Biomedical subjects

Rongling Wu

Publications and source records attributed to Rongling Wu.

At least 19 recordsLinked to original sources

PubMed2006

A framework to monitor environment-induced major genes for developmental trajectories: implication for a prenatal cocaine exposure study.

Whether there are specific genes involved in response to different environmental agents and how such genes regulate developmental trajectories during lifetime are of fundamental importance in health, clinical and pharmaceutical research. In this article, we present a novel statistical model for monitoring environment-induced genes of major effects on longitudinal outcomes of a trait. This model is derived within the maximum likelihood framework, incorporated by mathematical aspects of growth and developmental processes. A typical structural model is implemented to approximate time-dependent covariance matrices for the longitudinal trait. This model allows for a number of biologically meaningful hypothesis tests regarding the effects of major genes on overall growth trajectories or particular stages of development. It can be used to test whether and how major genetic effects are expressed differently under altered environmental agents. In a well-designed case-control study, our model has been employed to detect cocaine-dependent genes that affect growth trajectories for head circumference during childhood. The detected gene triggers significant effects on growth curves in both cocaine-exposed (case) and unexposed groups (control), but with different extents. Significant genotype-environment interactions due to this so-called environment-sensitive gene are promising for further studies toward its genomic mapping using polymorphic molecular markers.

Adult↗

PubMed2006

Multilocus linkage disequilibrium mapping of epistatic quantitative trait loci that regulate HIV dynamics: a simulation approach.

The time-dependent change of HIV particle load, i.e. HIV dynamics, is likely to be controlled by a multitude of quantitative trait loci (QTL) that interact with each other as well as with various developmental and environmental factors in a coordinated manner. In this article, we have derived a new statistical model for mapping the epistatic QTL responsible for HIV dynamics in a natural human population. This model, constructed on the integrated theme of functional mapping and linkage disequilibrium (LD) mapping, can make use of information from multiple markers genotyped from the human genome. It allows for the test and estimation of genetic actions and interactions involved in the control of HIV progression and provides a general platform to identify the detailed genetic architecture of resistance or susceptibility of humans to HIV on a dynamic scale. We have generalized this model to accommodate various complicated clincal designs for AIDS studies. Simulation studies with different scenarios are performed to examine the statistical behaviour of the model. The genetic and statistical extensions of this mapping model to HIV/AIDS genomic research are discussed.

Computer Simulation↗

PubMed2006

A statistical framework for genetic association studies of power curves in bird flight.

How the power required for bird flight varies as a function of forward speed can be used to predict the flight style and behavioral strategy of a bird for feeding and migration. A U-shaped curve was observed between the power and flight velocity in many birds, which is consistent to the theoretical prediction by aerodynamic models. In this article, we present a general genetic model for fine mapping of quantitative trait loci (QTL) responsible for power curves in a sample of birds drawn from a natural population. This model is developed within the maximum likelihood context, implemented with the EM algorithm for estimating the population genetic parameters of QTL and the simplex algorithm for estimating the QTL genotype-specific parameters of power curves. Using Monte Carlo simulation derived from empirical observations of power curves in the European starling (Sturnus vulgaris), we demonstrate how the underlying QTL for power curves can be detected from molecular markers and how the QTL detected affect the most appropriate flight speeds used to design an optimal migration strategy. The results from our model can be directly integrated into a conceptual framework for understanding flight origin and evolution.

Journal Article↗

PubMed2006

A statistical model for dissecting genomic imprinting through genetic mapping.

As a result of nonequivalent genetic contribution of maternal and paternal genomes to offsprings, genomic imprinting or called parent-of-origin effect, has been broadly identified in plants, animals and humans. Its role in shaping organism's development has been unanimously recognized. However, statistical methods for identifying imprinted quantitative trait loci (iQTL) and estimating the imprinted effect have not been well developed. In this article, we propose an efficient statistical procedure for genomewide estimating and testing the effects of significant iQTL underlying the quantitative variation of interested traits. The developed model can be applied to two different genetic cross designs, backcross and F(2) families derived from inbred lines. The proposed procedure is built within the maximum likelihood framework and implemented with the EM algorithm. Extensive simulation studies show that the proposed model is well performed in a variety of situations. To demonstrate the usefulness of the proposed approach, we apply the model to a published data in an F(2) family derived from LG/S and SM/S mouse stains. Two partially maternal imprinting iQTL are identified which regulate the growth of body weight. Our approach provides a testable framework for identifying and estimating iQTL involved in the genetic control of complex traits.

Algorithms↗

PubMed2006

Modeling extent and distribution of zygotic disequilibrium: implications for a multigenerational canine pedigree.

