The genetic dissection of complex traits in a founder population

We estimated broad heritabilities (H(2)) and narrow heritabilities (h(2)) and conducted genomewide screens, using a novel association-based mapping approach for 20 quantitative trait loci (QTLs) among the Hutterites, a founder population that practices a communal lifestyle. Heritability estimates ranged from.21 for diastolic blood pressure (DBP) to.99 for whole-blood serotonin levels. Using a multipoint method to detect association under a recessive model we found evidence of major QTLs for six traits: low-density lipoprotein (LDL), triglycerides, lipoprotein (a) (Lp[a]), systolic blood pressure (SBP), serum cortisol, and whole-blood serotonin. Second major QTLs for Lp(a) and for cortisol were identified using a single-point method to detect association under a general two-allele model. The heritabilities for these six traits ranged from.37 for triglycerides to.99 for serotonin, and three traits (LDL, SBP, and serotonin) had significant dominance variances (i.e., H(2) > h(2)). Surprisingly, there was little correlation between measures of heritability and the strength of association on a genomewide screen (P>.50), suggesting that heritability estimates per se do not identify phenotypes that are influenced by genes with major effects. The present study demonstrates the feasibility of genomewide association studies for QTL mapping. However, even in this young founder population that has extensive linkage disequilibrium, map densities <5 cM may be required to detect all major QTLs.     

Quantitative genetic dissection of complex traits in a QTL-mapping pedigree

This paper summarizes and modifies quantitative genetic analyses on a pedigree used to map genetic factors (i.e., QTLs) underlying a complex trait. The total genetic variance can be exactly estimated based on the F₂ family derived from two homozygous parents for alternative alleles at all QTLs of interest. The parents, F₁ hybrids, and two backcrosses are combined to each parent, and the total number of QTLs and the number of dominant QTLs are estimated under the assumptions of gene association with the two parents, equal gene effect, no linkage, and no epistasis among QTLs. Further relaxation for each of the assumptions are made in detail. The biometric estimator for the QTL number and action mode averaged over the entire genome could provide some basic and complementary information to QTL mapping designed to detect the effect and location of specific genetic factors.     

Production of congenic mouse strains carrying NOD-derived diabetogenic genetic intervals: An approach for the genetic dissection of complex traits

Insulin-dependent (Type 1) diabetes (IDD) in the NOD mouse is inherited as a complex polygenic trait making the identification of susceptibility genes difficult. Currently none of the non-MHC IDD susceptibility genes in NOD have been identified. In this paper we describe the congenic mouse approach that we are using for the dissection of complex traits, such as IDD. We produced a series of six congenic strains carrying NOD-derived diabetogenic genomic intervals, which were previously identified by linkage analysis, on a resistant background. These congenic strains were produced for the purpose of characterizing the function of each of these genes, alone and in combinations, in IDD pathogenesis and to allow fine mapping of the NOD IDD susceptibility genes. Histological examination of pancreata from 6 to 8-month-old congenic mice reveals that intervals on Chromosomes (Chrs) 1 and 17, but not 3, 6, and 11, contain NOD-derived genes that can increase the trafficking of mononuclear cells into the pancreas. Insulitis was observed only very rarely, even in older congenic mice, indicating that multiple genes are required for this phenotype. These results demonstrate the utility of this congenic approach for the study of complex genetic traits. Received: 1 September 1995 / Accepted: 20 December 1995     

A new approach to the study of genetic variability of complex characters

A new approach to multivariate genetic analysis of complex organismal traits is developed. It is based on examination of the distribution of parental strains and the F1 and F2 hybrids in a multidimensional space, and the determination of the directions corresponding to heterozygosity, epistatic and additive gene effects. The effect of heterozygosity includes variability produced by interaction between and within heterozygous loci. The additive gene effects and the remaining epistatic interactions between the homozygous loci can be visualized separately from the effects of heterozygosity by an appropriate projection of the points in multidimensional space. In all, 20 morphological, physiological and behavioural characters and 21 craniometric measures were studied in crosses between two laboratory rat strains. Linear combinations of craniometric and of morphophysiological characters with a high narrow-sense heritability could be identified. These combinations characterized the organismal stress response, which had been selected for in one of the strains. The prospects for the practical application of the new approach and also for the evaluation of the contribution of the genetic diversity to phenotypic variability in animals in natural populations are discussed.     

