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S W Guo

Publications and source records attributed to S W Guo.

At least 37 records · Page 2Linked to original sources
PubMed1996

Gametogenesis processes and multilocus gene identity by descent.

With few exceptions, the determination of unconditional probability of genes shared identical by descent (IBD) by relatives can be very difficult, especially if the relationship is complex or if multiple loci are involved. It is particularly difficult if one needs the IBD probability in a explicit form, expressed in terms of interlocus recombination fractions. In this paper, I will further extend the concept of gametogenesis process introduced elsewhere and indicate that it completely determines the gene IBD events of interest in pedigrees. I will demonstrate that the gametogenesis process not only serves as a convenient conceptual framework in considering IBD events in pedigrees but also provides a simple yet powerful tool to solve a wide range of seemingly difficult problems. In particular, I consider the problem of multilocus IBD probability for relative pairs, k siblings, and a group of pedigree members. In addition, I consider the problem of multilocus autozygosity probability and the problem of gene preservation in close relatives.

Gametogenesis↗
PubMed1995

Detection of genome similarity as an exploratory tool for mapping complex traits.

For one- and two-trait-locus models, we show that the lod score based on affected relative pairs or trios is a monotonically increasing function of the genome similarity measured by the proportion of alleles shared identical by descent (IBD) conditional on observed marker data. These results can be generalized to multitrait-locus models. Thus, we can use conditional probability of genes shared IBD as a tool to reveal chromosomal segments that are likely to harbor the genes underlying the complex traits.

Alleles↗
PubMed1995

Proportion of genome shared identical by descent by relatives: concept, computation, and applications.

One widely used measure of genetic similarity for pairs of relatives is gene identity-by-descent (IBD) sharing. Genes that are copies of a single gene in a common ancestor of the individuals who now carry them are said to be IBD. One obvious extension of the IBD concept is IBD gene(s) shared by more than two individuals. In this paper, I further extend the gene IBD concept to the proportion of genomes shared IBD by every member of a group of relatives. Genome may refer either to the entire autosomal genome or to one or more chromosomal segments or regions with known lengths. Consideration of a genome instead of one or two loci has several advantages. I present a model to describe the crossover process, based on the work of K. P. Donnelly. On the basis of this model, I give a mathematical definition of the proportion of genome shared IBD by relatives, or IBDP for short. Since the distribution of the IBDP is in general very difficult to determine, and since in most applications the mean and variance of the IBDP will suffice, I then provide a method for computing the first two moments of the IBDP. Applications to assessing gene survival, to genetic resemblance between two relatives, and to gene mapping are illustrated with examples. Finally, I discuss the utility of the IBDP in other areas.

Analysis of Variance↗
PubMed1994

Multicolor FISH mapping of YAC clones in 3p14 and identification of a YAC spanning both FRA3B and the t(3;8) associated with hereditary renal cell carcinoma.

Human chromosome band 3p14 contains two tightly linked cytogenetic markers of broad interest, FRA3B and the t(3;8) breakpoint associated with hereditary renal cell carcinoma (RCC). The common fragile site at 3p14.2 (FRA3B) is the most sensitive site on normal human chromosomes to breakage when DNA replication is perturbed by aphidicolin or folate stress. The t(3;8)(p14.2;q24.1) translocation segregates with RCC in a large family and could mark the location of a tumor suppressor gene involved in renal cancers. In studies aimed at positional cloning of FRA3B and the t(3;8) breakpoint, we have used multicolor fluorescence in situ hybridization analysis (FISH) on metaphase spreads and interphase nuclei to order 14 yeast artificial chromosomes (YACs) in 3p14. The YACs used in this study were identified by a group of unordered lambda clones that had been previously localized to the 3p14 region and mapped proximal or distal to the t(3;8) breakpoint. FISH analysis was used to order the YACs and to map them in relation both to the t(3;8) translocation breakpoint and to FRA3B induced on normal chromosomes by treatment with aphidicolin. YACs that closely flanked both the t(3;8) translocation breakpoint and the fragile site were identified. A YAC walk from the closest distal YAC allowed the identification of a 1.3-Mb YAC derived from the CEPH large insert YAC library that spans both the FRA3B and the t(3;8) breakpoint. The order of the YACs and cytogenetic landmarks in 3p14 is cen-(126E1/230B9)-181H6-B15-D20F4-258B7-++ +280D2-70E12-168A8- 403B2-143C5-413C6-468B10-[850A6/t(3;8)/ FRA3B]-74B2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Proportion of genes survived in offspring conditional on inheritance of flanking markers.

