Nonparametric Functional Mapping of Quantitative Trait Loci Underlying Programmed Cell Death

The development of an organism represents a complex dynamic process, which is controlled by a network of genes and multiple environmental factors. Programmed cell death (PCD), a physiological cell suicide process, occurs during the development of most organisms and is, typically, a complex dynamic trait. Understanding how genes control this complex developmental process has been a long-standing topic in PCD studies. In this article, we propose a nonparametric model, based on orthogonal Legendre polynomials, to map genes or quantitative trait loci (QTLs) that govern the dynamic features of the PCD process. The model is built under the maximum likelihood-based functional mapping framework and is implemented with the EM algorithm. A general information criterion is proposed for selecting the optimal Legendre order that best fits the dynamic pattern of the PCD process. The consistency of the order selection criterion is established. A nonstationary structured antedependence model (SAD) is applied to model the covariance structure among the phenotypes measured at different time points. The developed model generates a number of hypothesis tests regarding the genetic control mechanism of the PCD process. Extensive simulation studies are conducted to investigate the statistical behavior of the model. Finally, we apply the model to a rice tiller number data set in which several QTLs are identified. The developed model provides a quantitative and testable framework for assessing the interplay between genes and the developmental PCD process, and will have great implications for elucidating the genetic architecture of the PCD process.

[1]  J. Hart,et al.  Kernel Regression Estimation Using Repeated Measurements Data , 1986 .

[2]  H. Horvitz,et al.  Genetic control of programmed cell death in the nematode Caenorhabditis elegans. , 1999, Cancer research.

[3]  H. Horvitz,et al.  Mechanisms and functions of cell death. , 1991, Annual review of cell biology.

[4]  M. Raff,et al.  Programmed Cell Death in Animal Development , 1997, Cell.

[5]  G. Casella,et al.  A statistical model for the genetic origin of allometric scaling laws in biology. , 2002, Journal of theoretical biology.

[6]  Z. Zeng Precision mapping of quantitative trait loci. , 1994, Genetics.

[7]  S. Leal Genetics and Analysis of Quantitative Traits , 2001 .

[8]  Rongling Wu,et al.  A joint model for nonparametric functional mapping of longitudinal trajectory and time-to-event , 2006, BMC Bioinformatics.

[9]  H. Horvitz,et al.  A first insight into the molecular mechanisms of apoptosis , 2004, Cell.

[10]  Susan McCouch,et al.  RFLP mapping of isozymes, RAPD and QTLs for grain shape, brown planthopper resistance in a doubled haploid rice population , 2004, Molecular Breeding.

[11]  H. Horvitz Worms, Life, and Death (Nobel Lecture) , 2003, Chembiochem : a European journal of chemical biology.

[12]  Wei Zhao,et al.  A non-stationary model for functional mapping of complex traits , 2005, Bioinform..

[13]  R. Redner Note on the Consistency of the Maximum Likelihood Estimate for Nonidentifiable Distributions , 1981 .

[14]  W. G. Hill,et al.  Estimating the covariance structure of traits during growth and ageing, illustrated with lactation in dairy cattle. , 1994, Genetical research.

[15]  N. Altman,et al.  Nonparametric Empirical Bayes Growth Curve Analysis , 1995 .

[16]  G. Casella,et al.  A General Framework for Analyzing the Genetic Architecture of Developmental Characteristics , 2004, Genetics.

[17]  M. Pourahmadi Maximum likelihood estimation of generalised linear models for multivariate normal covariance matrix , 2000 .

[18]  V. Núñez-Antón,et al.  Kernel regression estimates of growth curves using nonstationary correlated errors , 1997 .

[19]  Rongling Wu,et al.  A statistical model for high‐resolution mapping of quantitative trait loci determining HIV dynamics , 2004, Statistics in medicine.

[20]  J. Johnson,et al.  Sequencing drug response with HapMap , 2005, The Pharmacogenomics Journal.

[21]  K. Martin Targeting Apoptosis with Dietary Bioactive Agents , 2006, Experimental biology and medicine.

[22]  R. Wu,et al.  Functional mapping for genetic control of programmed cell death. , 2006, Physiological genomics.

[23]  Philippe Vieu,et al.  Growth curves: a two-stage nonparametric approach , 1994 .

[24]  T. Meuwissen,et al.  Prediction of daily milk yields from a limited number of test days using test day models. , 1999, Journal of dairy science.

[25]  M. Kirkpatrick,et al.  A quantitative genetic model for growth, shape, reaction norms, and other infinite-dimensional characters , 1989, Journal of mathematical biology.

[26]  R. Fraiman,et al.  Smoothing dependent observations , 1994 .

[27]  Howard Hughes,et al.  WORMS, LIFE AND DEATH , 2002 .

[28]  R. Wu,et al.  Functional mapping — how to map and study the genetic architecture of dynamic complex traits , 2006, Nature Reviews Genetics.

[29]  J. Greenberg,et al.  Programmed cell death: a way of life for plants. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Albert D. Shieh,et al.  Statistical Applications in Genetics and Molecular Biology , 2010 .

[31]  M. Kenward,et al.  Parametric modelling of growth curve data: An overview , 2001 .

[32]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[33]  H. Horvitz,et al.  Genetic control of programmed cell death in the nematode C. elegans , 1986, Cell.

[34]  Naomi Altman,et al.  Kernel Smoothing of Data with Correlated Errors , 1990 .

[35]  T. Meuwissen,et al.  Genetic parameters of legendre polynomials for first parity lactation curves. , 2000, Journal of dairy science.

[36]  J. Zhu,et al.  Quantitative trait loci analysis for the developmental behavior of tiller number in rice (Oryza sativa L.) , 1998, Theoretical and Applied Genetics.

[37]  R. Doerge,et al.  Empirical threshold values for quantitative trait mapping. , 1994, Genetics.

[38]  R. Wu,et al.  An algorithm for molecular dissection of tumor progression , 2005, Journal of mathematical biology.

[39]  G. Casella,et al.  Functional mapping of quantitative trait loci underlying the character process: a theoretical framework. , 2002, Genetics.

[40]  P J Diggle,et al.  Nonparametric estimation of covariance structure in longitudinal data. , 1998, Biometrics.

[41]  D. Rubin,et al.  Maximum likelihood from incomplete data via the EM - algorithm plus discussions on the paper , 1977 .

[42]  Florence Jaffrézic,et al.  Structured antedependence models for genetic analysis of repeated measures on multiple quantitative traits. , 2003, Genetical research.

[43]  C. Lamb,et al.  Programmed Cell Death in Plants. , 1997, The Plant cell.

[44]  J. Ameisen On the origin, evolution, and nature of programmed cell death: a timeline of four billion years , 2002, Cell Death and Differentiation.

[45]  B. Zheng,et al.  Summarizing the goodness of fit of generalized linear models for longitudinal data. , 2000, Statistics in medicine.