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PubMed2006

Interval mapping for loci affecting unordered categorical traits.

Many traits including shapes and colors of flowers, fruits and seeds in plants, as well as coat colors and some behavioral properties in animals, are recorded in discrete categories. If categories are ordered, genetic analyses of the categorical traits are often performed using the threshold model, which considers a latent continuous variable, called the liability, underlying a trait and assumes the monotonic relationship between the phenotype and the liability. In some categorical traits, however, descriptions of phenotypes are purely nominal and the phenotypic scores cannot be ordered. The threshold model is unreasonable for the analyses of such unordered categorical traits. In this study, we developed a method for interval mapping of loci affecting unordered categorical traits with more than two categories. The probability of the phenotype of an individual falling in each of the categories was expressed by a polychotomous logistic model, in which the log-odds for each category relative to the reference category were assumed to follow a linear model including genotype at a locus affecting a trait as covariate. Based on the model, the interval mapping using a maximum likelihood method was devised for the analysis of complex categorical traits described with unordered categories. We confined ourselves to the case of F2 populations derived from a cross between two inbred lines, although this approach can easily be extended to the analyses for other populations of general structures. As results of analyses of simulated data show, the method showed high efficiency in detecting the loci affecting unordered categorical traits.

Animals↗
PubMed2001

Predictors of marker-informativeness for an outbred F2 design.

Generalization of the polymorphism information content (PIC) index to represent marker informativeness (MI) for a three-generation F2 design requires that two additional sources of non-informativeness be added to the PIC formula: the probability of matings between like-heterozygous F1 individuals, of which one is non-informative; and that of matings between like-heterozygous F1 individuals, which are both fully informative but where line of origin of the same alleles is reciprocal. Given the dense marker-maps currently available for some species, this F2 informativeness parameter constitutes the natural criterion for marker selection in F2 designs, and two computer programs to predict MI from grandparental marker-genotypes were developed for an F2 population originating from two divergent selection lines of outbred mice (F approximately 0.2). A total of 403 markers had been genotyped for the F0 grandparents (n=31), and 14 markers had also been genotyped in the complete pedigree including 559 F2 individuals. One program was based on assumptions of random-mating (RM), while the other (PED) accounted for the pedigreed mating structure. For the 403 markers, the correlation between MI from RM and from PED was 0.95, and the average deviation between the two predictions was 0.005 MI units (MI ranged from 0 to 1). Correlations between predicted and realized MI for the 14 fully genotyped markers were 0.97 for PED and 0.94 for RM, while the corresponding average of deviations between predicted and actual values were 0.01 and 0.04, respectively. Absolute deviations from realized MI never exceeded 0.09 and 0.16 for PED and RM, respectively. Simulated optimization of the mating system to maximize average MI of 28 markers on one chromosome led to improvements in the range of 15-20% average MI (0.07-0.09 MI units). The degree of relative advantage conferred by the F2 generalization of the PIC index over the traditional index was found to be of minor significance.

Animals↗
PubMed1998

Genetic factors in asthma severity.

The development of asthma in an individual depends upon the interaction of genetic factors with the environment. Asthma is a polygenic disease and both genome screening and candidate gene strategies have identified a number of putative genes that may predispose to the development of asthma. However, there are few data regarding genes that may either dictate disease severity or chronicity and genes that dictate response to treatment. Analysing asthma as a categorical variable will fail to identify genes solely involved in determining disease severity, whereas studies designed to analyse asthma as a semiquantitative trait may identify these genes in addition to disease-initiating genes. However, identifying genes specifically involved in the determination of disease severity (e.g. in airway remodelling) will be ideally performed in cohorts of asthmatics specifically recruited and using appropriate end points. This review discusses methodological issues concerned with identifying disease-modifying genes in individuals with asthma, and summarizes the potential contribution of known candidate genes to the determination of disease severity.

Anti-Asthmatic Agents↗
PubMed2001

The genetic bases of divergence in desiccation and starvation resistance among tropical and temperate populations of Drosophila melanogaster.