Unlike gametic linkage disequilibrium defined for a random-mating population, zygotic disequilibrium describes the nonrandom association between different loci in a nonequilibrium population that deviates from Hardy-Weinberg equilibrium. Zygotic disequilibrium specifies five different types of disequilibria simultaneously that are (1) Hardy-Weinberg disequilibria at each locus, (2) gametic disequilibrium (including two alleles in the same gamete, each from a different locus), (3) nongametic disequilibrium (including two alleles in different gametes, each from a different locus), (4) trigenic disequilibrium (including a zygote at one locus and an allele at the other), and (5) quadrigenic disequilibrium (including two zygotes each from a different locus). However, because of the uncertainty on the phase of the double heterozygote, gametic and nongametic disequilibria need to be combined into a composite digenic disequilibrium and further define a composite quadrigenic disequilibrium together with the quadrigenic disequilibrium. To investigate the extent and distribution of zygotic disequilibrium across the canine genome, a total of 148 dogs were genotyped at 247 microsatellite markers located on 39 pairs of chromosomes for an outbred multigenerational pedigree, initiated with a limited number of unrelated founders. A major portion of zygotic disequilibrium was contributed by the composite digenic and quadrigenic disequilibrium whose values and numbers of significant marker pairs are both greater than those of trigenic disequilibrium. All types of disequilibrium are extensive in the canine genome, although their values tend to decrease with extended map distances, but with a greater slope for trigenic disequilibrium than for the other types of disequilibrium. Considerable variation in the pattern of disequilibrium reduction was observed among different chromosomes. The results from this study provide scientific guidance about the determination of the number of markers used for whole-genome association studies.

Animals↗

PubMed2006

Identification of quantitative trait nucleotides that regulate cancer growth: a simulation approach.

A general growth model derived from basic cellular properties can be used to describe the dynamic process of cancer growth with mathematical equations. It has been recognized that cancer growth is under genetic control, with a multitude of interacting genes each segregating in a Mendelian fashion and displaying environmental sensitivity. In this article, we integrate the mathematical aspects of the pervasive growth model into a statistical framework for the identification of quantitative trait nucleotides that underlie cancer growth. This integrative framework is constructed with a single nucleotide polymorphism-based haplotype blocking analysis. Simulation studies have been performed to demonstrate the usefulness of the model. The proposed model provides a generic platform model for testing and detecting specific DNA sequence variants that regulates the timing of cancer emergence, growth and differentiation.

Algorithms↗

PubMed2006

A joint model for nonparametric functional mapping of longitudinal trajectory and time-to-event.

BACKGROUND: The characterization of the relationship between a longitudinal response process and a time-to-event has been a pressing challenge in biostatistical research. This has emerged as an important issue in genetic studies when one attempts to detect the common genes or quantitative trait loci (QTL) that govern both a longitudinal trajectory and developmental event. RESULTS: We present a joint statistical model for functional mapping of dynamic traits in which the event times and longitudinal traits are taken to depend on a common set of genetic mechanisms. By fitting the Legendre polynomial of orthogonal properties for the time-dependent mean vector, our model does not rely on any curve, which is different from earlier parametric models of functional mapping. This newly developed nonparametric model is demonstrated and validated by an example for a forest tree in which stemwood growth and the time to first flower are jointly modelled. CONCLUSION: Our model allows for the detection of specific QTL that govern both longitudinal traits and developmental processes through either pleiotropic effects or close linkage, or both. This model will have great implications for integrating longitudinal and event data to gain better insights into comprehensive biology and biomedicine.

Algorithms↗

PubMed2006

A statistical model to analyse quantitative trait locus interactions for HIV dynamics from the virus and human genomes.

Viruses can be considered 'parasites' because they cannot survive outside of a host. The progression rate to AIDS caused by human immunodeficiency virus type-1 (HIV-1) is therefore a consequence of HIV-host cell interactions. In this article, we present an innovative statistical model for detecting the effects of genetic interactions on HIV-1 dynamics triggered by different quantitative trait loci (QTL) from the HIV and human genomes. Our model integrates the principles of functional mapping for longitudinal traits and of linkage disequilibrium analysis for high-resolution mapping of QTL within the maximum likelihood context and is implemented with the EM algorithm. We performed Monte Carlo simulation studies to investigate the impacts of different heritability levels and sample sizes on the power to detect interacting QTL. Our model allows for the tests of a number of clinically meaningful hypotheses and provides a powerful tool for unravelling the genetic architecture of HIV-1 dynamics and therefore AIDS progression rate.

Algorithms↗

PubMed2006

Functional mapping for genetic control of programmed cell death.

