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At least 37 records · Page 2Linked to original sources

Genetics, statistics and human disease: analytical retooling for complexity.

Molecular biologists and geneticists alike now acknowledge that most common human diseases with a genetic component are likely to have complex etiologies. Yet despite this belief, many statistical geneticists continue applying, in slightly new and different ways, methodologies that were developed to dissect much simpler etiologies. In this article, we characterize, with examples, the various factors that can complicate genetic analysis and demonstrate their shared features and how they affect genetic analysis. We describe a variety of approaches that are currently available, revealing methodological gaps and suggesting new directions for method development. Finally, we propose a comprehensive two-step approach to analysis that systemically addresses the different genetic factors that are likely to underlie complex diseases.

Genetic Diseases, Inborn↗

[Methods of statistical genetics and use of database for genome information].

Knowledge and technology of bioinformatics have become inevitable for gene and genome research. Education and research in this field of science are not sufficient in Japan. There are two different approaches to trait mapping, the way by which traits are mapped on the genome. Thus, the knowledge-based approach uses functions of molecules while the statistics-based approach uses polymorphisms. Statistics-based approach uses two different methods, linkage analysis and analysis based on linkage disequilibrium. Various phenotypes are efficiently mapped on the genome using such methods. Recently, bioinformatic data base search is mostly performed using internet. Anyone can perform sequence-search, homology-search and SNP-search. Since such data bases change quickly, readers should access the databases themselves and be used to the procedures for them.

Computational Biology↗

[Genetic-statistical characterization of the novel different-height donors of the stem shortness in winter rye].

Three donors for the dominant stem shortness in winter rye were developed. The genetic determination of the difference in a plant height for each donor was revealed. There were additive genes for the stem shortness in the donors Gnom 1 and Gnom 2 and dominant-epistatic ones in the donor Gnom 3. The investigation of genetic correlation between the number of quantitative traits and the plant height was carried out. On the basis of the data obtained, the strategy of using each donor for stem shortness in rye breeding was determined.

Biometry↗

DHLAS: A web-based information system for statistical genetic analysis of HLA population data.

DHLAS (database HLA system) is a user-friendly, web-based information system for the analysis of human leukocyte antigens (HLA) data from population studies. DHLAS has been developed using JAVA and the R system, it runs on a Java Virtual Machine and its user-interface is web-based powered by the servlet engine TOMCAT. It utilizes STRUTS, a Model-View-Controller framework and uses several GNU packages to perform several of its tasks. The database engine it relies upon for fast access is MySQL, but others can be used a well. The system estimates metrics, performs statistical testing and produces graphs required for HLA population studies: (i) Hardy-Weinberg equilibrium (calculated using both asymptotic and exact tests), (ii) genetics distances (Euclidian or Nei), (iii) phylogenetic trees using the unweighted pair group method with averages and neigbor-joining method, (iv) linkage disequilibrium (pairwise and overall, including variance estimations), (v) haplotype frequencies (estimate using the expectation-maximization algorithm) and (vi) discriminant analysis. The main merit of DHLAS is the incorporation of a database, thus, the data can be stored and manipulated along with integrated genetic data analysis procedures. In addition, it has an open architecture allowing the inclusion of other functions and procedures.

Databases, Genetic↗

Phenotypic and genetic statistics of components of milk and two measures of somatic cell concentration.

Heritabilities, genotypic and phenotypic correlations for milk, fat, and protein yields, and two traits related to somatic cell concentration (cumulative lactation score and lactational somatic cell concentration) were estimated. A total of 18,416 first lactations of Holstein cows were analyzed by a new procedure for estimating variance components. Heritabilities were .21, .23, .19, .17, and .61 for milk, fat, and protein yields, cumulative lactation score, and lactational somatic cell concentration. Addition of protein yields to the current selection for two traits with nil economic value for protein would improve genetic gains for fat and milk yields in the northeastern United States. If cumulative lactation score and lactational somatic cell concentration were incorporated in current selection for two traits, restricted selection indexes should be used to avoid reduction in genetic gains for milk and fat yields.