A mathematical approach to multiple genetic relationships

A fundamental concept in the treatment of genetic relationships is that of gene identity which first was introduced by Cotterman (1940). Based on this notion several measures of relationship evolved such as the inbreeding coefficient, the coefficient of kinship, and the identity coefficients; by means of these quantities joint and conditional phenotype probabilities could be derived. This paper is an attempt at a general mathematical treatment of genetic relationships: Identity states are defined for any number of individuals, a method is given for the calculation of the corresponding identity coefficients by means of generalized coefficients of kinship, and applications are emphasized.     

A genetic approach to the species problem in wild potato

Wild potatoes are native to the Americas, where they present very wide geographical and ecological distribution. Most are diploid, obligate out-crossers due to a multiallelic gametophytic self-incompatibility (S) locus that prevents self-fertilisation and crossing between individuals carrying identical S-alleles. They have two alternative modes of reproduction: sexual (by seeds) and asexual (by stolons and tubers), which provide, respectively, for genetic flexibility in changing environments and high fitness of adapted genotypes under stable conditions. Since the early twentieth century, their taxonomic classification has been mostly based on morphological phenotypes (Taxonomic Species Concept). More recently, attempts have been made to establish phylogenetic relationships, applying molecular tools in samples of populations (accessions) with a previously assigned specific category. However, neither the reproductive biology and breeding relations among spontaneous populations nor the morphological and genetic variability expected in obligate allogamous populations are considered when the taxonomic species concept is applied. In nature, wild potato populations are isolated through external and internal hybridisation barriers; the latter, which are genetically determined, can be either pre-zygotic (pollen-pistil incompatibility) or post-zygotic (abortion of embryo, endosperm or both tissues, sterility, and hybrid weakness and breakdown in segregating generations). The internal barriers, however, can be incomplete, providing opportunities for hybridisation and introgression within and between populations and ploidy levels in areas of overlap. The widespread occurrence of spontaneous hybrids in nature was recognised in the mid-twentieth century. Using genetic approaches, results have been obtained that provide strong support to the assertion that populations are at different stages of genetic divergence and are not at the end of the evolutionary process, as presupposed by the Taxonomic Species Concept. Furthermore, since wild potatoes have uniparental and biparental overlapping generations, the Biological Species Concept - developed for sexually reproducing biparental organisms - cannot be applied to them. In this paper, morphological, genetic, molecular and taxonomic studies in wild potato are reviewed, considering the genetic consequences of their reproductive biology, in an attempt to shed light on the species problem, because of its relevance in germplasm conservation and breeding.     

High-resolution genetic mapping of complex traits.

Positional cloning requires high-resolution genetic mapping. To plan a positional cloning project, one needs to know how many informative meioses will be required to narrow the search for a disease gene to an acceptably small region. For a simple Mendelian trait studied with linkage analysis, the answer is straightforward. In this paper, we address the situation of a complex trait studied with affected-relative-pair methods. We derive mathematical formulas for the size of an appropriate confidence region, as a function of the relative risk attributable to the gene. Using these results, we provide graphs showing the number of relative pairs required to narrow the gene hunt to an interval of a given size. For example, we show that localizing a gene to 1 cM requires a median of 200 sib pairs for a locus causing a fivefold increased risk to an offspring and 700 sib pairs for a locus causing a twofold increased risk. We discuss the implications of these results for the positional cloning of genes underlying complex traits.     

A genetic approach to characterizing complex promoters in E. coli

The chromosomal distributions of five families of mouse r-protein genes (S16, L18, L19, L30 and L32/33) were studied by Southern blot analysis of DNA from a panel of mouse-hamster hybrid cells containing various complements of mouse chromosomes. Our results indicated that members of a particular family are often located on more than one chromosome, that extensive clustering of many r-protein gene families on a few chromosomes is unlikely, and that there is no obligatory linkage of r-protein and rRNA genes.     

