Learning gene regulatory networks using gaussian process emulator and graphical LASSO

Author(s):  
H. Chatrabgoun ◽  
A. R. Soltanian ◽  
H. Mahjub ◽  
F. Bahreini

Large amounts of research efforts have been focused on learning gene regulatory networks (GRNs) based on gene expression data to understand the functional basis of a living organism. Under the assumption that the joint distribution of the gene expressions of interest is a multivariate normal distribution, such networks can be constructed by assessing the nonzero elements of the inverse covariance matrix, the so-called precision matrix or concentration matrix. This may not reflect the true connectivity between genes by considering just pairwise linear correlations. To relax this limitative constraint, we employ Gaussian process (GP) model which is well known as computationally efficient non-parametric Bayesian machine learning technique. GPs are among a class of methods known as kernel machines which can be used to approximate complex problems by tuning their hyperparameters. In fact, GP creates the ability to use the capacity and potential of different kernels in constructing precision matrix and GRNs. In this paper, in the first step, we choose the GP with appropriate kernel to learn the considered GRNs from the observed genetic data, and then we estimate kernel hyperparameters using rule-of-thumb technique. Using these hyperparameters, we can also control the degree of sparseness in the precision matrix. Then we obtain kernel-based precision matrix similar to GLASSO to construct kernel-based GRN. The findings of our research are used to construct GRNs with high performance, for different species of Drosophila fly rather than simply using the assumption of multivariate normal distribution, and the GPs, despite the use of the kernels capacity, have a much better performance than the multivariate Gaussian distribution assumption.

2018 ◽  
Author(s):  
P. Tsakanikas ◽  
D. Manatakis ◽  
E. S. Manolakos

ABSTRACTDeciphering the dynamic gene regulatory mechanisms driving cells to make fate decisions remains elusive. We present a novel unsupervised machine learning methodology that can be used to analyze a dataset of heterogeneous single-cell gene expressions profiles, determine the most probable number of states (major cellular phenotypes) represented and extract the corresponding cell sub-populations. Most importantly, for any transition of interest from a source to a destination state, our methodology can zoom in, identify the cells most specific for studying the dynamics of this transition, order them along a trajectory of biological progression in posterior probabilities space, determine the "key-player" genes governing the transition dynamics, partition the trajectory into consecutive phases (transition "micro-states"), and finally reconstruct causal gene regulatory networks for each phase. Application of the end-to-end methodology provides new insights on key-player genes and their dynamic interactions during the important HSC-to-LMPP cell state transition involved in hematopoiesis. Moreover, it allows us to reconstruct a probabilistic representation of the “epigenetic landscape” of transitions and identify correctly the major ones in the hematopoiesis hierarchy of states.


2021 ◽  
Author(s):  
Ewen Burban ◽  
Maud Irene Tenaillon ◽  
Arnaud Le Rouzic

The domestication of plant and animal species lead to repeatable morphological evolution, often referred to as the phenotypic domestication syndrome. Domestication is also associated with important genomic changes, such as the loss of genetic diversity and modifications of gene expression patterns. Here, we explored theoretically the effect of domestication at the genomic level by characterizing the impact of a domestication-like scenario on gene regulatory networks. We ran population genetics simulations in which individuals were featured by their genotype (an interaction matrix encoding a gene regulatory network) and their gene expressions, representing the phenotypic level. Our domestication scenario included a population bottleneck and a selection switch (change in the optimal gene expression level) mimicking canalizing selection, i.e. evolution towards more stable expression to parallel enhanced environmental stability in man-made habitat. We showed that domestication profoundly alters genetic architectures. Based on the well-documented example of the maize (Zea mays ssp. mays) domestication, our simulations predicted (i) a drop in neutral allelic diversity, (ii) a change in gene expression variance that depended upon the domestication scenario, (iii) transient maladaptive plasticity, (iv) a deep rewiring of the gene regulatory networks, with a trend towards gain of regulatory interactions between genes, and (v) a global increase in the genetic correlations among gene expressions, with a loss of modularity in the resulting coexpression patterns and in the underlying networks. Extending the range of parameters, we provide empirically testable predictions on the differences of genetic architectures between wild and domesticated and forms. The characterization of such systematic evolutionary changes in the genetic architecture of traits contributes to define a molecular domestication syndrome.


Genetics ◽  
2021 ◽  
Author(s):  
Ewen Burban ◽  
Maud I Tenaillon ◽  
Arnaud Le Rouzic

Abstract The domestication of plant species lead to repeatable morphological evolution, often referred to as the phenotypic domestication syndrome. Domestication is also associated with important genomic changes, such as the loss of genetic diversity compared to adequately large wild populations, and modifications of gene expression patterns. Here, we explored theoretically the effect of a domestication-like scenario on the evolution of gene regulatory networks. We ran population genetics simulations in which individuals were featured by their genotype (an interaction matrix encoding a gene regulatory network) and their gene expressions, representing the phenotypic level. Our domestication scenario included a population bottleneck and a selection switch mimicking human-mediated directional and canalizing selection, i.e., change in the optimal gene expression level and selection towards more stable expression across environments. We showed that domestication profoundly alters genetic architectures. Based on four examples of plant domestication scenarios, our simulations predict (i) a drop in neutral allelic diversity, (ii) a change in gene expression variance that depends upon the domestication scenario, (iii) transient maladaptive plasticity, (iv) a deep rewiring of the gene regulatory networks, with a trend towards gain of regulatory interactions, and (v) a global increase in the genetic correlations among gene expressions, with a loss of modularity in the resulting coexpression patterns and in the underlying networks. We provide empirically testable predictions on the differences of genetic architectures between wild and domesticated forms. The characterization of such systematic evolutionary changes in the genetic architecture of traits contributes to define a molecular domestication syndrome.


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