Animals↗

Genetics statistics and relationships of teat and udder traits, somatic cell counts, and milk production.

Teat lengths and diameters, udder clearance, cleft depth, and distances between teats were measured from 1967 to 1982 on Holstein cows. Numbers of observations per trait ranged from 5934 to 11,449. Cows were from six herds owned by the North Carolina Department of Agriculture and two research herds of North Carolina State University. Repeatabilities between adjacent lactations for physical traits of udder were mostly between .60 and .80. Repeatabilities between first and second lactations for average somatic cell count and mean log somatic cell count were .11 +/- .04 and .21 +/- .04. Heritabilities in first lactation were .63 for front teat length, .44 for teat diameter, .56 for rear udder clearance, .10 for cleft depth, .32 for mature equivalent milk, and .18 for somatic cell counts. Heritabilities of distances between teats ranged from .33 to .48. Cows with udder clearance higher from the ground, deeper clefts, smaller distances between teats, and teats of smaller diameter had lower somatic cell counts. Multiple regression analysis showed that dams' somatic cell counts and rear udder clearances were not significant predictors of daughters' somatic cell counts. Lactation average somatic cell counts of daughters were predicted with greater accuracy from averages of somatic cell counts of multiple lactations of dams than from single lactations of dams. Milk production and somatic cell counts seemed positively genetically correlated, more so in first than later lactations.

Animals↗

Least squares estimation of variance components for linkage.

We develop least squares (LS) procedures for variance components estimation in genetic linkage studies. The LS procedure is expressed by simple expressions, and does not require inversion of large matrices. Simulations comparing LS with maximum likelihood (ML) procedures for normal data show that both yield unbiased estimators, but the efficiency of the LS procedure was less than 50% of the ML procedure. For bivariate normal data, the efficiency of the LS procedure relative to the ML method was better, generally over 60%. For skewed data, the LS method was markedly more efficient than ML for parameter estimation. The LS method was computationally rapid, over 4,000 times faster than ML estimation for bivariate data. Because ML estimation is time consuming, LS methods are suggested for initial interval mapping with multivariate data.

Computer Simulation↗

Statistical genetic comparison of two techniques for assessing molar crown size in pedigreed baboons.

Dental anthropologists and paleoanthropologists commonly use an estimated molar crown area (mesiodistal length multiplied by buccolingual width) to describe and compare individuals, populations, and species. Advances in digital imaging now allow researchers to measure the actual crown area of a molar in an occlusal two-dimensional plane. Because error is reduced by this more accurate measurement, actual crown area is thought to be a better representation of the mechanisms that determine tooth crown size, meriting the additional time required to collect it. We tested this assumption by estimating the heritability of both these measurements for the second left mandibular molar from a sample of individuals (n = 332) from a captive breeding colony of baboons. Heritability estimates of both the actual and estimated crown areas of molars are approximately 0.83. Therefore, both measurements are informative as population descriptors, with no significant difference between the accuracy of either to reflect additive genetic contributions to molar crown size. This is fortunate, because genetic studies and inference can be based on estimated areas rather than actual crown area. The heritability estimates for mesiodistal length and buccolingual width are both substantial but lower: approximately 0.67 and approximately 0.73, respectively. The best fitting models in these analyses show that sex, body size, and subspecific affinity differentially affect molar length and width. We interpret these results to suggest that potentially some of the genetics underlying these covariates also underlie tooth size. As such, measurements designed to describe molar crown size are useful for general descriptive purposes, but do not conform to the assumption of independence inherent in phylogenetic analyses, such as cladistics (Hennig [1966] Phylogenetic Systematics. Urbana: University of Illinois Press). Therefore, if variables like actual crown area and estimated crown area are to be used in phylogenetic parsimony analyses, we suggest that researchers account for the effects of covariates such as sex and body size in their analyses.