"Naturally occurring" or "programmed" cell death (PCD) in which the cell uses specialized cellular machinery to kill itself is a ubiquitous phenomenon that occurs early in organ development. Such a cell suicide mechanism that enables metazoans to control cell number and eliminate cells threatening the organism's survival has been thought to be under genetic control. In this report, we develop a novel statistical model for mapping specific genes or quantitative trait loci (QTL) that are responsible for the PCD process based on polymorphic molecular markers. This model incorporates the biological mechanisms of PCD that undergoes two different developmental stages, exponential growth and polynomial death. We derived a parametric approach to model the exponential growth and a nonparametric approach based on the Legendre function to model the polynomial death. A series of stationary and nonstationary models has been used to approximate the structure of the covariance matrix among cell numbers at a multitude of different times. The statistical behavior of our model is investigated through simulation studies and validated by a real example in rice.

Apoptosis↗

PubMed2006

Model for mapping imprinted quantitative trait loci in an inbred F2 design.

The role of imprinting in shaping development has been ubiquitously observed in plants, animals, and humans. However, a statistical method that can detect and estimate the effects of imprinted quantitative trait loci (iQTL) over the genome has not been extensively developed. In this article, we propose a maximum likelihood approach for testing and estimating the imprinted effects of iQTL that contribute to variation in a quantitative trait. This approach, implemented with the EM algorithm, allows for a genome-wide scan for the existence of iQTL. This approach was used to reanalyze published data in an F(2) family derived from the LG/S and SM/S mouse strains. Several iQTL that regulate the growth of body weight by expressing paternally inherited alleles were identified. Our approach provides a standard procedure for testing the statistical significance of iQTL involved in the genetic control of complex traits.

Algorithms↗

PubMed2006

Modelling epistatic effects of embryo and endosperm QTL on seed quality traits.

Coordinated expression of embryo and endosperm tissues is required for proper seed development. The coordination among these two tissues is controlled by the interaction between multiple genes expressed in the embryo and endosperm genomes. In this article, we present a statistical model for testing whether quantitative trait loci (QTL) active in different genomes, diploid embryo and triploid endosperm, epistatically affect a trait expressed on the endosperm tissue. The maximum likelihood approach, implemented with the EM algorithm, was derived to provide the maximum likelihood estimates of the locations of embryo- and endosperm-specific QTL and their main effects and epistatic effects. This model was used in a real example for rice in which two QTL, one from the embryo genome and the other from the endosperm genome, exert a significant interaction effect on gel consistency on the endosperm. Our model has successfully detected Waxy, a candidate gene in the embryo genome known to regulate one of the major steps of amylose biosynthesis in the endosperm. This model will have great implications for agricultural and evolutionary genetic research.

Algorithms↗

PubMed2006

Genetic mapping of allometric scaling laws.

Many biological processes, from cellular metabolism to population dynamics, are characterized by particular allometric scaling relationships between rate and size (power laws). A statistical model for mapping specific quantitative trait loci (QTLs) that are responsible for allometric scaling laws has been developed. We present an improved model for allometric mapping of QTLs based on a more general allometry equation. This improved model includes two steps: (1) use model II regression analysis to estimate the parameters underlying universal allometric scaling laws, and (2) substitute the estimated allometric parameters in the mixture-based mapping model to obtain the estimation of QTL position and effects. This model has been validated by a real example for a mouse F2 progeny, in which two QTLs were detected on different chromosomes that determine the allometric relationship between growth rate and body weight.

Algorithms↗

PubMed2006

Functional mapping - how to map and study the genetic architecture of dynamic complex traits.

The development of any organism is a complex dynamic process that is controlled by a network of genes as well as by environmental factors. Traditional mapping approaches for analysing phenotypic data measured at a single time point are too simple to reveal the genetic control of developmental processes. A general statistical mapping framework, called functional mapping, has been proposed to characterize, in a single step, the quantitative trait loci (QTLs) or nucleotides (QTNs) that underlie a complex dynamic trait. Functional mapping estimates mathematical parameters that describe the developmental mechanisms of trait formation and expression for each QTL or QTN. The approach provides a useful quantitative and testable framework for assessing the interplay between gene actions or interactions and developmental changes.

Animals↗

PubMed2006

A bivariate functional mapping model for identifying haplotypes that control drug response for systolic and diastolic blood pressures.

A bivariate functional mapping model has been proposed to detect haplotype-based DNA sequence variants that regulate the response curves of systolic and diastolic blood pressures (SBP and DBP) to a particular drug. This model capitalizes on the haplotype structure constructed by single nucleotide polymorphisms (SNPs) and incorporates the mathematical aspects of pharmacodynamic reactions into the estimation process, aimed to identify DNA sequence variants responsible for drug response. In this way, by estimating and testing the curve parameters that define drug response, many genetically and clinically meaningful hypotheses regarding the degree and pattern of the genetic control of SBP and DBP can be formulated, tested and disseminated. In a pharmacogenetic study composed of 107 subjects, our bivariate model has probed two haplotypes within the beta 2AR candidate gene that exert a significant effect on both SBP and DBP respond to dobutamine. With this candidate gene, two SNPs are genotyped, with allele Gly16 (G) and Arg16 (A) at codon 16 and alleles Glu27 (G) and Gln27 (C) at codon 27, respectively. The significant haplotypes are [AC] for SBP and [GG] for DBP. This model provides a powerful tool for elucidating the genetic variants of drug response and ultimately designing personalized medications based on each patient's genetic makeup.