Desiccation and starvation resistance are two stress-related traits which vary geographically with climate in Drosophila melanogaster. To investigate the contribution of epistasis to population divergence for these traits, we crossed tropical and temperate populations from two different geographical regions to produce F1, F2 and first backcross generations. Line-cross analysis of generation means revealed that genetic bases of divergence for both traits were complex and remarkably similar in a number of respects. Strong additive and dominance effects were present in most of the models, whereas epistatic and maternal effects were less common. The presence of epistatic effects in approximately half of the models presented in this study is consistent with line-cross studies of diverged traits in other animals, and does not support the view that epistasis is the predominant means by which populations diverge. In addition, evidence of maternal effects in both traits adds to a growing body of recent evidence that suggests maternal contributions to population differentiation are more widespread than previously thought. This finding undermines the accuracy of studies inferring epistasis directly from the magnitude of F2 breakdown. More line-cross analysis studies of naturally diverged populations that take into account maternal effects will shed further light on the true incidence of epistasis and its importance in the evolutionary process.

Adaptation, Physiological↗
PubMed2004

Admixture in the Hispanics of the San Luis Valley, Colorado, and its implications for complex trait gene mapping.

Hispanic populations are a valuable resource that can and should facilitate the identification of complex trait genes by means of admixture mapping (AM). In this paper we focus on a particular Hispanic population living in the San Luis Valley (SLV) in Southern Colorado. We used a set of 22 Ancestry Informative Markers (AIMs) to describe the admixture process and dynamics in this population. AIMs are defined as genetic markers that exhibit allele frequency differences between parental populations >or=30%, and are more informative for studying admixed populations than random markers. The ancestral proportions of the SLV Hispanic population are estimated as 62.7 +/- 2.1% European, 34.1 +/- 1.9% Native American and 3.2 +/- 1.5% West African. We also estimated the ancestral proportions of individuals using these AIMs. Population structure was demonstrated by the excess association of unlinked markers, the correlation between estimates of admixture based on unlinked marker sets, and by a highly significant correlation between individual Native American ancestry and skin pigmentation (R2= 0.082, p < 0.001). We discuss the implications of these findings in disease gene mapping efforts.

Adult↗
PubMed2001

Genetics of airway hyperresponsiveness.

Asthma is a disease characterized by intermittent airway obstruction, inflammatory cell infiltrates, increased mucus production, lung epithelial remodeling, and airway hyperreactivity. The genetics of asthma, as investigated in animal models, is poorly understood. Because no animal model of asthma mimics all of the pathologic and physiological features of asthma, genetic studies have focused on several phenotypes, including intrinsic or native airway hyperreactivity. It is generally accepted that both genetic and environmental factors determine the phenotypic expression of this complex disease. The genetics of airway hyperresponsiveness, as investigated in the mouse, are presented in this review. The inbred mouse currently represents the most valuable genetic resource for understanding the factors that control this complex phenotype.

Airway Resistance↗
PubMed2001

Evolution of genome-phenome diversity under environmental stress.

The genomic era revolutionized evolutionary biology. The enigma of genotypic-phenotypic diversity and biodiversity evolution of genes, genomes, phenomes, and biomes, reviewed here, was central in the research program of the Institute of Evolution, University of Haifa, since 1975. We explored the following questions. (i) How much of the genomic and phenomic diversity in nature is adaptive and processed by natural selection? (ii) What is the origin and evolution of adaptation and speciation processes under spatiotemporal variables and stressful macrogeographic and microgeographic environments? We advanced ecological genetics into ecological genomics and analyzed globally ecological, demographic, and life history variables in 1,200 diverse species across life, thousands of populations, and tens of thousands of individuals tested mostly for allozyme and partly for DNA diversity. Likewise, we tested thermal, chemical, climatic, and biotic stresses in several model organisms. Recently, we introduced genetic maps and quantitative trait loci to elucidate the genetic basis of adaptation and speciation. The genome-phenome holistic model was deciphered by the global regressive, progressive, and convergent evolution of subterranean mammals. Our results indicate abundant genotypic and phenotypic diversity in nature. The organization and evolution of molecular and organismal diversity in nature at global, regional, and local scales are nonrandom and structured; display regularities across life; and are positively correlated with, and partly predictable by, abiotic and biotic environmental heterogeneity and stress. Biodiversity evolution, even in small isolated populations, is primarily driven by natural selection, including diversifying, balancing, cyclical, and purifying selective regimes, interacting with, but ultimately overriding, the effects of mutation, migration, and stochasticity.

Animals↗
PubMed2001

Structure of linkage disequilibrium and phenotypic associations in the maize genome.