In mammalian genetics and perhaps in human genetics as well, it is an interesting question as to how many offspring are needed in order to have a desired chance of preserving part of the entire genome of an individual. A more practical and perhaps more important question is: given k children and DNA marker data on a particular region of interest, what proportion of one's genes has been actually passed on to his children? To answer this question, I define the concept of identity by descent proportion, or IBDP for short. The IBDP is defined to be the proportion of genetic material shared identical by descent by a group of relatives in a specified chromosomal region. I provide a novel approach to computing the mean and variance of IBDP for k (> or = 2) half-sibs based on marker data, thus providing a means to compute the mean and variance of proportion of genes survived. I first show that each chromosome in an offspring can be represented by a two-state Markov chain, with the time parameter being the map distance along the chromosome. On this basis, I will show that IBDP can be written as a stochastic integral and that the computation of the EIBDP can be reduced to evaluating an integral of some elementary functions. Numerical examples are provided to illustrate the calculation.

Animals↗
PubMed1994

Regression analysis of multivariate grouped survival data.

Multivariate failure time data arise when each study subject may experience several types of event or when there are clusterings of observational units such that failure times within the same cluster are correlated. The failure times are often subject to interval grouping or have truly discrete measurements. In this paper, the marginal distribution for each discrete failure time variable is formulated by a grouped-data version of the proportional hazards model while the dependence structure is unspecified. Generalized estimating equations in the spirit of Liang and Zeger (1986, Biometrika 73, 13-22) are proposed to estimate the regression parameters and survival probabilities. The resulting estimators are consistent and asymptotically normal. Robust estimators for the limiting covariance matrices are constructed. Simulation studies demonstrate that the asymptotic approximations are adequate for practical use and that ignoring the intracluster dependence in the variance-covariance estimation would lead to invalid statistical inference. A psychological experiment is provided for illustration.

Age Factors↗
PubMed1994

Monte Carlo estimation of mixed models for large complex pedigrees.

In human quantitative genetics, computational complexity restricts the current methods for estimation of mixed models that include major gene effects to data on small pedigrees. However, large complex pedigrees are not uncommon in practice. Also, large pedigrees tend to provide more information on genetic transmission and are more genetically homogeneous than a pooled sample of many nuclear families. We present a Monte Carlo method, using jointly the EM algorithm and the Gibbs sampler, for estimation of mixed models. The approach also provides a Monte Carlo estimate of the asymptotic variance-covariance matrix of the parameters. The methods are conceptually simple, easy to implement, and can handle multiple heritable/nonheritable random components. A numerical example is given to illustrate the methods.

Algorithms↗
PubMed1994

Computation of identity-by-descent proportions shared by two siblings.

I provide a novel approach to computing the mean and variance of the proportion of genetic material shared identical by descent (IBD) by sibling pairs in a specified chromosomal region, conditional on observed marker data. I first show that each chromosome in an offspring can be represented by a two-state Markov chain, with the time parameter being the map distance along the chromosome. On this basis, I show that IBD proportion can be written as a stochastic integral and that the computation of its mean and variance can be reduced to evaluation of an integral of some elementary functions. In addition, I show how Goldgar's model can be extended to include dominance effects. Several examples are provided to illustrate the calculation.

Analysis of Variance↗
PubMed1994

The genetics of psoriasis.

BACKGROUND AND DESIGN: Psoriasis is a member of a class of common, HLA-associated conditions in which disease susceptibility appears to be heritable. However, the mode of inheritance of these diseases has been difficult to define in simple mendelian terms. Psoriasis displays one of the strongest HLA associations of this class of diseases. However, only a small fraction of those who carry the implicated HLA susceptibility alleles develop disease, and it has proven difficult to demonstrate that the HLA associations observed are due to formal genetic linkage between the disease and the HLA locus. Although the role of environmental factors in psoriasis and these other diseases cannot be denied, the participation of additional genes, not necessarily linked to HLA, has long been suspected. OBSERVATIONS: Epidemiologic and immunogenetic data are reviewed and analyzed, which demonstrate that a predisposition to psoriasis is heritable, and which implicate genes of the HLA locus as necessary but not sufficient determinants of psoriasis. Recent developments in human genome research are described, which make possible a systematic search for additional genetic determinants of psoriasis, including those unlinked to HLA. CONCLUSIONS: As one of the most common, most heritable, and most highly HLA-associated examples of this class of HLA-associated diseases, psoriasis represents an ideal target for the application of this emerging genomic technology.