Algorithms↗

PubMed2005

Structured antedependence models for functional mapping of multiple longitudinal traits.

In this article, we present a statistical model for mapping quantitative trait loci (QTL) that determine growth trajectories of two correlated traits during ontogenetic development. This model is derived within the maximum likelihood context, incorporated by mathematical aspects of growth processes to model the mean vector and by structured antedependence (SAD) models to approximate time-dependent covariance matrices for longitudinal traits. It provides a quantitative framework for testing the relative importance of two mechanisms, pleiotropy and linkage, in contributing to genetic correlations during ontogeny. This model has been employed to map QTL affecting stem height and diameter growth trajectories in an interspecific hybrid progeny of Populus, leading to the successful discovery of three pleiotropic QTL on different linkage groups. The implications of this model for genetic mapping within a broader context are discussed.

Journal Article↗

PubMed2005

Quantitative trait loci for hip dysplasia in a cross-breed canine pedigree.

Canine hip dysplasia is a common developmental inherited trait characterized by hip laxity, subluxation or incongruity of the femoral head and acetabulum in affected hips. The inheritance pattern is complex and the mutations contributing to trait expression are unknown. In the study reported here, 240 microsatellite markers distributed in 38 autosomes and the X chromosome were genotyped on 152 dogs from three generations of a crossbred pedigree based on trait-free Greyhound and dysplastic Labrador Retriever founders. Interval mapping was undertaken to map the QTL underlying the quantitative dysplastic traits of maximum passive hip laxity (the distraction index), the dorsolateral subluxation score, and the Norberg angle. Permutation testing was used to derive the chromosome-wide level of significance at p<0.05 for each QTL. Chromosomes 4, 9, 10, 11 (p<0.01), 16, 20, 22, 25, 29 (p<0.01), 30, 35, and 37 harbor putative QTL for one or more traits. Successful detection of QTL was due to the cross-breed pedigree, multiple-trait measurements, control of environmental background, and marked advancement in canine mapping tools.

Animals↗

PubMed2005

A hyperspace model to decipher the genetic architecture of developmental processes: allometry meets ontogeny.

To better utilize limited resources for their survival and reproduction, all organisms undergo developmental changes in both body size and shape during ontogeny. The genetic analysis of size change with increasing age, i.e., growth, has received considerable attention in quantitative developmental genetic studies, but the genetic architecture of ontogenetic changes in body shape and its associated allometry have been poorly understood partly due to the lack of analytical tools. In this article, we attempt to construct a multivariate statistical framework for studying the genetic regulation of ontogenetic growth and shape. We have integrated biologically meaningful mathematical functions of growth curves and developmental allometry into the estimation process of genetic mapping aimed at identifying individual quantitative trait loci (QTL) for phenotypic variation. This model defined with high dimensions can characterize the ontogenetic patterns of genetic effects of QTL over the lifetime of an organism and assess the interplay between genetic actions/interactions and phenotypic integration. The closed forms for the residual covariance matrix and its determinant and inverse were derived to overcome the computational complexity typical of our high-dimensional model. We used a worked example to validate the utility of this model. The implications of this model for genetic research of evo-devo are discussed.

Algorithms↗

PubMed2005

Functional mapping of quantitative trait loci that interact with the hg mutation to regulate growth trajectories in mice.

The high growth (hg) mutation increases body size in mice by 30-50%. Given the complexity of the genetic regulation of animal growth, it is likely that the effect of this major locus is mediated by other quantitative trait loci (QTL) with smaller effects within a web of gene interactions. In this article, we extend our functional mapping model to characterize modifier QTL that interact with the hg locus during ontogenetic growth. Our model is derived within the maximum-likelihood context, incorporated by mathematical aspects of growth laws and implemented with the EM algorithm. In an F2 population founded by a congenic high growth (HG) line and non-HG line, a highly additive effect due to the hg gene was detected on growth trajectories. Three QTL located on chromosomes 2 and X were identified to trigger significant additive and/or dominant effects on the process of growth. The most significant finding made from our model is that these QTL interact with the hg locus to affect the shapes of the growth process. Our model provides a powerful means for understanding the genetic architecture and regulation of growth rate and body size in mammals.

Age Factors↗