Genetic Loci for Retinal Arteriolar Microcirculation

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10⁻⁸. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10⁻¹² in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.     

Quantitative Trait Loci for Murine Growth

Body size is an archetypal quantitative trait with variation due to the segregation of many gene loci, each of relatively minor effect, and the environment. We examine the effects of quantitative trait loci (QTLs) on age-specific body weights and growth in the F(2) intercross of the LG/J and SM/J strains of inbred mice. Weekly weights (1-10 wk) and 75 microsatellite genotypes were obtained for 535 mice. Interval mapping was used to locate and measure the genotypic effects of QTLs on body weight and growth. QTL effects were detected on 16 of the 19 autosomes with several chromosomes carrying more than one QTL. The number of QTLs for age-specific weights varied from seven at 1 week to 17 at 10 wk. The QTLs were each of relatively minor, subequal effect. QTLs affecting early and late growth were generally distinct, mapping to different chromosomal locations indicating separate genetic and physiological systems for early and later murine growth.     

A Relationship Between two Fundamental Concepts in Drug Combination Theory

Theories for the dose response analysis of drug combinations have been developed along two separate lines. In the first line, mainly followed by pharmacologists, the concept of “additivity” is of central importance. A corresponding central concept in the second line, which was mainly followed by biometricians, is that of “simple similarity”. We show that simple similarity implies additivity and we give a condition under which the reverse holds.     

Fundamental aspects of arm repair phase in two echinoderm models

Regeneration is a post-embryonic developmental process that ensures complete morphological and functional restoration of lost body parts. The repair phase is a key step for the effectiveness of the subsequent regenerative process: in vertebrates, efficient re-epithelialisation, rapid inflammatory/immune response and post-injury tissue remodelling are fundamental aspects for the success of this phase, their impairment leading to an inhibition or total prevention of regeneration. Among deuterostomes, echinoderms display a unique combination of striking regenerative abilities and diversity of useful experimental models, although still largely unexplored.Therefore, the brittle star Amphiura filiformis and the starfish Echinaster sepositus were here used to comparatively investigate the main repair phase events after injury as well as the presence and expression of immune system and extracellular matrix (i.e. collagen) molecules using both microscopy and molecular tools.Our results showed that emergency reaction and re-epithelialisation are similar in both echinoderm models, being faster and more effective than in mammals. Moreover, in comparison to the latter, both echinoderms showed delayed and less abundant collagen deposition at the wound site (absence of fibrosis). The gene expression patterns of molecules related to the immune response, such as Ese-fib-like (starfishes) and Afi-ficolin (brittle stars), were described for the first time during echinoderm regeneration providing promising starting points to investigate the immune system role in these regeneration models.Overall, the similarities in repair events and timing within the echinoderms and the differences with what has been reported in mammals suggest that effective repair processes in echinoderms play an important role for their subsequent ability to regenerate. Targeted molecular and functional analyses will shed light on the evolution of these abilities in the deuterostomian lineage.     

Fundamental theorem of natural selection and frequency-dependent selection: analysis of the matrix game diploid model

Following Ewens' interpretation about Fisher's fundamental theorem of natural selection, the matrix game model for diploid populations undergoing non-overlapping, discrete generations is investigated. The total genetic variance is decomposed and it is shown that the partial change in the mean fitness, which is equal to the additive genetic variance over the mean fitness, can be thought of as a change due only to the partial changes in the phenotypic frequencies.     

构建数量性状基因图谱的几种统计方法

以线性数学模型为线索,概述了用于构建数量性状基因图谱的几种主要统计方法,包括方差分析法、标记回归法、区间作图法、复合区间作图法、Jansen的复合区间作图法、双侧标记回归法以及新近发展的多区间作图法和多亲本作图法等.讨论了各种方法的优缺点. Abstract:Statistical methods for mapping QTLs were summarized, including one marker analysis, arker regression analysis,interval mapping (IM),composite interval mapping (CIM),Jansen's composite interval mapping, flanking marker regression analysis,multiple interval mapping (MIM) and multiple families mapping.Their advantages and disadvantages were discussed.     

A genome-wide screen for hyposmia susceptibility Loci

Olfactory dysfunction is an important public health problem in the United States, with approximately 14 million elderly Americans having chronic olfactory impairment. We performed a genome-wide linkage scan for loci influencing susceptibility to hyposmia in the Hutterites, a founder population of European ancestry. Using interviews regarding the olfactory medical history and psychophysical smell testing, we identified 25 individuals with severe hyposmia. Elimination of subjects with confounding conditions yielded 7 hyposmics for analysis. A 52-member pedigree including all affected individuals was constructed from the larger, >1623-member pedigree, and a genome-wide screen for loci influencing the trait of hyposmia using 1123 markers was performed. The most significant evidence for linkage with hyposmia extended over a 45 cM region on chromosome 4q (P = 0.0013). Although this signal meets the criteria for suggestive linkage only and will require replication, these results offer the strongest data to date on the effects of genetic variation on olfactory dysfunction.     