Adolescent↗
PubMed1993

Multicolor FISH mapping with Alu-PCR-amplified YAC clone DNA determines the order of markers in the BRCA1 region on chromosome 17q12-q21.

A gene designated BRCA1, implicated in the susceptibility to early-onset familial breast cancer, has recently been localized to chromosome 17q12-q21. To date, the order of DNA markers mapped within this region has been based on genetic linkage analysis. We report the use of multicolor fluorescence in situ hybridization to establish a physically based map of five polymorphic DNA markers and 10 cloned genes spanning this region. Three cosmid clones and Alu-PCR-generated products derived from 12 yeast artificial chromosome clones representing each of these markers were used in two-color mapping experiments to determine an initial proximity of markers relative to each other on metaphase chromosomes. Interphase mapping was then employed to determine the order and orientation of closely spaced loci by direct visualization of fluorescent signals following hybridization of three probes, each detected in a different color. Statistical analysis of the combined data suggests that the order of markers in the BRCA1 region is cen-THRA1-TOP2-GAS-OF2-17HSD-248yg9-RNU 2-OF3-PPY/p131-EPB3-Mfd188- WNT3-HOX2-GP3A-tel. This map is consistent with that determined by radiation-reduced hybrid mapping and will facilitate positional cloning strategies in efforts to isolate and characterize the BRCA1 gene.

Breast Neoplasms↗
PubMed1993

Pedigree models for complex human traits involving the mitochondrial genome.

Recent biochemical and molecular-genetic discoveries concerning variations in human mtDNA have suggested a role for mtDNA mutations in a number of human traits and disorders. Although the importance of these discoveries cannot be emphasized enough, the complex natures of mitochondrial biogenesis, mutant mtDNA phenotype expression, and the maternal inheritance pattern exhibited by mtDNA transmission make it difficult to develop models that can be used routinely in pedigree analyses to quantify and test hypotheses about the role of mtDNA in the expression of a trait. In the present paper, we describe complexities inherent in mitochondrial biogenesis and genetic transmission and show how these complexities can be incorporated into appropriate mathematical models. We offer a variety of likelihood-based models which account for the complexities discussed. The derivation of our models is meant to stimulate the construction of statistical tests for putative mtDNA contribution to a trait. Results of simulation studies which make use of the proposed models are described. The results of the simulation studies suggest that, although pedigree models of mtDNA effects can be reliable, success in mapping chromosomal determinants of a trait does not preclude the possibility that mtDNA determinants exists for the trait as well. Shortcomings inherent in the proposed models are described in an effort to expose areas in need of additional research.

Computer Simulation↗
PubMed1993

BRCA1 maps proximal to D17S579 on chromosome 17q21 by genetic analysis.

Previous studies have demonstrated linkage between early-onset breast cancer and ovarian cancer and genetic markers on chromosome 17q21. These markers define the location of a gene (BRCA1) which appears to be inherited as an autosomal dominant susceptibility allele. We analyzed five families with multiple affected individuals for evidence of linkage to the BRCA1 region. Two of the five families appear to be linked to BRCA1. One apparently linked family contains critical recombinants, suggesting that the gene is proximal to the marker D17S579 (Mfd188). These findings are consistent with the maximum-likelihood position estimated by the Breast Cancer Linkage Consortium and with recombination events detected in other linked families. Linkage analysis was greatly aided by PCR-based analysis of paraffin-embedded normal breast tissue from deceased family members, demonstrating the feasibility and importance of this approach. One of the two families with evidence of linkage between breast cancer and genetic markers flanking BRCA1 represents the first such family of African-American descent to be reported in detail.

Base Sequence↗
PubMed1992

A Monte Carlo method for combined segregation and linkage analysis.