Association studies based on linkage disequilibrium (LD) can provide high resolution for identifying genes that may contribute to phenotypic variation. We report patterns of local and genome-wide LD in 102 maize inbred lines representing much of the worldwide genetic diversity used in maize breeding, and address its implications for association studies in maize. In a survey of six genes, we found that intragenic LD generally declined rapidly with distance (r(2) < 0.1 within 1500 bp), but rates of decline were highly variable among genes. This rapid decline probably reflects large effective population sizes in maize during its evolution and high levels of recombination within genes. A set of 47 simple sequence repeat (SSR) loci showed stronger evidence of genome-wide LD than did single-nucleotide polymorphisms (SNPs) in candidate genes. LD was greatly reduced but not eliminated by grouping lines into three empirically determined subpopulations. SSR data also supplied evidence that divergent artificial selection on flowering time may have played a role in generating population structure. Provided the effects of population structure are effectively controlled, this research suggests that association studies show great promise for identifying the genetic basis of important traits in maize with very high resolution.

Chromosome Mapping↗
PubMed1972

Detection and quantitation of simian virus 40 genetic material in abortively transformed BALB-3T3 clones (mice-diploid cells-virus equivalents).

Infection with simian virus 40 is known to induce many cells to synthesize DNA and to divide in a medium lacking serum protein growth factor(s) that is essential for growth of uninfected cells (factor-free medium). Cells infected under these conditions then go through several rounds of division, since colonies containing more than 100 cells are formed. Many of these colonies are abortively transformed since, upon subsequent passage of the cells in standard medium, they can no longer grow in factor-free medium and show no other properties of viral transformation. We have examined these abortively transformed cells for the presence of simian virus 40 DNA sequences. Of the three clones tested, two were found to contain viral genetic material despite the fact that they were phenotypically normal. The number of simian virus 40 genome equivalents present was determined by measurement of DNA reassociation kinetics on hydroxyapatite. Two of the abortively transformed lines contained approximately five viral genome equivalents per diploid cell, while the DNA from a third abortive transformant was indistinguishable from that of uninfected BALB/3T3 cells. A standard simian virus 40 transformant, isolated under similar conditions, contained two copies of the viral genome per cell. The abortive transformants also appear to contain the entire viral genome rather than multiple partial copies. Subclones of one abortively transformed line containing five copies per cell had 2.7-10 copies of viral genetic material per diploid cell.

Animals↗
PubMed2006

A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia.

The pathogenesis of malarial anemia is multifactorial, and the mechanisms responsible for its high mortality are poorly understood. Studies indicate that host mediators produced during malaria infection may suppress erythroid progenitor development (Miller, K.L., J.C. Schooley, K.L. Smith, B. Kullgren, L.J. Mahlmann, and P.H. Silverman. 1989. Exp. Hematol. 17:379-385; Yap, G.S., and M.M. Stevenson. 1991. Ann. NY Acad. Sci. 628:279-281). We describe an intrinsic role for macrophage migration inhibitory factor (MIF) in the development of the anemic complications and bone marrow suppression that are associated with malaria infection. At concentrations found in the circulation of malaria-infected patients, MIF suppressed erythropoietin-dependent erythroid colony formation. MIF synergized with tumor necrosis factor and gamma interferon, which are known antagonists of hematopoiesis, even when these cytokines were present in subinhibitory concentrations. MIF inhibited erythroid differentiation and hemoglobin production, and it antagonized the pattern of mitogen-activated protein kinase phosphorylation that normally occurs during erythroid progenitor differentiation. Infection of MIF knockout mice with Plasmodium chabaudi resulted in less severe anemia, improved erythroid progenitor development, and increased survival compared with wild-type controls. We also found that human mononuclear cells carrying highly expressed MIF alleles produced more MIF when stimulated with the malarial product hemozoin compared with cells carrying low expression MIF alleles. These data suggest that polymorphisms at the MIF locus may influence the levels of MIF produced in the innate response to malaria infection and the likelihood of anemic complications.

Alleles↗
PubMed1999

Genetic linkage of hyper-IgE syndrome to chromosome 4.

The hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated levels of serum IgE. HIES is now recognized as a multisystem disorder, with nonimmunologic abnormalities of the dentition, bones, and connective tissue. HIES can be transmitted as an autosomal dominant trait with variable expressivity. Nineteen kindreds with multiple cases of HIES were scored for clinical and laboratory findings and were genotyped with polymorphic markers in a candidate region on human chromosome 4. Linkage analysis showed a maximum two-point LOD score of 3.61 at recombination fraction of 0 with marker D4S428. Multipoint analysis and simulation testing confirmed that the proximal 4q region contains a disease locus for HIES.

Chromosome Deletion↗