ISSN:0001-5652    

DOI:10.1159/000154040

出版商:S. Karger AG    

年代:1992

数据来源: Karger

ISSN:0001-5652    

DOI:10.1159/000154041

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

This article recounts the background to the development of the Elston-Stewart algorithm for the genetic analysis of pedigree data. The algorithm can be used in the context of two contrasting research programmes. The first approach is analytical and reductionist. Traditional biological disciplines, such as physiology, embryology and comparative biology, describe phenomenological domains in which biological organisms are treated as complex systems with emergent properties. In the reductionist approach, these biological domains are largely abandoned in favour of descriptions in the domain of the component elements of these systems, resulting in a concentration on molecular genetics as the central object of biological science. In the second approach, it is explicitly recognized that genes and molecules, per se, cannot be explanatory with respect to emergent systemic properties. However, since the genetic variation which occurs in natural populations can influence virtually every aspect and level of biological organization, from cell lineages to ecology, the study of such variation opens new possibilities for establishing meaningful articulations between the various biological disciplines. The author’s expressed preference is for the second alternativ

ISSN:0001-5652    

DOI:10.1159/000154042

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

The Eiston-Stewart algorithm for a normally distributed trait under a polygenic model is explained in detail and extended to allow for other continuous environmental variables. This formulation is especially useful for large pedigrees, as it avoids the need to invert matrices. Whereas it may not be feasible by this method to estimate all the various components of previously suggested models for polygenic inheritance, it can allow for a reasonably flexible pedigree correlational structure under which valid tests can be performed for fixed effects that may affect the phenotype.

ISSN:0001-5652    

DOI:10.1159/000154043

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

The regressive models for the analysis of family data are extended to include cases in which the within-sibship covariation may exceed that implied by the class A regressive model, but for which birth order is not required. In addition to specified major genes, if any, and common parental phenotypes, the excess within-sibship covariation may come from a common cumulative risk from unspecified factors such as a shared environment, and other genes. The within-sibship cumulative risk has a probability distribution in the population. The sib-sib correlation (more generally within-sibship statistical dependence) is equal for all pairs within a given sibship. The compound regressive model is thus a version of the class D regressive model with the property of within-sibship interchangeability. The work is motivated here by comparing and contrasting the Elston-Stewart algorithm and the Morton-MacLean algorithm for the mixed model of inheritance. This points the way to derive practical algorithms for the compound regressive models proposed, with easy extensions to pedigrees of arbitrary structure, and to multilocus problems.

ISSN:0001-5652    

DOI:10.1159/000154044

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

Gene mapping and genetic epidemiology require large-scale computation of likelihoods based on human pedigree data. Although computation of such likelihoods has become increasingly sophisticated, fast calculations are still impeded by complex pedigree structures, by models with many underlying loci and by missing observations on key family members. The current paper ‘introduces’ a new method of array factorization that substantially accelerates linkage calculations with large numbers of markers. This method is not limited to nuclear families or to families with complete phenotyping. Vectorization and parallelization are two general-purpose hardware techniques for accelerating computations. These techniques can assist in the rapid calculation of genetic likelihoods. We describe our experience using both of these methods with the existing program MENDEL. A vectorized version of MENDEL was run on an IBM 3090 supercomputer. A parallelized version of MENDEL was run on parallel machines of different architectures and on a network of workstations. Applying these revised versions of MENDEL to two challenging linkage problems yields substantial improvements in computational sp

ISSN:0001-5652    

DOI:10.1159/000154045

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

We present a Monte Carlo approach to estimation of the recombination fraction θ and the profile likelihood for a dichotomous trait and a single marker gene with 2 alleles. The method is an application of a technique known as ‘Gibbs sampling’, in which random samples of each of the unknowns (here genotypes, θ and nuisance parameters, including the allele frequencies and the penetrances) are drawn from their posterior distributions, given the data and the current values of all the other unknowns. Upon convergence, the resulting samples derive from the marginal distribution of all the unknowns, given only the data, so that the uncertainty in the specification of the nuisance parameters is reflected in the variance of the posterior distribution of θ. Prior knowledge about the distribution of θ and the nuisance parameters can be incorporated using a Bayesian approach, but adoption of a flat prior for θ and point priors for the nuisance parameters would correspond to the standard likelihood approach. The method is easy to program, runs quickly on a microcomputer, and could be generalized to multiple alleles, multipoint linkage, continuous phenotypes and more complex models of disease etiology. The basic approach is illustrated by application to data on cholesterol levels and an a low-density lipoprotein receptor gene in a single large pedig

ISSN:0001-5652    

DOI:10.1159/000154046

出版商:S. Karger AG    

年代:1992

数据来源: Karger

摘要:

Pairwise linkage analysis is robust to genetic model misspecification provided dominance is correctly specified, the primary effect being inflation of the recombination fraction. By contrast, we show that multipoint analysis under misspecified models is not robust when a putative disease locus is placed between close flanking markers, with potentially spuriously negative multipoint lod scores being produced. The problem is due to incorrect attribution of segregation of a disease allele and the consequent conclusion of (unlikely) double crossovers between flanking markers. As a possible solution, we propose the use of high disease allele frequencies, as this allows probabilistically for nonsegregation (through parental homozygosity or dual matings). We show analytically and through analysis of pedigree data simulated under a two-locus heterogeneity model that using a disease allele frequency of 0.05 in the dominant case and 0.25 in the recessive case is quite robust in producing positive multipoint lod scores with close flanking markers across a broad range of conditions including varying allele frequencies, epistasis, genetic heterogeneity and phenocopies.

ISSN:0001-5652    

DOI:10.1159/000154047

出版商:S. Karger AG    

年代:1992

数据来源: Karger