We introduce a Monte Carlo approach to combined segregation and linkage analysis of a quantitative trait observed in an extended pedigree. In conjunction with the Monte Carlo method of likelihood-ratio evaluation proposed by Thompson and Guo, the method provides for estimation and hypothesis testing. The greatest attraction of this approach is its ability to handle complex genetic models and large pedigrees. Two examples illustrate the practicality of the method. One is of simulated data on a large pedigree; the other is a reanalysis of published data previously analyzed by other methods.

Algorithms↗
PubMed1992

Performing the exact test of Hardy-Weinberg proportion for multiple alleles.

The Hardy-Weinberg law plays an important role in the field of population genetics and often serves as a basis for genetic inference. Because of its importance, much attention has been devoted to tests of Hardy-Weinberg proportions (HWP) over the decades. It has long been recognized that large-sample goodness-of-fit tests can sometimes lead to spurious results when the sample size and/or some genotypic frequencies are small. Although a complete enumeration algorithm for the exact test has been proposed, it is not of practical use for loci with more than a few alleles due to the amount of computation required. We propose two algorithms to estimate the significance level for a test of HWP. The algorithms are easily applicable to loci with multiple alleles. Both are remarkably simple and computationally fast. Relative efficiency and merits of the two algorithms are compared. Guidelines regarding their usage are given. Numerical examples are given to illustrate the practicality of the algorithms.

Alleles↗
PubMed1991

Lack of evidence for linkage between low-density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia.

Low-density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small, dense LDL particles, appears to be a genetically influenced risk factor for coronary heart disease. Phenotype B, as determined by gradient gel electrophoresis, appears to be inherited in a manner consistent with the presence of a single major genetic locus, based on complex segregation analysis. Familial combined hyperlipidemia (FCHL) is a disorder characterized by elevations in total plasma cholesterol and/or triglyceride levels in probands and family members, variable lipoprotein phenotypes over time, and elevations in apolipoprotein B levels. Because apo B is the primary protein component of LDL particles, the present study was undertaken to determine whether LDL subclass phenotypes are controlled by the APOB locus in FCHL families. The evidence against linkage was very strong based on lod score analyses (total lod = -13.3), under assumptions that LDL subclass phenotypes are influenced by a major genetic locus and that the mode of inheritance and penetrance functions are known. Other methods requiring fewer assumptions also provided evidence against linkage, although the strength of this evidence was weaker. Thus the results demonstrate that the proposed gene responsible for LDL subclass phenotypes is unlikely to be the APOB gene in families with FCHL.

Alleles↗
PubMed1991

Evaluation of likelihood ratios for complex genetic models.

Although methods for computing likelihoods for simple genetic models on large and complex pedigrees have been known for some time, and although methods for evaluating likelihoods for complex genetic models on small pedigrees have likewise been well known, likelihood evaluation for complex models given data on extended pedigrees has remained an intractable problem. The Gibbs sampler provides a method of Monte Carlo evaluation of likelihood ratios for complex models on extended and/or complex pedigrees. With increasing computer speeds, this approach provides a tractable and efficient approach to many such likelihood evaluation problems in linkage and segregation analysis. In this paper, however, the authors restrict attention to two basic building-blocks of the overall process. The first is the sequential computation of Gaussian likelihoods for multiple random-effects models on extended pedigrees. The second is the use of this in the Monte Carlo evaluation of likelihoods for the classical mixed model of segregation analysis. The implementation of the Gibbs sampler on pedigrees that permits this Monte Carlo evaluation is detailed. An example is then presented, and finally, in the context of this same example, it is also shown how linkage analysis for a quantitative trait falls within this same framework.

Female↗
PubMed1991

Monte Carlo estimation of variance component models for large complex pedigrees.

Variance component models are widely used in animal and plant breeding. In human genetics, they can be used to identify, among other traits associated with the definition of disease, those that have a significant genetic component in their aetiology. In addition, they can be used in genetic counselling. Most of the methods currently proposed for estimating variance component models often involve repeated inversion of large matrices, resulting in intensive computations, large storage requirements, and numerical instability. Consequently, these methods are restricted to data on nuclear families, to small pedigrees, or to designed pedigrees of simple form. In this paper, the authors propose a method for estimating variance component models for large complex pedigrees using jointly the EM algorithm and the Gibbs sampler. The method can handle variance component models with multiple variance components, without the need for repeated inversion of large matrices even on large complex pedigrees. The method is conceptually simple, numerically stable, and easy to implement.

Algorithms↗