Evaluation of LEXF/FXLE rat recombinant inbred strains for genetic dissection of complex traits.

Recombinant inbred (RI) strains are formed from an outcross between two well-characterized inbred stains followed by at least 20 generations of inbreeding. RI strains can be utilized for the analysis of many complex phenotypic traits. The LEXF/FXLE RI strain set consists of 34 RI strains derived by reciprocal crossing of LE/Stm and F344/Stm. Here we report on genetic dissections of complex traits using this RI set and their parental strains. We have developed strain distribution patterns for 232 informative simple sequence length polymorphism markers. The framework map covers the rat genome except for chromosome Y. Seventy-six phenotype parameters, which included physiological and behavioral traits, were examined for these RI lines. Quantitative trait locus (QTL) analysis of these parameters revealed 27 significant and 91 suggestive QTLs, illustrating the potential of this RI resource for the detection of underlying gene functions for various phenotypes. Although this RI set was originally developed to study susceptibility to chemical-induced tumors, it has been shown to be equally powerful for a wide spectrum of traits. The LEXF/FXLE RI strains have been deposited at the National Bio Resource Project for the Rat in Japan and are maintained under specific pathogen-free conditions. They are available at http://www.anim.med.kyoto-u.ac.jp/nbr.     

Twins. Novel uses to study complex traits and genetic diseases

The challenge faced by research into the genetic basis of complex disease is to identify genes of small relative effect against a background of substantial genetic and environmental variation. This has focused interest on a classical epidemiological design: the study of twins. Through their precise matching for age, the common family environment and background environmental variation, studying diseases in non-identical twins provides a means to enhance the power of conventional strategies to detect genetic influence through linkage and association. The unique matching of identical twins provides researchers with ways to isolate the function of individual genes involved in disease together with approaches to understanding how genes and the environment interact.     

TAMAL: an integrated approach to choosing SNPs for genetic studies of human complex traits

SUMMARY: Investigators conducting studies of the molecular genetics of complex traits in humans often need rationally to select a set of single nucleotide polymorphisms (SNPs) from the hundreds or thousands available for a candidate gene. Accomplishing this requires integration of genomic data from distributed databases and is both time-consuming and error-prone. We developed the TAMAL (Technology And Money Are Limiting) web site to help identify promising SNPs for further investigation. For a given list of genes, TAMAL identifies SNPs that meet user-specified criteria (e.g. haplotype tagging SNPs or SNP predicted to lead to amino acid changes) from current versions of online resources (i.e. HapMap, Perlegen, Affymetrix, dbSNP and the UCSC genome browser). AVAILABILITY: TAMAL is a platform independent web-based application available free of charge at http://neoref.ils.unc.edu/tamal. SUPPLEMENTARY INFORMATION: http://neoref.ils.unc.edu/tamal/.     

A new approach to the problem of oxygen formation in photosynthesis

A detailed quantum-mechanical analysis of the model of water oxidizing complex, based on recent X-ray data on the structure of PSII, was made. A mechanism of water oxidation was suggested and explained for the first time. The role of three manganese atoms that are not involved directly in water oxidation, the role of the cubic structure of the complex, and the necessity of the presence of calcium and chlorine atoms during water oxidation are discussed. Theoretical computations of the energies of the complex in each S-state were made.     