Animals↗

Statistical genetics of normal variation in family data for oligogenic diseases.

A quadrivariate quantitative genetic analysis detected significant heritabilities for four simulated quantitative traits (Q1-Q4) with additive genetic pleiotropy between traits Q1, Q2, and Q3. Using univariate segregation analysis, we tentatively detected five major loci: one each for Q2, Q3, and Q4 and two, at different maxima, for Q1. Bivariate one-locus segregation analysis identified significant major locus pleiotropy for Q1, Q2, and Q3 only; and suggested identity between one of Q1's major genes and that for Q2, and between the second Q1 major gene and that for Q3. Patterns of linkage, supportive of inferences from the bivariate segregation analyses, were detected between three candidate genes and the major genes for Q1, Q2 and Q4.

Alleles↗

Statistical genetics of molar cusp patterning in pedigreed baboons: implications for primate dental development and evolution.

Gene expression and knock-out studies provide considerable information about the genetic mechanisms required for tooth organogenesis. Quantitative genetic studies of normal phenotypic variation are complementary to these developmental studies and may help elucidate the genes and mechanisms that contribute to the normal population-level phenotypic variation upon which selection acts. Here we present the first quantitative genetic analysis of molar cusp positioning in mammals. We analyzed quantitative measures of molar cusp position in a captive pedigreed baboon breeding colony housed at the Southwest National Primate Research Center in San Antonio, Texas. Our results reveal complete pleiotropy between antimeric pairs of traits--i.e., they are influenced by the same gene or suite of genes. Mandibular morphological homologues in the molar series also exhibit complete pleiotropy. In contrast, morphological homologues in maxillary molar series appear to be influenced by partial, incomplete pleiotropic effects. Variation in the mandibular mesial and distal molar loph orientation on the same molar crown is estimated to be genetically independent, whereas the maxillary molar mesial and distal loph orientation is estimated to have partially overlapping genetic affects. The differences between the maxillary and mandibular molar patterning, and the degree of genetic independence found between lophs on the same molar crown, may be indicative of previously unrecognized levels of modularity in the primate dentition.

Animals↗

Statistical genetic analysis of plasma levels of vitamin D: familial study.

The present study attempted to evaluate the relative importance of familial/genetic factors in interindividual variation of plasma concentrations of vitamin D (calcidiol). Ninety-five nuclear pedigrees (187 males and 168 females, aged 18-91 and 18-86 years old respectively), from the Chuvasha Autonomy, Russia, were assessed for calcidiol and sex hormones. Age-adjusted 25-hydroxy-vitamin D (25OHD) measures showed very high pair-wise correlations between all members of families, which suggest that there may be a genetic factor transmitted within the families. To test this assumption, complex segregation analysis of non-adjusted 25OHD data was undertaken, in which genotype-sex specific dependence of the trait on age was incorporated. The analysis showed that some 44% of the 25OHD variance was attributable to all genetic and non-genetic factors incorporated into the model. About 22% of the variation was accounted for by a putative major gene effect.

Adolescent↗

Statistical genetics of an annual plant, Impatiens capensis. II. Natural selection.

Measurement of natural selection on correlated characters provides valuable information on fitness surfaces, patterns of directional, stabilizing, or disruptive selection, mechanisms of fitness variation operating in nature, and possible spatial variation in selective pressures. We examined effects of seed weight, germination date, plant size, early growth, and late growth on individual fitness. Path analysis showed that most characters had direct or indirect effects on individual fitness, indicating directional selection. For most early life-cycle characters, indirect effects via later characters exceed the direct causal effect on fitness. Selection gradients were uniform across the experimental site. There was no evidence for stabilizing or disruptive selection. We discuss several definitions of stabilizing and disruptive selection. Although early events in the life of an individual have important causal effects on subsequent characters and fitness, there is no detectable genetic variance for most of these characters, so little or no genetic response to natural selection is expected.

Least-Squares Analysis↗