A Genomewide Screen for Autism Susceptibility Loci

We report the analysis of 335 microsatellite markers genotyped in 110 multiplex families with autism. All families include at least two "affected" siblings, at least one of whom has autism; the remaining affected sibs carry diagnoses of either Asperger syndrome or pervasive developmental disorder. Affected sib-pair analysis yielded multipoint maximum LOD scores (MLS) that reach the accepted threshold for suggestive linkage on chromosomes 5, X, and 19. Nominal evidence for linkage (point-wise P<.05) was obtained on chromosomes 2, 3, 4, 8, 10, 11, 12, 15, 16, 18, and 20, and secondary loci were found on chromosomes 5 and 19. Analysis of families sharing alleles at the putative X chromosomal linked locus and one or more other putative linked loci produced an MLS of 3.56 for the DXS470-D19S174 marker combination. In an effort to increase power to detect linkage, scan statistics were used to evaluate the significance of peak LOD scores based on statistical evidence at adjacent marker loci. This analysis yielded impressive evidence for linkage to autism and autism-spectrum disorders with significant genomewide P values <.05 for markers on chromosomes 5 and 8 and with suggestive linkage evidence for a marker on chromosome 19.     

Genic Heterogeneity within Electrophoretic "Alleles" and the Pattern of Variation among Loci in DROSOPHILA PSEUDOOBSCURA

An investigation, similar to our previously reported xanthine dehydrogenase study, was undertaken to examine the extent of hidden genic variation at nine loci (five larval proteins, three esterases and one aldehyde oxidase) by sequential application of various electrophoretic criteria employing pH, gel concentration and buffer variation. Polymorphic loci appear to fall into two distinct groups: weakly polymorphic, including larval protein 6, 7, 8, 10 and 13 and esterase-1 and -6; and highly polymorphic, including esterase-5, Xdh and possibly Ao. Monomorphic loci may belong to a third group different from all polymorphic loci. Bogota, a geographical isolate that is reproductively isolated from the mainland population, was found to be genetically distinct at four of the ten loci examined in detail so far, including Xdh, whereas previously it was found to be genetically distinct at none. These results are discussed in the light of balancing selection, neutral and mutation-selection hypotheses of genic variation in natural populations.     

乳蛋白座位与泌乳性状座位连锁关系的研究

本文利用杂合度分析和连锁群分析对乳蛋白基因座位与产奶量及乳成分等数量性状基因间的连锁关系进行了探讨。结果表明,各乳蛋白基因均具有较高的纯合度,但３个酪蛋白基因同时考虑时纯合度较低。泌乳性状的变差对乳蛋白基因座位杂合度没有明显的回归关系。Ｋ－ＣＮ基因与乳脂率和乳蛋白率,α_（ｓ１）－ＣＮ基因与３０５无产奶量间有显著的连锁关系。     

Sucrose consumption in mice: Major influence of two genetic Loci affecting peripheral sensory responses

Individual variability in sucrose consumption is prominent in humans and other species. To investigate the genetic contribution to this complex behavior, we conducted behavioral, electrophysiological, and genetic studies, using male progeny of two inbred mouse strains (C57BL/6ByJ [B6] and 129/J [129]) and their F₂ hybrids. Two loci on Chromosome (Chr) 4 were responsible for over 50% of the genetic variability in sucrose intake. These loci apparently modulated intake by altering peripheral neural responses to sucrose. One locus affected the response threshold, whereas the other affected the response magnitude. These findings suggest that the majority of difference in sucrose intake between male B6 and 129 mice is due to polymorphisms of two genes that influence receptor or peripheral nervous system activity. Received: 27 January 1997 / Accepted: 17 March 1997     

A Nonparametric Approach for Mapping Quantitative Trait Loci

Genetic mapping of quantitative trait loci (QTLs) is performed typically by using a parametric approach, based on the assumption that the phenotype follows a normal distribution. Many traits of interest, however, are not normally distributed. In this paper, we present a nonparametric approach to QTL mapping applicable to any phenotypic distribution. The method is based on a statistic Z(w), which generalizes the nonparametric Wilcoxon rank-sum test to the situation of whole-genome search by interval mapping. We determine the appropriate significance level for the statistic Z(w), by showing that its asymptotic null distribution follows an Ornstein-Uhlenbeck process. These results provide a robust, distribution-free method for mapping QTLs.     