细胞类型特异的遗传学操作：揭开复杂神经环路的面纱

现代神经科学的一个重要课题足阐明复杂神经环路及其细胞组成形成行为的机制。我们希望可以通过对特定神经元群体的区分和操作在引发行为的神经计算和特定神经元群体活性之间建立一种因果联系。运用BAC重组工程技术,我们建立了超过20个“敲入”驱动品系。在这些驱动品系中,Cre或者是可诱导的CreER能够在特定类掣的GABA能细胞中表达。另外,我们还建立了一些Cre报告小鼠品系和一。个基于病毒转染的蛋白表达系统。这些病毒包含一个Cre-激活的表达元件,可以将一些荧光蛋白或分了开关在体内以很高的效率表达。这种基因操作的策略可以使我们进行如下的一些观察和操作：（1）在突触水平观察中间神经元的形态和他们之间的联系;（2）观察中间神经元的活性及其过往的活动;（3）在生理的时间分辨率上操纵特定细胞群的发放和突触传递。这将使我们对复杂神经环路功能和组织的认识进入。个全新的领域。     

A new approach to the job scheduling problem in computational grids

Job scheduling is one of the most challenging issues in Grid resource management that strongly affects the performance of the whole Grid environment. The major drawback of the existing Grid scheduling algorithms is that they are unable to adapt with the dynamicity of the resources and the network conditions. Furthermore, the network model that is used for resource information aggregation in most scheduling methods is centralized or semi-centralized. Therefore, these methods do not scale well as Grid size grows and do not perform well as the environmental conditions change with time. This paper proposes a learning automata-based job scheduling algorithm for Grids. In this method, the workload that is placed on each Grid node is proportional to its computational capacity and varies with time according to the Grid constraints. The performance of the proposed algorithm is evaluated through conducting several simulation experiments under different Grid scenarios. The obtained results are compared with those of several existing methods. Numerical results confirm the superiority of the proposed algorithm over the others in terms of makespan, flowtime, and load balancing.     

A new approach to the species classification problem in floristic analysis

A new method of species (inverse) classification of vegetation data, i.e. classification of species into groups with similar ecological tolerances, is presented which overcomes the problems of species abundance distorting the results. The algorithm TWO-STEP is based on the use of an asymmetric measure of dissimilarity: where i, j are species, h is the stand, n is the total number of stands, and x_ih is the amount of species i in stand h. The algorithm uses the rows of the asymmetric dissimilarity matrix generated as above to form a second symmetric dissimilarity matrix using the measure: where m is the number of species and k the species. Flexible sorting is applied to generate a species classification. Comparison of results after applying the TWO-STEP algorithm and a standard alternative to an artificial data set demonstrates its efficacy. TWO-STEP also shows considerable advantages over previous analyses for a Queensland rainforest data set (quantitative) and an English heath (qualitative) data set. Normalization of species data appears advantageous for quantitative data only.     

The future of path analysis, segregation analysis, and combined models for genetic dissection of complex traits.

Appropriate combined models are discussed for the analysis of complex traits. It is argued that combined models may be necessary for optimally extracting the information from family studies. It is further argued that, especially as we face genes with much smaller effects, our ability to find these genes will depend on how precisely and accurately we are able to model the interrelationships. We need these newer models and methods for optimally extracting the information from family data, and we also need to reorient ourselves as to how we interpret the very information extracted. It is projected that path and segregation analysis, as seen in terms of combined models, will be useful in the new millennium.     

A systems biology approach to genetic studies of complex diseases

Revealing mechanisms underlying complex diseases poses great challenges to biologists. The traditional linkage and linkage disequilibrium analysis that have been successful in the identification of genes responsible for Mendelian traits, however, have not led to similar success in discovering genes influencing the development of complex diseases. Emerging functional genomic and proteomic ('omic') resources and technologies provide great opportunities to develop new methods for systematic identification of genes underlying complex diseases. In this report, we propose a systems biology approach, which integrates omic data, to find genes responsible for complex diseases. This approach consists of five steps: (1) generate a set of candidate genes using gene-gene interaction data sets; (2) reconstruct a genetic network with the set of candidate genes from gene expression data; (3) identify differentially regulated genes between normal and abnormal samples in the network; (4) validate regulatory relationship between the genes in the network by perturbing the network using RNAi and monitoring the response using RT-PCR; and (5) genotype the differentially regulated genes and test their association with the diseases by direct association studies. To prove the concept in principle, the proposed approach is applied to genetic studies of the autoimmune disease scleroderma or systemic sclerosis.