador Retrievers, Greyhounds, and mixed-breed dogs. PROCEDURES: Necropsy scores ranging from 0 to 4 were obtained for each hip joint. Seven unaffected Greyhounds with normal hip joint conformation were also used for genetic modeling, but were not euthanized. Sixty-six male and 71 female dogs were allocated to 2 groups (< or = 12 months of age and > 12 months of age). Statistical models were developed to establish the inheritance pattern of hip joint osteoarthritis that developed secondary to hip dysplasia. RESULTS: 62 dogs had evidence of osteoarthritis in a hip joint, and 75 had no evidence of osteoarthritis. After sex was adjusted for, the necropsy score was found to be inherited additively but without dominance. Each Labrador Retriever allele increased the necropsy score by 0.7 to 0.9 points, compared with the Greyhound allele, and male sex increased the necropsy score 0.74 over female sex. Approximately 10% of the variation in necropsy score was attributable to the litter of puppies' origin. CONCLUSIONS AND CLINICAL RELEVANCE: Because secondary hip joint osteoarthritis is inherited additively, selection pressure could be applied to reduce its incidence. Similar statistical models can be used in linkage and association mapping to detect the genes in the underlying quantitative trait loci that contribute to hip joint osteoarthritis.

Age Factors↗