Evidence for Close Linkage of Human Amylase Loci

HUMAN α-amylase (α-1,4-glucan 4-glucanohydrolase, E.C. 3.2.1.1) is primarily in the pancreas and salivary glands and can be detected in serum and urine (UAmy) as well as in saliva (SaAmy) and duodenal secretions. The SaAmy locus (Amy₁) has at least three mutant alleles with the combined frequency of electrophoretic variant phenotypes totalling approximately 0.01 in Caucasian Americans¹. Subsequently, UAmy was shown to be a convenient source of pancreatic amylase. The pancreatic amylase locus (Amy₂) has at least two mutant alleles in Caucasian and Afro-Americans². The variant UAmy Ss is common in Caucasians whereas UAmy Sp has been found only in Afro-Americans; the frequency of variant phenotypes is 0·086 in each population².     

Bayes factors for detection of Quantitative Trait Loci

A fundamental issue in quantitative trait locus (QTL) mapping is to determine the plausibility of the presence of a QTL at a given genome location. Bayesian analysis offers an attractive way of testing alternative models (here, QTL vs. no-QTL) via the Bayes factor. There have been several numerical approaches to computing the Bayes factor, mostly based on Markov Chain Monte Carlo (MCMC), but these strategies are subject to numerical or stability problems. We propose a simple and stable approach to calculating the Bayes factor between nested models. The procedure is based on a reparameterization of a variance component model in terms of intra-class correlation. The Bayes factor can then be easily calculated from the output of a MCMC scheme by averaging conditional densities at the null intra-class correlation. We studied the performance of the method using simulation. We applied this approach to QTL analysis in an outbred population. We also compared it with the Likelihood Ratio Test and we analyzed its stability. Simulation results were very similar to the simulated parameters. The posterior probability of the QTL model increases as the QTL effect does. The location of the QTL was also correctly obtained. The use of meta-analysis is suggested from the properties of the Bayes factor.     

A Genomewide Search for Quantitative-Trait Loci Underlying Asthma

A genomewide screen for quantitative-trait loci (QTLs) that underlie asthma was performed on 533 Chinese families with asthma, by the unified Haseman-Elston method. Nine asthma-related phenotypes were studied, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), airway responsiveness as indicated by methacholine (MTCH)-challenge test, serum total immunoglobulin E (TIgE), serum-specific immunoglobulin E, eosinophil count in peripheral blood, and skin-prick tests with three different allergens (cockroach, Dermatophagoides pteronyssinus, and D. farinae). Our study showed significant linkage between airway responsiveness to MTCH and D2S1780 on chromosome 2 (P<.00002) and provided suggestive evidence (P<.002) for six additional possible QTLs: D10S1435 and D22S685, for FEV1; D16S412, for FVC; D19S433, for airway responsiveness to MTCH; D1S518, for TIgE; and D4S1647, for skin reactivity to cockroach. No significant or suggestive evidence of linkage for the other four traits was found.     

构建分子标记连锁图谱的图论构图方法

结合统计学、遗传学和图论原理,建立了一种新的分子标记连锁图谱构建的方法,即图论构图法．应用这种方法,从７７个家蚕ＲＡＰＤ标记位点中构建了７个标记位点的两个连锁群．与ＭＡＰＭＡＲＫＥＲ程序所构建的结果相比表明,图论构图法具有更为可靠的构图效果．     

A "signal-on" electrochemical aptasensor for simultaneous detection of two tumor markers

In this paper, we report a "signal-on" electrochemical aptasensor for simultaneous determination of two tumor markers MUC1 and VEGF(165), by using a ferrocene-labeled aptamer-complementary DNA (cDNA) as probe. Since the cDNA immobilized on an electrode surface can hybridize with both MUC1 aptamer and VEGF(165) aptamer to form a long double strand with ferrocene far away from the electrode surface, the probe cannot give electrochemical signal. Nevertheless, the presence of the two tumor markers will inhibit the hybridization of cDNA with the aptamers, thus the distance between ferrocene and the electrode is changed, and a "signal-on" electrochemical method to detect two tumor markers is developed. Experimental results show that the electrochemical signal increases with the addition of either tumor markers, but the biggest electrochemical signal can only be obtained when both tumor markers are present. Therefore, the proposed electrochemical aptasensor can not only detect the two markers but also distinguish their co-existence. It may also display high selectivity and sensitivity towards the detection of the tumor markers, so it might have potential clinical application in the future.